Macrocycles as potential therapeutic agents in neglected diseases.

Future

Review

Medicinal Chemistry

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Macrocycles as potential therapeutic agents in neglected diseases

Macrocycles possess desirable properties that make them promising candidates for the discovery of novel drugs. They present structural features to favor bioactive conformations, selectivity to the receptors, cell permeability and metabolic stability. More effective and nontoxic drugs to cure human African trypanosomiasis, Leishmaniasis and Chagas disease are needed, especially because resistance has been detected. Therefore, major efforts should be made for investigation in new bioactive compounds exhibiting different mechanisms of action. Macrocycles might fulfill the expectations for the development of new drugs to treat those diseases. In the current review, we focus on macrocycles exhibiting biological activities as antitrypanosomal and/or antileishmanial. The isolation, synthetic and biological studies of this class of compounds published from 2005 to 2014 are summarized.

Stella Peña1, Laura Scarone1 & Gloria Serra*,1 Cátedra de Química Farmacéutica, (DQO), Facultad de Química, Universidad de la República, Gral. Flores 2124, Montevideo, CP 11800, Uruguay *Author for correspondence: [email protected]

1

Keywords: antichagasic • antilesihmania • antitrypanosomal • macrocyles

During the last years, an important number of bioactive macrocycles has been reported [1] . These compounds possess a number of desirable properties that make them promising candidates for the discovery of novel drug molecules. In general, they present structural features to favor bioactive conformations, selectivity to the receptors and metabolic stability [2] . In addition, cell permeability and oral bioavailability could be enhanced by controlling hydrophobicity and the number of hydrogen-bond by N-methylation [3] . Recent reviews have discussed the role that macrocycles, in particular macrocyclic natural products, can play in medicinal chemistry [1–3] . Driggers and colleagues have argued that these products are underexplored and poorly exploited class of compounds for the discovery of novel drug molecules [3] . From the 68 marketed macrocycles, 19 are orally bioavailable and from the 30 cyclic peptides marketed, cyclosporine is the only one orally administered. Giordanetto and Kihlberg note emergence in ‘oral de novo designed’ macrocycles [1] . Human African trypanosomiasis (HAT) or sleeping sicknes is caused by

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Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Both subspecies are transmitted by the bite of an infected tsetse fly (Glossina Genus) and have a fatal outcome if left untreated. In the early stage of the disease, the parasite is found in the bloodstream and lymphatic system. In the second stage, parasites are established in the CNS [4,5] . The current statistics in Africa’s endemic countries report about 60 million people at risk. T. b. gambiense is endemic in 24 countries of west and central Africa and causes more than 98% of reported cases of sleeping sickness. T. b. rhodesiense is endemic in 13 countries of eastern and southern Africa, representing less than 2% of reported cases. Between 1999 and 2012, the reported number of new cases of the chronic form of human African trypanosomiasis (T. b. gambiense) fell by 76%, from 27,862 to 7106 [6] . This success in bringing HAT under control led to its inclusion in the WHO Roadmap for eradication, elimination and control of neglected tropical diseases, with a target set to eliminate the disease as a public health problem by 2020 [7,8] .

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ISSN 1756-8919

Review Peña, Scarone & Serra

Key terms Macrocycle: molecule with a ring size of 12 or more atoms. Bioactive conformation: could be defined as the conformation that a molecule must adopt in order to binds to the biological target. Neglected tropical diseases: are a diverse group of diseases with distinct characteristics found mainly among the poorest populations of the world. Drug resistance: refers to a decrease in the effectiveness of a drug. Selectivity index: in order to evaluate the antiparasitic activity and cytotoxicity, we introduced a selectivity index, which is obtained by dividing IC50 of cytotoxicity result by IC50 of antiparasitic activity.

Current chemotherapy is based on four registered drugs: pentamidine, suramin, melarsoprol and eflornithine; three of them were developed over 60 years ago. Pentamidine and suramin are used in the first stage of the illness. The arsenic-based drug, melarsoprol is used in the second stage. Eflornithine, is effective in the second stage of the disease caused by T. b. gambiense. In 2009, the combination nifurtimox (used for Chagas disesase) and eflornithine is introduced with the aim of simplifing the eflornithine monotherapy. All these drugs are not completely satisfactory, due to poor efficacy, undesirable route of administration, drug resistance and undesirable side effects. Toxicity is also a major problem, for example, Melarsoprol have associated 5% death due to the side effects. In November 2013, the WHO Expert Committee argued that, despite the advancements in HAT treatment, all currently available options are suboptimal, and the development of new, safe compounds that are effective against both disease stages and are easy to use is a high priority [5] . Leishmaniasis is caused by a protozoa parasite from over 20 Leishmania species and is transmitted to humans by the bite of infected female phlebotomine sandflies. There are three main forms of the disease: visceral leishmaniasis (VL, also known as kala-azar), fatal if left untreated; cutaneous leishmaniasis (CL), the most common form of leishmaniasis and mucocutaneous leishmaniasis which leads to partial or total destruction of mucous membranes of the nose, mouth and throat. Leishmaniasis is one of the world’s most neglected diseases, affecting mainly in developing countries; 350 million people are considered at risk of contracting leishmaniasis, and an estimated 1.3 million new cases and 20,000 to 30,000 deaths occur annually [9] . In 2012, the first update of the empirical database for leishmaniasis, since 1991, was reported [10] . An

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estimated 0.2 to 0.4 million VL cases, 0.7 to 1.2 million CL cases and 20,000 to 40,000 leishmaniasis deaths occur each year. The authors deliberately used conservative assumptions for the underreporting rates; therefore, true leishmaniasis incidence rates may be substantially higher. More than 90% of global VL cases occur in just six countries: India, Bangladesh, Sudan, South Sudan, Brazil and Ethiopia. Cutaneous leishmaniasis is more widely distributed, with about a third of cases occurring in each of three regions: the Americas, the Mediterranean basin, and western Asia from the Middle East to Central Asia. The pentavalent antimonials, for example, the generic sodium stibogluconate (pentosam) and branded meglumine antimoniate, are being used in the treatment for all forms of leishmaniasis. The antifungal Amphotericin B, is being used in endemic regions where resistance to antimonials was detected. In the past ten years, lipid formulations of amphotericin B, miltefosine and paromomycin have been approved for the treatment of visceral leishmaniasis [11] . The WHO Expert Committee on the Control of Leishmaniases considered that although considerable work has been done to find new medicines for leishmaniasis, the effectiveness of treatment programs has been affected by problems of toxicity, adherence and treatment response [11] . Chagas disease or American trypanosomiasis, is a tropical disease caused by the protozoan Trypanosoma cruzi and spread by insects known as triatomine bugs [12] . Infection can also be acquired through blood transfusion, congenital transmission (from infected mother to child) and organ donation. The symptoms change over the course of the infection. In the early stage, symptoms could be: fever, swollen lymph nodes, headaches or local swelling at the site of the bite. The chronic phase begins after 8–12 weeks. Approximately 30 to 40% of people develop further symptoms 10 to 30 years after the initial infection. This includes enlargement of the ventricles of the heart in 30% leading to heart failure and 10% develop digestive, neurological or mixed alterations. About 7 to 8 million people are estimated to be infected worldwide, mostly in Latin America countries. Approximately 300000–400000 infected people lives in nonendemic countries, including the United States, Canada, many European and some Western Pacific countries. An estimated 41200 new cases occur annually in endemic countries, and 14400 infants are born with congenital Chagas disease annually. In addition, approximately 10300 deaths occurred in 2010. The disease is curable if treatment is initiated soon after infection.

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Chagas disease can be treated with benznidazole and also nifurtimox. Both medicines are effective in curing the disease if given soon after infection at the acute phase. The efficacy of benznidazole in the chronic phase remains controversial. There is no satisfactory ways to evaluate cure when benznidazole or nifurtimox are used during the chronic phase. Positive parasitological tests are verified in ∼20% of treated patients but, the serology can remain reactive in cured patients for several years, and on the other hand a negative result does not indicate the absence of parasites. In addition, adverse reactions occur in up to 40% of treated patients leading to premature termination or temporary suspension of treatment. The most frequent side effects observed in the use of nifurtimox are: anorexia, loss of weight, psychic alterations, excitability, sleepiness, nausea and vomiting. In the case of benzinidazole, skin manifestations are the most notorious (e.g., hypersensitivity, dermatitis with cutaneous eruptions, generalized edema, fever and lymphoadenopathy), and depression of bone marrow is the more severe side effect. In addition, resistance to these drugs has been reported [13] . In the current review, we focus on macrocyclic natural products, their analogs and synthetic macrocycles exhibiting biological activities as antitrypanosomal (against T. brucei and/or T. cruzi) and/or antileishmanial. The isolation, synthetic and biological studies of this class of compounds from 2005 to 2014 are summarized. Bioactives natural products & analogs against Trypanosoma brucei Antibiotic as antitrypanosomals

Recently, Omura and colleagues have determined the in vitro antitrypanosomal activity of the well-known 18-membered lactam antitumor antibiotic leinamycin (1), Figure 1 [14] . This natural product was isolated from Streptomyces sp. by Hara et al. [15] and the first total synthesis was achieved by Kanda and Fukuyama [16] . Leinamycin present nanomolar activity against T. b. brucei (IC50 = 17 nM). However, cytotoxicity against human diploid embryonic cell line (MRC-5) was detected (IC50 = 313 nM), with low selectivity index (SI = 18) T. b. brucei. Echinomycin (2), Figure 1, is a cyclic depsipeptide with a thioacetal cross bridge which presents antibiotic, antitumor and antibacterial activities. It was isolated by Corbaz et al. [17] from Streptomyces echinatus and the cited biological activities were determined in 1957; notwithstanding, the antitrypanosomal activity was determined by Omura and colleagues in 2008 [18] . Due to the complexity of the thioacetal cross bridge, no total synthesis have been reported yet, nonetheless


Review

biosynthetic approaches were done by various research groups [19] . Eechinomycin presents IC50 = 20 ng/ml against GUTat 3.1 strain of T. b. brucei and IC50 = 14 ng/ml against STIB900 strain of T. b. rhodesiense. In addition, selectivity of compounds was evaluated against human MRC-5 cell line and calculated for each parasite, SI = 316 for GUTat 3.1 strain of T. b. brucei and SI = 451 for STIB900 strain of T. b. rhodesiense. Irumamycin (3a), Figure 1, is 20-membered ring macrolide with antibiotic and antifungal activities isolated from Streptomyces subflavus by Omura et al. [20] . Almost three decades later, Omura and colleagues determined the antitrypanosomal activity and found that irumamycin is active against both trypanosome strains (IC50 = 20 and 31 ng/ml) with very high selectivity indexes (Supplementary Table 1) [18] . No total synthesis was achieved for this antibiotic; only Akita et al. reports are on bibliography dated of the end of the 1980s and in the early 1990s principally referred to venturicidins [21–23] . Recently, Omura and colleagues published the synthesis of C(15)-C(27) fragment [24] . Venturicidin (3b), Figure 1, was isolated from Streptomices by Rhodes et al. [25] and was completely synthesized by Akita et al. [22,23] . In the period covered by this review, Omura and colleagues determined the antitrypanosomal activity of this compound [18] . Venturicidin showed submicromolar IC50 against the parasites and high SI for STIB900 strain of T. b. rhodesiense, Table 1. Virustomycin A (4), Figure 1, is a macrolide antibiotic isolated from Streptomyces sp. [26] with antiviral and anti-Trichomonas foetus activities [27] . Recently, the antitrypanosomal activity was discovered by Omura et al. [18] . Virustomycin A resulted in one of the most active of the antibiotics presented in this review, against the strain GUTat 3.1; however, it is also highly toxic (cytotoxicity on MRC-5, IC50 = 80 ng/ml), Table 1. Elaiophylin (5), Figure 1, is a 16-membered macrodiolide antibiotic isolated from Streptomyces strain found in a soil sample by Arcamone et al. [28] and elucidated by Kaiser and Keller-Schierlein [29] . In 2010, Omura et al. established that this macrocycle exhibit antitrypanosomal activity against GUTat 3.1 strain (IC50 = 460 ng/ml), a 3.4-fold more potent than the current used drug suranim but with a very poor selectivity index (SI = 2) [30] . Tsushimycin (6), Figure 1, is a ten-membered cyclopeptide antibiotic isolated from cultures of Streptomyces strain which presents unusual amino acids in their structure and an exocyclic amino acid with the α-NH2 group acylated by a fatty-acid residue [31,32] . In 2009, Omura and colleagues studied the in vivo and in vitro antitrypanosomal activity of this

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Review Peña, Scarone & Serra macrocycle [33] . In vitro studies showed that tsushimycin presents similar activity on strain GUTat 3.1 compared with the widely used drug suramin, although the antitrypanosomal activity on strain STIB900 was lower than the cited commercial drug. The cytotoxicity evaluation showed no toxicity against

N

O

O

O

H N

N

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N H N

OH O

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O S S O

O

O

MRC-5, higher SI than suranim for GUTat 3.1 but lower for strain STIB900. The in vivo antitrypanosomal activity was done using the T.b.brucei S-427 acute mouse. Tsushimycin showed a curative effect at a dose of 50 mg/kg × 4; however, this dose is 50-fold greater than the dose of suramin.

N

O H N

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O

O O

N

N H

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O

H2N

R1

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R2

Echinomycin (2)

O H

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N H

S S +

OH

R2

O O

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O

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R1

OH Irumamycin (3a) O

H2 Venturicidin A (3b)

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HO

O O

Leinamycin (1) OH O H N

OH

O N H

N

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OH

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NH

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OH OH

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NH2

NH O

N H

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Virustomycin A (4)

OH

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Tsushimycin (6)

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OH

OH HO O

Antibiotics against Trypanosoma brucei

O

O O

HO O

OH

Elaiophylin (5)

OH OH

O

O

Figure 1. Bioactive natural products and analogs against Trypanosoma brucei.

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N

H N

OH

OH O

OH

O

HO

O

Review

Br

R

O Br

Br OH

Br

OH

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N H

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OH

Plagiochin A (9)

Marine Natural Products as anti-trypanosomals

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Br (E, E)-Bastadin 19 (7) H Isobastadin 13 (8) O

OH O OH

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OH

O O

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OH

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Latrunculin A (10)

OH HO

Latrunculol A (11)

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Latrunculone B (12)

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H OH

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O O

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Fijianolide A (13)

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H O

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O

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O

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O H

OH

O

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O

O H

Fijianolide B (14)

H

H

Fijianolide D (15)

Figure 1. Bioactive natural products and analogs against Trypanosoma brucei (cont.).

Tsushimycin is a lipophilic macrocyclic peptide antibiotic, with different structure than suramin, consequently the mode of action could be different. Previous studies revealed that tsushimycin acts inhibiting transfer of sugars from sugar nucleotides to dolichyl phosphate, preventing the formation of dolichol-linked monosaccharides [34] . Crystallized tsushimycin was studied by Bunkóczi et al., suggesting that bioactive tsushimycin involves a dimmer that expose the fatty-acids chains to the exterior and in the interior both molecules interacts with Ca 2+ ions [35] . According to these results, interaction with the membrane-lipid layer of the parasites could be the mode of action of this antibiotic.


Marine natural products as antitrypanosomals

Bastadins are a group of brominated natural products isolated form Ianthella marine sponges. Bastadin 13 (7) [36] and (E, E)-Bastacidin 19 (8) [37] , Figure 1, were isolated previously to the considered period of this review; however, the biological assays against T. brucei were done recently by Crews and colleagues. Bastadine 13 showed IC50 = 1.77 μM and (E, E)-Bastacidin 19, IC50 = 1.31 μM [38] . Plagiochin A(9), Figure 1, is a bis(bibenzyl) macrocycle isolated from Plagiochila sp. having a biphenyl linkage between one pair of benzyls [39] . The total synthesis was done by Kametler et al. in 1992 [40] . Bioassays against T. b. brucei were done by Otoguro

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Review Peña, Scarone & Serra et al. obtaining an IC50 value of 930 ng/ml with a low SI = 18 (IC50MCR-5/ IC50 GUTat 3.1) [41] . Latrunculins are a family of natural products isolated form the Red Sea sponge Negombata magnifica [42,43] . In general terms, their structures consist of a macrolide ring fused to a tetrahydropyran and a thiazolidinone on the side chain. The first total synthesis of latrunculin A (10), Figure 1, was realized by White et al. [44] . Latrunculin A presents widely studied antineoplastic activity with potent actin inhibitor properties [45] . Also, it is the most widely used small molecule molecular probe for biochemistry. Recently, Crews and colleagues have developed high-throughput LC-MSUV-ELSD-based natural product libraries with the aim of find new or known natural products with new bioactivities. During this work, they discovered the antitrypanosomal bioactivity of latrunculin A, which exhibited and IC50 = 1.2 μg/ml against T. b. brucei that was not previously reported [46] . Latrunculol A (11) and latrunculone B (12), Figure 1, are natural products recently isolated and elucidated by Crews and colleagues, related to latrunculin compounds which had demonstrated antineoplasic activity [42] . Even though the total synthesis of the analog 18-epi-latrunculol A [47] was reported recently, neither the total synthesis of latrunculol A nor of latrunculone B have been achieved. The antitrypanosomal bioactivity was evaluated three years later also by Crews and colleagues in their HT method mentioned previously [46] . Latrunculol A presents high inhibitory activity (IC50 = 0.09 μg/ml) against T. b brucei. They also reported that this compound also presented considerably cytotoxicity (< 0.75 μg/ml) for colon cancer (HT-29), non-small-cell lung cancer (H522-T1) and lymphoma (U937) tumor cell lines. In previous studies, the same group reported the selectivity of latrunculone A for colon cancer (C38) versus normal bone marrow (CFU-GM) cell lines [42] . Latrunculone B exhibits an IC50 of 1.0 μg/ml against T. b. brucei but slightly minor cytotoxicity with an IC50 between 0.8 and 2.5 μg/ml against named solid tumor cell lines. Fijianolides are a family of 20-membered ring macrolide; fijianolide A (13) and B (14), Figure 1, were simultaneously isolated from marine sponge Cacospongia mycofijiensis and Hyatella in 1988 [48,49] . These compounds present widely studied cytotoxicity, with a mechanism of action involving stabilization of microtubules like paclitaxel does [50] . However, their antitrypanosomal activity was unknown until 2011 when Crews and colleagues determined the IC50 against T. b. brucei. TheIC50 values are1.4 μg/ml for 13 and 0.08 μg/ml for 14 [46] . Fijianolide B is the most active of the fijianolides against T. b. brucei, but it is also highly cytotoxic

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against solid tumor cell lines (HT-29, H522-T1 and U937). Fijianolide A is 10-fold less toxic for named cancer cell lines than 14 but also 17-fold less active for T. b. brucei. Fijianolide D (15), Figure 1, is an analog of 13 which was isolated and characterized also by Crew’s group [51] . The structure of this compound was established by one- and two-dimensional NMR and HRESIMS studies. Few years later, they reported the bioactivity of 15 against T. b. brucei (IC50 = 1.4 μg/ml) [46] . Cytotoxicity studies in solid tumor cell lines including melanoma (MDA-MB 435), HT-29, H522-T1 and U937 revealed no relevant inhibition (IC50 > 2.5 μg/ml). This result suggest that the presence of a carbonyl group in the pyran side chain decrease the cytotoxic activity while the antitrypanosomal activity remains intact when compared with 13. Comparing 13 and 14, it could be concluded that the presence of the epoxide instead of the tetrahydrofuran ring, favors the antiparasitic activity as well as the cytotoxicity. Various total syntheses of 14 have been reported since the first total synthesis was achieved in 2000 by Ghosh and Wang [52] . The first total synthesis of 13 was achieved in 2009 by Mulzer and colleagues, Figure 2 [53,54] . They developed a convergent, stereo controlled and efficient route where fijianolide A was obtained from 24 steps in 2% overall yield. Aldehyde segment was prepared starting from protection with tert-Butyldimethylsilyl (TBS) and Kulinkovich reaction of the commercially available diol (16), followed by mesylation and MgBr2 · OEt2 mediated cyclopropyl rearrangement to obtain allylbromide 17, Figure 2. Then, Evan’s alkylation followed by reduction with LiBH4, Mitsunobu reaction and nitrile reduction gave the aldehyde 18. Transformation of 18 into the dihydropyran 19 was done by allylation, ring closing metathesis and incorporation of the side chain. The aldehyde was obtained using BestmannOhira reagent to get terminal alkyne, then deprotection of terminal TBS ether and oxidation of resulted in the aldehyde 20. Starting from 21, sulfone 22 was obtained by selective deprotection of the primary alcohol, transformation into sulfide by Mitsunobu conditions using 1-phenyl-1-H-tetrazol-5-thiol, Luche reduction to obtain the syn alcohol with good diastero selectivity and protection with MOM and oxidation. After key fragments were obtained, Julia-Kocienskiolefination of the aldehyde 20 and the sulfone 22, furnished the corresponding olefin. Deprotection of TBS, sharpless epoxidation, removal of MOM protecting group, intramolecular epoxide opening and protection with TBS gave the tetrahydrofuran (23).


Review


Mulzer’s retrosynthetical analysis of Fijianolide A

OH HO

O

S

H

TBSO H

O

O

O

H

Ph N N

sulfone

+

OMOM

O

N N

OPMB O

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OTBS O

O H

O

OMOM

H

H

H

H

H

O

H aldehyde

Fijianolide A (13)

i. i. TBSCl, imidazole CH2CI2 ii. Ti(Oi-Pr)4 EtMgBr, THF

O

HO

OEt

OH

N Bn

OTBS

OTBS

Br

17

iii. PPh3, DIAD, THF acetone cyanhydrin iv. DIBALH, CH2CI2

PO3Me2

i. K2CO3

TBSO

MeOH

OTBS O

iii. CI2(PCy3)2Ru=CHPh, CH2CI2,

H

O

O

N2

OTBS H

H

O

H

ii. NH4F, EtOH iii. IBX, MeCN

montmorilonite K10, vinyloxy TMS

20 28% (14 steps)

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H

OTES

i. HE.Pyr, THF ii. PPh3, DEAD, PTSH, THF iii. NaBH4, CeCI3. 7H2O, MeOH

O

OPMB 21

+ 22

O 18

O

ii. (ETO)2CHCH=CH, PPTS, PhMe

20

TBSO

TBSO

i. (-)-Ipc-allylborane, Et2O, pentane

O

O

NaHMDS, THF ii. LiBH4,Et2O

iii. MsCl, NEt3, Et2O iv. MgBr2.Et2O, CH2CI2

16

O

O

Synthesis of Fijianolide A

i. KHMDS, THF ii. HF.Pyr, THF iii. Ti(OiPr)4, (+) DIPT, tBuOH, CH2CI2 iv. BF3.Et2O, PhSH, THF v. TBSOTf, 2,6-lutidine, CH2CI2 36% (5 steps)

H

OMOM

O S

O

OPMB iv. NaBH4, CeCI3. 7H2O, MeOH v. MOMCI, NEtiPr2, CH2CI2 vi. H2O2, (NH4)6MoO24.4H2O

O

OPMB O H

H 23

N N

N

22 65% (6 steps)

OTBS H

TBSO

Ph N

H

O

i. DDQ, CH2CI2 ii. BuLi, CO2, THF iii. CI3C6H2COCI, Et3N DMAP, C6H6 iv. HF.Pyr, THF v. H2, Lindlar cat. quinoline EtOAc, C6H10 24% (5 steps)

Fijianolide A (13)

Figure 2. Retrosynthetic scheme and synthesis of fijanolide A.


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N

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H N

N

N

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m

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Compound

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IB01212 24 25 26 27 28 29 30 31

32 33 34

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1

1

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1

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1

1

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3

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1

Figure 3. Structures of IB-01212 and analogs.

PMB removal, C1 elongation and macrolactonization using Yamaguchi conditions followed by deprotection of TBS and reduction of triple bond gave the (Z)-enoate of fijianolide A. Natural products & analogs as antileshmanial

In 2010, Rivas and Albericio group reported the leishmanicidal activity of IB-01212 (24), an antitumoral cyclodepsipeptide isolated from the mycelium of the marine fungus Clonostachys sp [55] . In addition, they studied a set of analogs, for which key residues were substituted, with variation of the cycle size and symmetry, obtaining compounds 25–34, Figure 3. All the compounds, except 32, showed effective leishmanicidal activity on both parasite forms (promastigotes from Leishmania donovani and amastigotes from Leishmania fanoi) at micromolar concentration range (Supplementary Table 2) . IB-01212 was the most active against promastigotes form and on amastigotes stage, compound 31 with Y = N and n = 3 from an ornithine amino acidic residue, was the most active. However all the compounds showed low selectivity (18 < IC50 < 48 against peritoneal macrophages, Supplementary Table 2). The group also presented studies of their mechanism of action and discussed that it was associated with the depolarization of the mitochondrial electrochemical gradient (ΔΨm), which in some cases led to an apoptotic-like process. IB-01212 and the derived depsipeptides, were prepared by solid-phase synthesis and solution

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macrocyclization. The group designed two strategies to the synthesis: a convergent one for the synthesis of analogs with ester and/or thioester linkages (24–25) in the macrocycle. They used the chlorotrityl chloride resin (CTC-resin) and Wang resin to prepare two tetrapeptides that were then coupled and finally cyclized in solution; a linear strategy performed on the CTCresin to obtain analogs with amide and/or amide (thio)ester bond linkages in the macrocycle (26–34) (Supplementary Figures 1 & 2) [56,57] . Kahalalide F (KF), 35, Figure 4, is a tumoricidal cyclic depsipeptide derived from the Hawaiian herbivorous marine species of mollusk, Elysiarufescens, and its diet, the green alga Bryopsis sp. Albericio and Rivas group’s reported the activity against Leishmania sp. of KF and its synthetic depsipeptides analogs with a micromolar range of concentrations (Supplementary Table 3) [58] . The KF analogs set was developed by substituted residues of key relevance for tumoricidal activity, as shown in 2008 by SAR’s study [59] . The group discussed that these modifications affect the overall charge and hydrophobicity of the peptide, although the internal cycle and the N-terminal aliphatic acid were preserved throughout the whole set. KF and its derived depsipeptides were prepared by solid-phase synthesis usin gFmoc strategy on CTC-resin, following the previously published methods [60] . In 2009, Férézou and colleagues investigated the effect of ivermectin (IVM) and several analogs or secoanalogs, Figure 5, on Leishmania amazonensis, a causative agent of cutaneous/muco-cutaneous in South America [61] . To use ivermectin as starting material, they argued that it is an orally active drug with an improved efficient industrial fermentation/hydrogenation process, and its availability as generic drug. Therefore, they prepared semisynthetic IVM macrocyclic analogs which were tested to perform a comparative study of their bioactivities. Compounds 43–44 were obtained from IVM hydrolysis conditions reported by Mrozik et al. [62] . According to known procedure, Δ2,3-IVM (45) was prepared from commercial ivermectin with substoichiometric amount of DBU until total consumption of IVM, Figure 5 [63] . The in vitro antileishmanial activities of the compounds were determined against both the insect promastigote and the intramacrophage amastigote forms of L. amazonensis, using pentostam and amphotericin B as reference drugs, respectively (Supplementary Table 4) . Interesting the conjugation of the C3–C4 double bond of IVM analogs resulted in an increase of the antipromastigote activity, opposed to the analog Δ2,3-IVM which increase the antiamastigote activity.


Review


D-allo-lle (7)

D-Pro (9) D-Val (10) H N O

O

H N

N

N H

O

NH

Val (11)

O

Thr (12)

OH

O

H2N

D-alo-Thr (6) O H N

O

HN

35

O 5-MeHex (14)

O

O

H N N H

Pro

Phe

(3)

4-CI-Phe (37)

Phe

(3)

2-Naph (38)

Orn

(8)

Glu (39)

D-Pro

(9)

Pro (40)

D-Val

(13)

D-Cha (41)

5-MeHex

(14)

4-CF3-Cinn (42)

Cl

HN

HN

D-Cha

N H

O

2-Naph

HO

O

Glu

NH

O N H

O

H N

4-CI-Phe

O N

D-Val (36)

HN O

D-Val

Analogues

(1)

Phe (3)

(Z)- Dhb (2)

O

Residue

Val

O

HN

NH

NH

D-Val (13)

O

O

Val (1)

Natural KF

D-Val (4)

H N

N H

O

Orn (8)

O

HN

D-allo-lle (5)

O CF3 4-CF3-Cinn

Figure 4. Structures of kahalalide F and analogs.

Synthetic macrocycles against Trypanosoma cruzi Pirazole-containing macrocyclic & macrobicyclic poliamines

Sanchez-Moreno and colleagues evaluated in vitro and in vivo activities against Trypanosoma cruzi of a series of previously synthetized macro bicyclic polyamine (46) [64] , two monocyclic polyamines (47–48) [65] and the more lipophilic monocyclic poliamine (49), Figure 6 [66] . The synthesis of the macrocyclic polyamines 46, 47 and 49 were performed from 1H-pyrazole-3,5-dicarbaldehyde following a previously reported procedure as showed in Figure 6 [67] . The monocyclic polyamine containing two 1-benzyl-pyrazole units (48) was obtained from 1-benzylpyrazole-3,5-dicarbaldehyde in two steps, as was reported previously, Figure 6 [68] . The authors evaluated the in vitro activity of these compounds in their hydrochloride forms against T. cruzi extracellular epimastigotes, axenic amastigotes of an SN3 strain isolated from Colombian R. prolixus and intracellular amastigotes; compounds 46 and 47 showed low micromolar IC50. Toxicity against Vero cells was tested and compared with values obtained for the reference drug benznidazole (Supplementary Table 5) . In addition, they studied the propagation of the parasite in Vero cells by measuring the infection rates and the average number of amastigotes and


trypomastigotes present during a ten-day treatment period. The results of this study for compounds 46–48 showed that the infection rate decreased in all cases and always was greater than 50%, making them much more effective than benznidazole (23%). Compounds 46 and 47 decreased the infection rate in 74 and 80%, respectively, compared with the control. These results prompted them to study the in vivo activity of 46, 47 and 48 on female BALB/c mice on acute and chronic phases. Macrocycles 46 and 47 reduced the level of parasitemia on day 30 by 53 and 39%, respectively. Moreover, these compounds reduced antibodies levels respect to the control. The order of in vivo activity was as follows: 46 > 47 >> 48 > BZN. Several experiments were performed to elucidate a possible mechanism of action: nature and percentage of the metabolites excreted by the tryponosomatid during its in vitro culture using1H RMN, in order to study the effects on the glycolytic pathway, morphological alterations of T. cruzi epimastigotes were analyzed with transmission electron microscopy, to evaluate the damage caused to the parasite cells, inhibitory effect on the T. cruzi Fe-SOD (iron superoxide dismutase) enzyme, to test their potential as enzyme inhibitors. Compound 47 resulted in the most effective and selective compound for Fe-SOD inhibition with respect to human SOD.

10.4155/FMC.14.133


Ivermectine and analogs

RO

H

O

14

O 25

11 10

H

RO

2

H HO

H

O

Me

O OH 1 5

HO

O

H

O

O

MeO O

O

O

L-ole (oleandrose)

OH MeO

3

HO

O

4

MeO

H HO

R = (L-ole)2 IVM R = L-ole, IVM monosaccharide (43) R = H IVM aglycone (44)

R = (L-ole)2

O

Me

(L-ole)2

∆2,3-IVM (45)

O Me

O

Preparation of ∆ 2,3-IVM (45)

H

RO

O O

O

H

RO H

O

O O

DBU, THF 85°C, 15 h

O

H

O

OH

OH O

O H HO

H HO ∆2,3-IVM

IVM

Figure 5. Structures of ivermectin and analogs and preparation of D2,3-IVM.

Authors have tested the Mn(II) complexes of these compounds and in all cases a decrease of activity and selectivity was observed. They ascribed these results to the protective effect that has been described for Mn(II) complexes of azascorpiand ligands [69] . Bioactive macrocycles as anti-HAT & antimalarials Natural products & analogs

Gademann and colleagues have isolated four new cyclohexapeptides, Aerucyclamide A (50), B (51), C (52) and D (53) (Figure 7), from toxic fresh water Microcystis aeruginosa PCC 7806; structural elucidation and bioactivities against T. b. rhodesiense STIB 900 and Plasmodium falciparum K1 were also determined [70,71] . These compounds were selective for the parasites over rat myoblast L6 cells. Aerucyclamide are cyclohexapeptides alternating hydrophobic and heterocycized amino acids. Aerucyclamide B is the oxidized analog of aerucyclamide A, with an IC50 = 15.9 and 0.7 μM against T. b. rhodesiense and P. falciparum K1,

10.4155/FMC.14.133


respectively. Aerucyclamide B was obtained by the authors through oxidation of the natural aerucyclamide A using MnO2 /benzene. The most active aerucyclamide as antytrypanosomal is aerucyclamide C which displays an IC50 value of 9.2 μM. As part of a search for candidates of antiparasitic new drugs, in 2012, our group reported the synthesis and antimalarial activity of macrocycle (54) [72] , Figure 7, a predicted metabolite of Microcystis aeruginosa PCC 7806 [73] . We planned to obtain first the open precursor of 54 from three heterocycles building blocks by a convergent macrocycle-assembly methodology, Figure 7. Macrocyclization reaction was performed in diluted conditions (0.001 M) using HBTU; compound 54, which resulted in a stable compound, was obtained in 40% yield. This compound displays an IC50 value of 0.18 μM against the chloroquine-resistant K1 strain of P. falciparum showing enhanced activity when compared with its analog 51 (IC50 = 0.7 μM).



Review

H N N H HN

NH N N

H N

N

H N

H N N

NH

N N

H N

H N

H

H H N

N N

H N

R N

H N

H N N

R

N

N N

NH

NH

HN

R N

H N HN

HN

47 (R = Me) 48 (R = Bn)

46

49 (R = (CH2)7CH3)

Synthesis of compound 46-49

NH2

1)

H2N CHO

NH2

N

HN

NH H

MeOH, 25°C

N

2) NaBH4, MeOH, 25°C

N

OHC

H N N

H

H N

N

65% (two steps)

N N H N N

NH

1) H2N

HCI 1N, EtOH

H N

46.8HCI

N

85%

HN

46 NH2

N

H

MeOH, 25°C 6 N


H N

N N

6

H N

HCI 1N, EtOH

N

H

65% (two steps)

NH

N N

49.6HCI

85%

HN

49 H H2N

CHO

1) MeOH, 25°C

N N

OHC

H

NH2

N

H N

N N

H N

H N

HCI 1N, EtOH 47.6HCI

Me


Me

H N NH

N N

88% HN

70% (two steps)

47

CHO

N

N OHC

Bn N N

Bn N N H

NaBH4, MeOH, 25°C

N

MeCN, 25°C

N

Bn H 2N

N

55%

H

N N

N

N N Bn NH2

NH

N

H

83%

HN

NH

HN NH

HN

HCI 1N, EtOH

48.6HCI

85%

N N

48

Bn

Figure 6. Strucures and synthesis of pirazole-containing macrocyclic and macrobicyclic poliamines.


10.4155/FMC.14.133

Review Peña, Scarone & Serra In 2013, the first total synthesis of aerucyclamide B (51) was reported by our group, Figure 7 [74] . Based on the well-known oxazoline instability, the cyclodehydration reaction to obtain it, was selected as the last step of the route. Macrocycle 55 was obtained in poor yield (12%) by C- and N-deprotection of 56 followed by coupling using O-Benzotriazole-N,N,N’,N’-tetramethyl-uroniumhexafluoro-phosphate (HBTU) in diluted conditions (0.005 M), Figure 7. However, C- and N- deprotection of the linear precursor 57 followed by macrocyclization rendered the desired macrocycle 55, in a higher yield (40%), suggesting that the selection of the point for macrolactame formation is relevant in this case. Finally, cyclodehydration reaction of 55, using Deoxo-Fluor, rendered aerucyclamide B and the fluo-

rous derivative (58) in 67 and 28% yield, respectively. The formation of 58 could be explained by a loss of nucleophilicity of the β-hydroxyamide of 55. Employing the same strategy used for the synthesis of 54, new analogs of aerucyclamides (59– 61), Figure 8, were obtained and evaluated against T. b. brucei [75] . Recently, the evaluation of compounds 55, 58, 59–61 as antiplasmodials and the synthesis and evaluation against T. b. brucei and P. falciparum K1 of cyclohexapeptides 62–68 were reported, Figure 8 [76] . These compounds (62–68), containing cysteine or threonine/serine amino acids, which are biomimetic precursors of thiazoline/thiazole or oxazoline/oxazole, respectively, were prepared and evaluated to study the influence of the azole rings and of the open precursors on biological activity.

Aerucyclamides isolated from Microcystis aeruginosa PCC 7806 and synthesized analogue 54

H

O

H

O N

H

NH O

S

N H

O

N

N H

O

N

N

H

O N

HN

NH

54

S

O

O

N HN

N

N H

NH

O O

H

Aerucyclamide C (52)

S N O

HN N

H

S

S

Aerucyclamide D (53)

O

Retrosynthetic analysis for macrocycle 54

NHBoc

O O N

H

CO2Me N H

NH O

S

O

N HN

S

N

H

N

N

OMe

O

NHBoc

H NH

O

N S

H

S

H

N

O

N

O

H

O

N

NH

O

O N H

S

N H

Aerucyclamide B (51)

H

O

O

HN

S

Aerucyclamide A (50)

S

N

H

S

O

NH

O

HN N

H

N

H

O

O H

HN

O

S

S

BocNH

N

N

H

OMe O

NHBoc N S

EtO

O

H

Figure 7. Structures, retrosynthesis and synthesis of aerucyclamides and analogs.

10.4155/FMC.14.133



Review


Retrosynthetic analysis for aerucyclamide B (51)

O

H O

N H

N

H

NH

O O

N

H O

H

S

NH

H

S

N H

HO

N HN

O

O

H

S

O

S

CO2Et H

N

NHBoc BocHN

H

S

N

NH

O

HN

Aerucyclamide B (51)

OMe

HO

N

NH

BocHN

O

N

MeO2C

H S

55

Synthesis of aerucyclamide B (51)

O

H

NHBoc

O

N

NH

H O

NH

NH

H O

H

H

O

N

NH BocHN N S

H O

S

N H

CO2Et

NH

i) KOHaq/THF ii) HCI/ Dioxane iii) HBTU, CH2CI2 40%

N H

N

H

O

HO

O

HO O

O

HN

O

O

i) KOHaq/THF ii) HCI/Dioxane iii) HBTU, CH2CI2 12%

N S 56

H

H

S

OMe

HO

NH N H

NH

HN

O

N S

S

H

NH

H O

57

O

F O

H

H

51 (67%)

+

H

55

O

N

O

DeoxoFluor CH2CI2, -20°C

N HN

S N

S

N H

NH

S N HN

O

N S

H

58 (28%)

Figure 7. Structures, retrosynthesis and synthesis of aerucyclamides and analogs (cont.).

Cyclohexapeptides 62–68 were obtained in very good yields by a combination of solid-phase peptide synthesis, for the linear peptide, and solution macrocyclization. The linear sequence of the hexapeptides, was build-up on a 2-CTC-resin using Fmoc stategy. The hexapeptides were obtained in excellent yields and purities and then, macrocyclization was performed in high dilution conditions (1–5 mM) by activation with HBTU affording the desired compounds in rather good yields (40–83%), see Supplementary Table 6. Several of the compounds evaluated (Supplementary Table 7) showed increased antimalarial and antitrypanosomal activities compared with their natural product analogs. The evaluation against P. falciparum K1, resulted in the following conclusions: a thiazole instead of L-Cys in the macrocycle increases the potency; replacement of 5-methyloxazole


by its corresponding β-hydroxyamide does not affect bioactivity; the more flexible non-azolic macrocyles (compounds 62, 63, 65 and 66) are less potent than the azolic ones; the chemical nature of the aminoacidic residues seems to be critical for the activity of non-azolic cyclohexapeptides and L-Met and the dipeptide L-PheL-Ser(tBu) increase the potency of this compound class. The evaluation of the antitrypanosomal activity revealed that the presence of two or three heterocycles in the macrocycles impairs the biological activity. The most active compound is a nonazolic- cyclohexapeptide (62) showing 82-fold selectivity for the parasite than against murine macrophages. Cyclohexapeptides containing only one thiazole (67 and 68) showed satisfactory cytotoxic profiles against both protozoan parasites. Bispolides are 20-membered ring macrodiolide with a symmetric cyclic structure consisting of two conju-

10.4155/FMC.14.133


O

O O N

H

O

S

N H

N

NH

HN H

O

NH

H

NH

O H

OtBu O H H

HN

O

HN

H N O STrt

O

NH

H N H

H

NH

O

H

H

62

H N

O STrt

H

O

H

NH NH

O

H

H

O

NH

H

NH

O H

H N

OtBu O H

HN HN

O STrt

H

H

O

NH

H S

66

H

HN

H N

HN

H

O

O

NH

STrt H

H

65

O

NH

S

N H

N

O

O

HN

NH

H

NH H

O STrt

O

H

O STrt

OtBu O H

N

H

HN

H N

O

S

N H

HN

STrt

NH

O STrt

O

N H

O

STrt O

O

64

O

N H

N H

O

TrtS H

H

O

63

OtBu O H

H

61

OtBu O

HN

O

HN

O

OH

STrt

N

N

O

H

O

HN

O

NH

60

O

N H

N

O

HN

S

59

OtBu O H

N

H N H

N

O

O

O H

NH

O

N

O

N H

N

H

O

S

O

H

HN

NH NH H

67

O STrt

H

S

68

Figure 8. Azolic and non-azolic cyclohexapeptides evaluated as antitrypanosomal and antiplasmodium.

gated trienes and hexopyranoses in the side chains. Bispolides A1 (69), A3 (70), B1 (71) and B3 (72) were purified from the culture broth of Microbispora sp. A34030 by Otoguro et al., see Figure 9 [30] . Omura’s group prepared two derivatives of these natural products and determined the in vitro antitrypanosomal and antiplasmodium activities together with cytotoxicity against MRC-5 [77] . Bispolide derivative 73, Figure 9, was obtained from 69 by reaction with 0.04% HCl in MeOH, followed by reduction with NaBH3CN in EtOH. Bispolide derivative 74, Figure 9, was prepared by partial hydrolysis of derivative 73 with p-toluensulfonic acid in aqueous acetonitrile. The in vitro antiprotozoal activities of bispolides, their derivatives, elaiophylin and some stan-

10.4155/FMC.14.133


dard

antiprotozoal

drugs

were

determined

(Supplementary Table 8) . Elaiophylin (5), Figure 1, was

obtained from the antibiotic library of the Kitasato Institute for Life Sciences. Bispolides, derivative 73 (13,13’-dideoxybispolide A1) and elaiophylin showed the more potent antimalarial activity against the drug-resistant K1 strain of P. falciparum, in the 260–620 ng/ml range. With respect to antitrypanosomal activity, bispolides and derivative 73 showed the most potency against the GUTat 3.1 strain of T. b. brucei, in the 57–150 ng/ml range. The antitrypanosomal activities were 10–40-fold more potent than that of the standard drugs, suramin and eflornithine. The compounds present moderate or low SI. The data suggest that the hexose moieties at 15-OH and 15’-OH and



R1 R2 OH OH A1 (69): A3 (70): OMe OMe H Derivative 73: H OH OH B1 (71): B3 (72): OMe OMe

R3 H H H OH OH

O O HO O

R1

O

R3

OH

HO

HO

O

O

Review

HO

O H

O O OH

R2 O

HO O

O

OH

O

O O

Bispolides H

OH

O

Derivative 74 OH

Figure 9. Structures of bispolides and derivatives.

the two conjugated trienes in the 20-membered ring present in bispolides have a significant antiprotozoal activity and cytotoxicity. The preliminary in vivo antitrypanosomal activities of bispolides 70 and 72 were measured in the T. b. brucei S-427 acute mouse model. At a dose of 25 mg/kg bispolides 70 and 72 did not achieve cure but did extend the mean of survival days. Under the same conditions, suramin showed a curative effect (MSD: 430 days) at a dose of 1 mg/kg. Malformins, produced from Aspergillus niger, are a family of pentacyclopeptide with a disulfur bond which present a wide range of biological activities. Malformins A1 (75) and A2 (76), Figure 10, were isolated [78] , and synthesized [79] , several years ago. Nonetheless, the bioactivity against T. brucei was determined in 2009 by Omura and colleagues [80] . Malformin A1 (IC50 = 190 ng/ml) has almost three times more potency than malformin A2 (76) (IC50 = 560 ng/ml), see Supplementary Table 9. Malformin B2 (77) [81] and C (78) [82] were isolated many years ago. The first total synthesis of malformin C was achieved in 2008 by Kojima et al. [78] who followed a convergent strategy in solution phase (Supplementary Figure 3) . Firstly, they obtained two building blocks, a tripeptide and a dipeptide to obtain the linear pentapeptide, which undergo cyclization using HATU/HOAt as coupling reagents. The last step is an oxidative disulfide bond formation employing iodine in DMF resulting in 78 with 30% overall yield in nine steps.


In 2009, the same research group developed the solid-phase synthesis of malformin A1, A2, B2, C and derivatives together with studies of the antiparasitic activities of these compounds [83] . The synthesis was done following Fmoc-SPPS strategy using 4-methoxytrityl chloride resin and PyBOP as coupling reagent (Supplementary Figure 3) . Previous selective deprotection, the cyclization was performed on-resin using HBTU/HOBt. The last step for the synthesis of 77, 78 and the unnatural analog (79) is the cleavage and oxidative disulfide formation using I 2 /DMF. Malformin A1, A2, B2 and C were obtained in 6, 13, 7 and 15% yield, respectively. The authors explain the low yields by the oxidative conditions used in the last steps that allowed undesired interactions with the solid support. In the case of the analogs 80 and 81, the last step was the cleavage from the resin, with different conditions, in order to preserve the Trt-protecting group or not. Malformins C and B2 showed antiparasitic activity against both parasites. In contrast malformin C analogs, compounds 80 and 81, are less potent (Supplementary Table 9) . Thus, the disulfide bond seems to be necessary for the antiparasitic activity. In the case of the unnatural analog (79), which substitutes the branched Leu of malformin C for Ala the activity against T. b. brucei decreases 437-folds. It is interesting to note that the substitution of Leu in malformin C by Val (malformin B2) rendered the most active compounds of this series against P. falciparum.

10.4155/FMC.14.133

Review Peña, Scarone & Serra Synthetic products

lowed by reductive removal of the metal template in the resulting diimine as shown in Figure 11. A number of aromatic substituted compounds showed activities against Trypanosoma brucei and P. falciparum (Supplementary Table 11) . Compound 92 is the most active of the series with poor selectivity index. Benzamidine and guanidine-derived polyazamacrocycles were later developed and evaluated as anti-HAT, (Supplementary Figure 4) [86] . Although, they were not toxic against HEK cells, the activity against T. b. brucei was decreased.

Sutherland and colleagues have developed series of antiprotozoal polyazamacrocycles [84] . They reported a small library N-functionalized carbamate-derivated polyazamacrocycles which were synthesized starting from diethylenetriamine and diethanolamine, Figure 11. Cyclization was performed after to sylation by phase transfer catalyst and deprotection was done following a two-step procedure. The functionalization of the 1,4,7,10-tetraazacyclododecane was achieved using ethylene oxide to obtain the tetraol intermediate, then different carbamate analogs were obtained using the corresponding isocyanate. Submicromolar antiprotozoal activities against T. brucei were found for compound 84 and 86 (Supplementary Table 10) . Compound 86 do not present selectivity and was toxic to human embryonic kidney (HEK) cells, and the selectivity index of compound 84 is low (SI = 20). With the aim to obtain nontoxic polyazamacrocycles, a second generation of these compounds, C2-substituted polyazamacrocycles without the reactive carbamate side-chains were synthesized and tested for antimalaric and anti-HAT activities [85] . The series of C2-substituted analogs were obtained starting from triethylene tetraamine and using metaltemplated condensation with a series of glioxales, fol-

O

NH

O

In 2009, nonpeptide macrocyclic skeletons derived from 14- and 15-membered macrolides were reported as human HDACi [87] . These compounds are suberoylanilide hydroxamicacids (SAHA)-macrolide conjugate that incorporate the 15-membered azalide ring of azithromycin or the 14-membered ring of clarithromycin, Figure 12, as the macrolide template. The HDAC inhibiting group was attached to a macrolide moiety that is remote from the macrocyclic ring. In 2010, Oyelere and colleagues reported the antiparasitic activities against P. falciparum and L. donovani of those macrolides, Figure 12 [88] . These human pathogens are responsive to HDACi because their

N H

HN

NH

O

N H

O HN

NH

O

NH HN O S

S

O

S

Malformin A2 (76)

O

NH

O

N H

O HN

O

NH

O

NH

N H

HN

Unnatural malformin (79)

HN

O

S S

S

Malformin B2 (77)

Malformin C (78)

O

NH

N H

NH

HN

O HN HN

O

O SH O

O

S

HN

O

O

O

TrtS

O

O

O

NH

HN

NH

O

O

NH S

HN

N H

O

S

Malformin A1 (75)

N H

O

NH HN

O

O

O

O

O O

NH HN S

Macrocycles as antileishmanials & antimalarials

TrtS

HS

80

81

Figure 10. Structures of malformins and analogs.

10.4155/FMC.14.133




Review

Synthesis of first generation poliazamacrocycles H N

H2N

NH2

TsCl/NaOH

diethylene triamine

H N

Ts N

TsHN

NHTs

H2O, Et2O 99%

LiOH/Bu4NBr

HO OH TsO diethanolamine TEBA, CH2Cl2 91% H R N i. ethylene oxide, H2O quantitative

O

ii. RNCO, Bu2Sn(OAc)2, CH2Cl2

O R N H

toluene 71%

Ts N

TsCl/NaOH

N

N

N

O O O

O

N

N

N

N

Ts i. H SO /HBr 2 4

Ts

ii. NaOH toluene 88%

NH

HN

NH

HN

H N R

O N

Ts

OTs

O

Ts

N R H

82 (56%) 83 (64%) 84 (79%) 85 (46%) 86 (60%)

Synthesis of second generation poliazamacrocycles. O NH2 diethylene triamine

FeCl3, MeOH

NH NH

Fe

R

H Cl Cl

NH2

O glyoxal's series

Cl H

N

N

Cl

Fe N

R

i. NaBH4, MeOH ii. HCl then NaOH

NH

HN

NH

HN

R

N

H

C2-substituted tetraazacyclododecanes R = 4-Cl-Ph

(87)

CF3 CF3

4-CF3-Ph

(88) (89)

(90) (91) (92)

Figure 11. Synthesis of poliazamacrocyles.

genomes contain multiple genes encoding different HDAC isozymes, some of which are essential for their survival and proliferation. The synthesis of these macrolides was performed as was previously reported by Oyelere’s group [87] . These compounds were then evaluated as HDACi. These nonpeptide macrocyclic HDACi inhibit the proliferation of the sensitive and the resistant strains of P. falciparum with an IC50 value ranging from 0.1 to 3.5 μg/ml (Supplementary Table 12) . Compounds 99–102, derived from either the 14- or 15-membered macrolide analogs and having six methylene spacers separating the triazole ring from the zinc binding hydroxamic acid group (n = 6), have the most potent antimalarial activities in this serie. These compounds are equipotent or are more than four times more potent than the control compound SAHA. In addition, they are several folds more selectively toxic to either strain


of P. falciparum compared with SAHA. The highest antileishmanial activities (IC50 = 3.4–3.5 μg/ml) were for analogs that have eight or nine methylene spacer groups (compounds 107, 109 and 110, Supplementary Table 12). In order to obtain evidence for the involvement of P. falciparum HDACs as one of the potential intracellular targets for these compounds, the activities of selected analogs against P. falciparum HDAC-1 (pfHDAC-1), was investigated (Supplementary Table 13) . Many of these compounds inhibited the activity of pfHDAC-1 with IC50 values similar to their antimalarial activities. The most potent antimalarial compounds, 99 and 101, which represent the 14- and 15-membered analogs, respectively, demonstrated the highest anti-pfHDAC-1 activities. Compounds 95, 96, 98, 109 and 110, analogs with attenuated antimalarial activities relative to 99 and 101, are less potent against pfHDAC-1.

10.4155/FMC.14.133


R2

O

N

R1 = H or

HO O

O

cladinose

R2

OH O

O

HO

N

O

HO O O

N N

R2 = -

OR1

n 5 5 5 5 6 6 6 6

OH

N H

Macrocycle Type 93 93 94 94 93 94 93 94

R1 cladinose H cladinose H cladinose cladinose cladinose cladinose

n 7 7 7 7 8 8 9 9

N

HO Hunig’s base, DMSO, 85°C, 2h

O

HO O

O

O

OR

O

n

Comp. 103 104 105 106 107 108 109 110

O

HO

OR1 Macrocycles derived from azithromycin (94)

O

O

N

OMs

HO O

HO

HO

O

R1 Macrocycle Type 93 cladinose 93 H 94 cladinose 94 H 93 cladinose 93 H 94 cladinose 94 H

NH

OH

OH

N H

N N

R2 =

O

n

HO O

O

N

Macrocycles derived from clarithromycin (93)

Comp. 95 96 97 98 99 100 101 102

HO

N

N3

O

n

N H

O

OTBDPS

TBTA, Cul, THF, Hunig’s base, rt, 24h

HO

63%

OR

O

O

99%

O R = cladinose

HCl, rt, 24h 79%

O N3

R=H

n

N H

OH

TBTA, CuI, THF, Hunig’s base, rt

N N N

N HO O

O HO

O n

N H

OTBDPS N N

O

N

O

HO

HO O

O OR

O O

N

TBAF, THF, rt, 2h

HO

38%

HO

O n

N H

OH

O O

OR

O O

Figure 12. Structure and synthesis of 14 and 15-membered macrolides.

10.4155/FMC.14.133




Natural products & analogs as anti-HAT, antileishmanials & antimalarials

Symplocamide A (111), Figure 13, isolated from Symploca sp. found in Papua New Guinea was screened against three parasites with the following results: malaria (W2 P. falciparum, IC50 = 0.95 μM), Chagas disease (T. cruzi amastigote, IC50 > 9.5 μM), and leishmaniasis (L. donovani amastigote, IC50 > 9.5 μM) [89] . It was active against NCI-H460 non-small lung cancer cells and neuro-2A mouse neuroblastoma cells (IC50 = 40 and 29 nM, respectively). In 2014, Gademann and colleagues reported the isolation and structure determination of new heterocyclic peptides isolated from Mycrocystis aeruginosa EAWAG 251, Balgacyclamides A (112), B (113) and C (114), Figure 13 [90] . The structures were determined using 2D-NMR methods, mass spectrometry, ozonolysis and hydrolysis by HPLC-MS methods using Marfey’s method and GC-MS. Balgacyclamides A(112) and B(113) displayed micromolar activity (IC50 of 9.0 and 8.2 μM, respectively) against the chloroquine-resistant strain K1 of P. falciparum. The compounds showed low activity against other parasites, IC50 = 59 and 51 μM, respectively, against T. b. rhodesiense STIB 900 and IC50 = 28 μM for 113 against L. donovani MHOM-ET-67/L82. In addition, no activity against L6 rat myoblast cell line was detected. The authors noted that opening of the oxazoline ring in 112 to render 113 did not result in significantly lower bioactivity. Viscosamine (115), Figure 14, is a marine natural product isolated in 2003 by Volk and Köck from the Arctic sponge Haliclona visocsa [91] . The first total synthesis was achieved in nine steps and in 3% overall yield by Timm and Köck [92] . However, the antiparasitic activity of this trimeric 3-alkyl pyridinium alkaloid and analogs were determined by Koning and colleagues in 2011 with an improved synthesis of viscosamine and a tetramer 3-alkyl pyridinium analog [93] . The first total synthesis was achieved following a convergent strategy. Building blocks 116, 117 and 118, were prepared as is showed in Figure 14. Coupling of 116 and 117 to form 119, followed by deprotection of N(Boc)2 and coupling with 118 gave the open precursor 120. After activation and deprotection to prepare the intermediate 121, viscosamine was obtained by cyclization in 3% overall yield. Koning and colleagues performed the total synthesis of viscosamine starting from pyridyl alkanol 122, Figure 14. Iodide 124 was obtained after protection of the nitrogen with a p-methoxybenzyl (PMB) group and reaction with NaI. Dimerization occurred by refluxing 122 and 124, to obtain alcohol 125; then


Review

it was converted to the corresponding iodide 126 and condensed with 122 to give the trimer 127. Deprotection of the PMB group followed by iodination gave the precursor 128 which was cyclized by refluxing in acetonitrile to give viscosamine in eight steps in 21% overall yield. The tetramer analog (132) was obtained in seven steps following a similar sequence as is showed in Figure 14 in 27% overall yield (seven steps). The bioactivities of the macrocycles 115 and 132 were tested in bloodstream form (BF) of T. brucei showing submicromolar activities. The compounds were also tested in two clonal lines of the derived form T. brucei s427: ΔTbAt1 and B48 in order to evaluate if there is cross-resistance. T. brucei s427 ΔTbAt1 line lacks the TbAt1/P2 aminopurine transporter and presents less sensitivity to diamidines and melaminophenyl arsenicals; T. brucei s427 B48 is derived from the ΔTbAt1 form and do not present the activity of the second drug transporter HAPT1 so is highly resistant to diminazene, pentamidine and melaminophenyl arsenicals. There is no substantial difference between the IC50 against the wild form and the two drug resistant lines (Supplementary Table 14) . This result, allowed the authors to suggest that the absorptivity of these compounds is independent of these transporters and that cross resistance seems to not happen. The EC50 values were determined after at least 72 h of drug treatment. The authors also studied the trypanocidal dynamics in more detail, finding that the oligomers presented rapid lysis at 10–15 × EC50. Cytotoxicity was evaluated on human HEK293 cells; the selectivity index is 92–53-fold higher for the parasite than HEK cells in viscosamine and 33–21-folds in the cyclic tetramer. Viscosamine presented submicromolar activity against L. major (IC50 = 0.72 μM, SI = 36) and L. mexicana (IC50 = 0.81 μM, SI = 32). In addition this compound showed relevant antimalarial activity (IC50 = 0.053 μM, SI = 490). The tetramer analog presented similar activity against L. major (IC50 = 0.64 μM, SI = 22) and L. mexicana (IC50 = 1.1 μM, SI = 13). In contrast, 132 showed lower antimalarial activity (IC50 = 0.19 μM) and selectivity (SI = 73). Venturamides A (133) and B (134), Figure 13, were isolated from cyanobacterium Oscillatoria species from Buenaventura Bay. An organic crude extract was subjected to normal phase vacuum liquid chromatography to give nine prefractions. All of them were evaluated for their biological activities and two contiguous fractions showed strong antimalarial activity. These fractions were separate by HPLC-MS and then fractionated by C18 reversed-phase HPLC to give 133 and 134 as optically active white solids [94] . Compounds 133 and 134 were tested for their antimalarial activity against the W2 chloroquine-resistant

10.4155/FMC.14.133


O Br O

O

N

O

O

N H O

N

NH

O HN

H N

N

O

O

H

N

N

NH

HN

S

Venturamide A (133)

N

O

H

S

HN

O

O OH

S

Balgacyclamide C (114)

OH

N H

O

OH

R

O

N

H N

O

Venturamide B (134)

R H

HN

O OH

H N H

O

N

O

O

O

H

NH

O

N

O

N

N

H N

H

S

Balgacyclamide B (113)

S

N H

O

HN

NH

O O

OH

O

S

N

NH

Balgacyclamide A (112)

Symplocamide A (111)

O

N O

H N H

O

HN

O

N H

S

N

NH2

O

H

N

NH

NH2

O

H N H

O O

H N

O

H

O

O

HO

H N

HN

O

O

O

O

Marchantin A (135)

O

Marchantin E (136)

O

OCH3

O O

O HN

OH

NH

O O

O O

O

Valinomycin (137)

O

O

O

O NH

N H OAc OAc

AcO

AcO OAc

BzO

R

O

OH

O

BzO

N

R = OH Ilicifoliunines A (138) R = OAc Aquifoliunine E-I (140)

AcO

OAc

O O

O

OAc OAc

O OAc

OH

AcO

OAc

O

O OAc

O

O O

OAc OBz

OH

O O

O O

N

Ilicifoliunines B (139)

N

Mayteine (141)

Figure 13. Natural products as anti-HAT, antileishmanials and antimalarials.

strain of the malaria parasite and showed in vitro activities against P. falciparum, with IC50 values of 8.2 and 5.2 μM, respectively. Both compounds presented mild cytotoxicity to mammalian Vero cells, with IC50 values

10.4155/FMC.14.133


of 86 and 56 μM, respectively. Additionally, exhibited mild activity against T.cruzi (IC50 = 14.6 μM to 133 and IC50 = 15.8 μM to 134), negligible activity against L. donovani (IC50 > 20 μM to 133 and IC50 > 19 μM



to 134), and to MCF-7 cancer cells (IC50 = 13.1 μM to 133 and IC50 > 54 μM to 134). In 2013, Zhang and colleagues reported a solidphase-based cyclitive cleavage strategy to synthetize azole cyclopeptide derivatives. They employed Kaiser oxime resin which is compatible with t-Boc strategy to elaborate the solid phase synthesis (Supplementary Figure 5) . The procedure was applied to synthetize 133 in 60% yield and more than 98% purity [95] . Natural products and analogs as anti-HAT, antichagasics, antileishmanials & antimalarials

Marchantins are a family of bis(bibenzyls) macrocyclic compounds isolated from the liverwort Marchantina polymorpha [96,41] . Marchantin A (135), Figure 13, presents many biological activities such as antifungal, antitumor, antimicrobial, enzyme inhibitions and others. The biological assays against the cattle pathogen T. b. brucei were reported in 2012 by Otoguro et al. Marchantin A (135) and E (136), Figure 13, present IC50 value of 270 ng/ml (IC50 = 0.61 μM) and 690 ng/ml, respectively [41] . These activities are sixfold and twofold more potent than suramin. Both compound presents slightly cytotoxicity against MRC-5, with a SI = 13 for 135 and SI = 6 for 136. Comparison of 135 and 136 shows that the absence of the metoxyl group in 135 increases almost three times the bioactivity and the selectivity. In the same year, 2012, Olafsdottir and colleagues reported the biological evaluation of 135 against different parasites, see Supplementary Table 17 [97] . The results for T. b. rhodesiense (IC50 = 2.09 μM) are in accordance with the report of Otoguro et al. but the cytotoxicity against the L6 rat cells is higher showing a very low selectivity index (CC50 /IC50 [T. b. rhodesiense] = 3.2). The evaluation against L. donovani showed IC50 = 1.59 μM and low selectivity (SI = 4.2). In addition, 135 exhibited activity against two erythrocytic stage strains of P. falciparum, chloroquine-sensitive NF54 strain (IC50 = 3.41 μM) and chloroquine- and pyrimethamine resistant K1 strain (IC50 = 2.02 μM). Marchantin A was evaluated against three key elongation enzymes involved in the fatty acid biosynthesis pathway (FASII) of P. falciparum. This compound did not inhibit the reductases PfFabI (enoyl-ACPreductase) or PfFabG (α-ketoacyl-ACP reductase) enzymes (IC50 values >100 μM), and only a moderate activity (IC50 = 18.18 μM) was observed against the dehydratase type enzyme, PfFabZ (β-hydroxyacyl-ACP dehydratase). Natural products & analogs as anti-HAT & antileishmanials

The dodeca-depsipeptide valinomycin (137), Figure 13, isolated from Streptomyces sp. several years ago [98] , was


Review

recently evaluated against T. brucei and L. major by Hentschel’s group [99] . The biological assays yielded IC50 < 0.11 against L. major and significant inhibitory activity against T. b. brucei with an IC50 = 0.0032 μM at 48 h and IC50 = 0.0036 μM at 72 h. Valinomycin was found to exhibit general cytotoxicity against 293T kidney epithelial cells (IC50 = 11.24 μM) and J774.1 macrophages (IC50 < 0.10 μM). This macrocycle acts as an ionophore that transports potassium ions to the interior of the cells due to the polar groups are oriented toward the center of the cavity exhibiting only the nonpolar groups to the exterior. Macrocycles as antichagasics & antileishmanials Natural products & analogs

Santos group reported in 2012, two new sesquiterpene pyridine alkaloids, ilicifoliunines A (138) and B (139), along with the known alkaloids aquifoliunine E-I (140) and mayteine (141), Figure 13, isolated from an ethanolic extract of root bark of Maytenus ilicifolia [100] . This plant is native to Brazil and has been employed for its supposed anticancer and contraceptive properties in South America. It was also used in the treatment of gastric ulcers and inflammation, as well as in the reduction of vascular tension. The work was part of a bioprospecting program aimed at the discovery of antiprotozoal agents from the Brazilian flora. The macrocyclic structure is formed by two ester linkages between the sesquiterpene moiety and the pyridine dicarboxylic acids. In previous biological investigations, the group has demonstrated weak and selective effect in a mechanism-based DNA-modifying yeast assay of 140, suggesting its cytotoxic activity [101] . Aquifoliunine E-I (140) was found to have moderate activity against L. chagasi with IC50 = 1.4 μM similar to that the positive control pentamidine (IC50 = 5.1 μM). The IC50 against T cruzi of 140 was 41.9 μM. In the evaluation against T. cruzi the IC50 for the positive control benznidazole was higher (IC50 = 42.7 μM) than in others published assays (see, e.g., Figure 6) . Ilicifoliunines A (138) displayed low antitrypanosomal activity (IC50 = 27.7 μM) and was inactive against both Leishmania species. Ilicifoliunines B (139) and mayteine (141), did not exhibit activity against the protozoan species tested at 100 μM. Synthetic azamacrocycles

Sanchez-Moreno group designed a family of polyamine compounds that consists of a macrocyclic pyridinophane core appended with lateral chains containing additional donor atoms, Figure 15 [102] . The synthesis of the compounds 142, 143, 144 and 145 was performed following the Richman-Atkins

10.4155/FMC.14.133

Review Peña, Scarone & Serra strategy, Figure 15 [103] . For the synthesis of 146, the authors followed Inclán methodology, Figure 15 [104] . These azamacrocycles were evaluated against L. infantum and L. braziliensis using promastigotes, axenic and intracellular amastigotes forms and also include the value of reference drug meglumine antimoniate (Glucantime). For compounds 142, 143, 144, 145, the leishmanicidal activities against L. infantum, in extra- and intracellular forms, were of the same order than the control drug Glucantime (Supplementary Table 15). All compounds are from 14 to 30-fold less toxic (J774–2 macrophages) than Glucantime, thus, SI exceeds that of the reference drug. Similar conclusions were reported from the evaluation against L. braziliensis. The aza-scorpiand like macrocyclic derivatives 145 had the lowest toxicity and the highest SI values in both L. infantum and L. braziliensis. In addition, they determined by pH-metric titration the basicity constants of the polyamines and reported

that all the compounds inhibited the Lehismania sp. Fe-SOD activity showing little inhibition on Mn-SOD and Cu/Zn-SOD of human erythrocytes. The same group proposed the iron superoxide dismutase (Fe-SOD) as a promising target for new drugs against Chagas disease and evaluated the effectiveness of the polyamine compounds as selective inhibitors of Fe-SOD in relation to human Cu, Zn and Mn-SOD. The in vitro antiparasitic activity and toxicity against Vero cells were tested and compared with the values obtained for the reference drug benznidazole (BZN) (Supplementary Table 16 & 17) [105] . The compounds with the best selectivity indexes were selected for performing in vivo trypanocidal activity tests on female BALB/c mice, in the acute and chronic phases. The authors reported that all the tested compounds greatly reduced the number of circulating parasites until day 60 post infection. Furthermore, 142 and 145 reduce the levels of antibodies respect to BZN

First total synthesis of viscosamine. ( ) 10

O

O

N

92%

118

NO2 92%

()

OH

10

() 10

N

() 10

+ N

85% ( )10

( )9

116+117 64%

+ -N Cl

+ N O

+ N O

( )10

( )9

+ -N Br

+ N Cl 120

+ N Br H

+ 118 69%

( )9

+ N O

I

( )9

+ N Cl

98%

OH

( )9

( )9

H2N

+ N I

N(Boc)2

117

N (Boc)2N

Br

116

O

Br

N

85%

O

Cl

O2N

80%

O

() 10

+ N

119

Br

( )9

13 () + N

( )9

J + N Br-

( )9

29% from 120

121

+ N ( )13

+ () N 13

3TFA-

Viscosamine (115)

(a) 1-chloro-2,4-dinitrobenzene (2eq.), MeOH, ∆, 2d; (b) HClaq (2eq.), MeOH, r.t, 12h; (c) HBraq., 110°C, 12h. (d) MCPBA, CH2Cl2, 0°C to rt; (e) NaH (1.2eq.), NH(Boc)2 (1.1eq.), THF-DMF, 80°C, 5h (f) NaI (1.2eq.), butan-2-one, ∆, 2d; (g) AcCl (10eq.), MeOH, rt, 8h; (h), n-BuOH-toluene, Et3N, ∆, 3h; (i) PBr3 (6eq.), CHCl3, 0°C→∆, 1h; (j) NaI (4eq.), butan-2-one, ∆, 4d.

Figure 14. Synthesis of viscosamine and its tetramer analog.

10.4155/FMC.14.133




Review

Synthesis of viscosamine and tetramer analogue. () n OH N

+ N

87%

122

() n X

124. X = I

126. X = I () n X 43% from 127

b

() + nN

() + nN

() n OH

+ N PMB

125. X = OH

() + n N

122, c

PMB

123. X = OH

+ 57% from 125 N PMB

() nX

+ N

95%

PMB

() + nN

() + n N

122, c

+ N () n

() + nN

127 . X = OH

+ ( ) Viscosamine (115) N n n = 13 Counter ions: iodide

128 . X = I

125

() + n N 85%

N 129

() + nN

() n OH 126, c then d 73%

() + nN

() + nN

N

() nX 53% from 130

( )n

(a) PBMCL, KI, ACN. (b) I2, TPP, imidazole, toluene-acetonitrile. (c) acetonitrile, reflux. (d) Pyridine, reflux

+ N + N

130. X = OH 131. X = I

() + n N

+ N

( )n

( )n

132

n = 13 Counter ions: iodide

Figure 14. Synthesis of viscosamine and its tetramer analog (cont.).

and founded that the order of in vivo decreasing activity in the chronic phase was 145 > 142 >> 144 > BZN. They also tested compound 145 with immuno-suppressed mice and performed a histopathological analysis on mice infected with the parasite. Authors highlighted compound 145 as the most effective stopping T. cruzi from setting down as a chronic disease. They reported several experiments to elucidate a possible mechanism of action for the aza-scorpiand like macrocycles such as: nature and percentage of the metabolites excreted by 1H RMN, in order to study effects on the glycolytic pathway; morphological alterations of T. cruzi epimastigotes were analyzed with transmission electron microscopy, in order to study the type of damage caused to the parasite cells and inhibitory effect on T. cruzi Fe-SOD enzyme, to test their potential as enzyme inhibitors. Conclusion & future perspective An important number of macrocyles have been reported as antitrypanosomals and/or antileishmanials during the period 2005–2014. Based on the activity and selectivity against the parasites, some macrocycles that seem to be the most promising in the fight against these neglected diseases are highlighted below. Macrocycles against T. brucei: the antibiotics echinomycin and irumamycin (IC50 14–20 ng/ml, SI > 316); the trimeric 3-alkyl pyridinium alkaloid, viscosamine (submicromolar IC50 against the parasite and 53 < SI < 92); bispolides A1 (IC50 = 67 ng/ml and SI = 57) and B1


(IC50 = 57 ng/ml and SI = 63); the polyazamacrocycle 87 (IC50 against the parasite = 2.8 μM, SI = 64) and some aerucyclamides analogs (micromolar IC50 against the parasites and good selectivity, SI = 82 and 95). However, in vivo studies are needed to corroborate the potential of all of these compounds as antitrypanosomals and synthetic efforts have to be made in the next years for the preparation of echinomycin, irumamycin and bispolides. Malformin C and B2 and the dodecadepsipeptide valinomycin showed nanomolar activity against T. b. brucei, but studies to determine the selectivity of the compounds are needed. Malformins and aerucyclamide analogs present the advantage that their syntheses were investigated using SPPS strategy that accelerates the process; however, in the case of malformins, the yields have to be improved. Macrocycles against T cruzi: the pirazole-containing macrocyclic polyamines 46 and 47 (lower IC50 and higher selectivity against the parasite than benznidazole; order of in vivo activity: 46 > 47 >> benznidazole) and the scorpiand-like azamacrocycles (higher activity against the parasite and lower cytotoxicity against Vero cells than benznidazole). The in vivo studies showed that compound 145 is the most promising compound of this class. Investigations on mechanism of action revealed that the scorpiand-like azamacrocycles are selective inhibitor of T. cruzi Fe-SOD. In addition, synthetic methodologies were investigated and compounds 46 and 47 were prepared in three steps in 55 and 61% overall yields; the azamacrocycle 145 was obtained in six steps in 16%

10.4155/FMC.14.133


Compound

142

143

144

145

146

N NH

NH R

N

H

N

NH2

N

NHR

Synthesis of Azamacrocyles N Br NH2

NH2

TsCl, K2CO3 THF/H2O

N

NHTs

NHTs N

63%

NH2

Br

N

K2CO3,CH3CN reflux 51%

NHTs

NTs

NTs N

NHTs

TREN HBr/HAc PhOH reflux 66%

R1CHO EtOH

N NH

NH

NH N

142

1) NaBH4 2) HCl 37%

N NH

N NH N

N N

NH2 O

NH

143 65% (3 steps) 144 66% (3 steps) 145 76% (3 steps)

NHR

R1

Br

N O

N NTs

NTs N

K2CO3, CH3CN 98%

N2H4 EtOH 90%

N NTs

NTs

HBr/HAc PhOH reflux

N

NHTs

Ts N

63% NH2

N NH

NH N 146

H N NH2

Figure 15. Synthesis and bioactivities of azamacrocycles.

overall yield. Macrocycles against Leishmania sp: the aza-scorpiand like macrocyclic derivatives 142, 143, 144 and 145 present the same order of leishmanicidal activity and higher SI than glucantime. These polyamine compounds are selective inhibitors of the Leishmania sp. Fe-SOD. The macrolides 107, 109 and 110 present micromolar IC50 against L. donovani, but more cytotoxicity studies are needed in order to determine the selectivity of this class of compounds. Several macrocycles: bispolide A1, aerucyclamides analogs, malformins, viscosamine and some macrolides showed satisfactory cytotoxic profiles toward more than one parasite; this may open the possibility for developing new compounds for multidisease intervention in multiendemic areas. Even though the pharmaceutical industry has been cautious about development of macrocyclic drugs, in the last ten years several drug discovery companies have been emerged focusing exclusively on them. This may be a result of the development of new synthetic methodologies that allow the preparation of macrocycles in

10.4155/FMC.14.133


high yields and purities and of the consideration that macrocycles represent a new drug class complementary to the classical small molecules and large biopharmaceuticals. The successful of these enterprises in the research of macrocycles as drugs would encourage academic and industrial laboratories for the development of: new synthetic methodologies to the preparation of complex macrocycles in short times, new tools for the optimization of pharmacokinetics and toxicology of macrocycles and new screening programs of macrocyclic libraries. If those efforts are made it could be possible that in the coming years we will have new macrocyclic drugs to treat neglected diseases on the market. Supplementary data To view the supplementary data that accompany this paper please visit the journal website at: www.future-science.com/doi/full/10.4155/FMC.14.133.

Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial



interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Review

Ethical conduct of research The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Executive summary Macrocycles have relevant bioactivities against parasites which cause neglected tropical diseases • Many macrocyclic natural products and their analogs have demonstrated relevant and selective bioactives against Trypanosome brucei, Trypanosome cruzi and/or Leishmania sp. • Synthetic macrocycles are being reported in the discovery of new compounds against human African trypanosomiasis, Leishmaniasis and Chagas diseases.

Investigations on macrocylization reactions are needed to improve the discovery of bioactives macrocycles • Synthetic routes to the preparation of various complex macrocycles are still a challenge.

Macrocycles need to be incorporated earlier into the drug-discovery process • More screening programs of macrocyclic libraries should be developed as a very useful tool for the aim of fight against neglected diseases.

References

9

Papers of special note have been highlighted as: • of interest; •• of considerable interest

World Health Organization. Leishmaniasis Fact Sheet. www.who.int/mediacentre/factsheets/fs375/en/

10

Alvar J, Vélez ID, Bern C et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE 7(5), e35671 (2012)

11

Report of a meeting of the WHO Expert Committee on the control of Leishmaniases, Geneva (2010). http://whqlibdoc.who.int/trs/WHO_TRS_949_eng.pdf

1

Giordanetto F, Kihlberg J. Macrocyclic drugs and clinical candidates: what can medicinal chemists learn from their properties? J. Med. Chem. 57(2), 278–295 (2014).

••

Excellent review about macrocyclic drugs and clinical candidates.

2

Driggers EM, Hale SP, Lee J, Terrett NK. The exploration of macrocycles for drug discovery: an underexploited structural class. Nat. Rev. Drug Discov. 7(7), 608–624 (2008).

12

Chagas disease (American trypanosomiasis). Fact Sheet No. 340. www.who.int/mediacentre/factsheets/fs340/en/

••

Excellent review about the exploration of macrocycles as drugs.

13

3

Mallinson J, Collins I. Macrocycles in new drug discovery. Future Med. Chem. 4(11), 1409–1438 (2012).

4

World Health Organization. Human African trypanosomiasis (HAT) control. www.afro.who.int/en/clusters-a-programmes/dpc/neglectedtropical-diseases/programme-components/human-africantrypanosomiasis-control.html

Research priorities for Chagas disease, Human African Trypanosomiasis and Leishmaniasis. Technical report of the TDR disease reference group on Chagas disease, human African trypanosomiasis and leishmaniasis. http://apps.who.int/iris/bitstream/10665/77472/1/WHO_ TRS_975_eng.pdf

14

Ishiyama A, Otoguro K, Iwatsuki M et al. In vitro antitrypanosomal activity of five low-MW antibiotics. J. Antibiot. 65(2), 113–114 (2012).

15

Hara M, Takahashi I, Yoshida M et al. DC 107: a novel antitumor antibiotic produced by a Streptomyces sp. J. Antibiot. 42(2), 333–335 (1989).

16

Fukuyama T, Kanda Y. Total synthesis of (+)-leinamycin. J. Am. Chem. Soc. 115(8), 8451–8452 (1993).

17

Corbaz R, Ettlinger L, Gaumann, et al. Stoffwechsel produkte von Actinomyceten. 7. Mitteilung. Echinomycin Helvet. Chim. Acta 40, 199–204, (1957).

18

Otoguro K, Ishiyama A, Namatame M et al. Selective and potent in vitro antitrypanosomal activities of ten microbial metabolites. J. Antibiot. 61(6), 372–378 (2008).

•

Article of interest with information about ten antibiotic as antitrypanosomals.

5

World Health Organization. Trypanosomiasis, human African (sleeping sickness). www.who.int/mediacentre/factsheets/fs259/en/

6

World Health Organization. Human African trypanosomiasis: situation and trends. www.who.int/gho/neglected_diseases/human_african_ trypanosomiasis/en/

7

London Declaration on Neglected Tropical Diseases. (2014). www.who.int/neglected_diseases/London_Declaration_ NTDs.pdf

8

Control and surveillance of human African trypanosomiasis: report of a WHO Expert Committee. http://apps.who.int/iris/ bitstream/10665/95732/1/9789241209847_eng. pdf?ua=1


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Review Peña, Scarone & Serra 19

Sato M, Nakazawa T, Tsunematsu Y, Hotta K, Watanabe K. Echinomycin biosynthesis. Curr. Opin. Chem. Biol. 17(4), 537–545 (2013).

20

Omura S, Tanaka Y, Nakagawa A, Iwai Y, Inoue M, Tanaka H. Irumamycin: a new antibiotic active against phytopathogenic fungi. J. Antibiot. 35(2), 256–257 (1982).

21

22

Akita H, Yamada H, Matsukura, H, Nakata T, Oishi T. Total synthesis of the aglycone of venturicidins A and B-I. Synthesis of C1-C14 segment. Tetrahedron Lett. 31(12), 1731–1734 (1990).

Butler MS, Lim TK, Capon RJ, Hammond LS. The bastadins revisited: new chemistry from the Australian marine sponge ianthellabasta. Aust. J. Chem. 44, 287–296 (1991).

37

Mack MM, Molinskis TF, Buck ED, Pessahs IN. Novel modulators of skeletal muscle calcium channel complex from lanthella basta. J. Biol. Chem. 269(37), 23236–23249 (1994).

38

Calcul L, Inman WD, Morris AA et al. Additional insights on the bastadins: isolation of analogues from the sponge lanthella reticulata and exploration of the oxime configurations. J. Nat. Prod. 73(3), 365–372 (2010).

39

Hashimoto T, Tori M, Asakawa Y, Fukazawa Y. Plagiochins A, B, C, and D, new type of macrocyclicbis(bibenzyls) having a biphenyl linkage between the ortho positions to the benzyl methylenes, from the liverwort Plagiochila acanthophylla subsp. Japonica. Tetrahedron Lett. 28(50), 6295–6298 (1987).

40

Kametler L, Keseru GM, Nogradi M, Mezey-Vandor G, Vermes B, Kajtar-Peredy M. Synthesis of plagiochins A and B, macrocyclicbis(bibenzyl) ethers from Plagiochilla acantophylla. Liebigs Annalen der Chemie 12, 1239–1242. (1992).

41

Otoguro K, Ishiyama A, Iwatsuki M et al. In vitro antitrypanosomal activity of bis(bibenzyls)s and bibenzyls from liverworts against Trypanosoma brucei. J. Nat. Med. 66(2), 377–382 (2012).

23

Akita H, Yamada H, Matsukura H, Nakata T, Oishi, T. Total synthesis of the aglycone of venturicidins A and B- II. Tetrahedron Lett. 31(12), 1735–1738 (1990).

24

Hirose T, Sunazuka T, Yamamoto D et al. Studies toward the total synthesis of irumamycin: stereoselective preparation of the C(15)–C(27) segment via two-directional chain synthesis. Tetrahedron Lett. 48(3), 413–416 (2007).

25

Rhodes A, Fantes KH, Boothroyd B et al. Venturicidin: a new antifungal antibiotic of potential use in agriculture. Nature 192(4806), 952–954 (1961).

26

Omura S, Shimizu H, Iwai Y et al. Am-2604 a: a new antiviral of antibiotic produced by a strain of Streptomyces. J. Antibiot. 35(12), 1632–1637 (1982).

42

Omura S, Otoguro K, Tanaka H. The mode of action of a novel 18-membered macrolide, virustomycin a (am-2604 a), on trichomonasfoetus. J. Antibiot. (Tokyo). 36(12), 1755–1761 (1983).

Kashman Y, Groweiss A, Shmueli U. Latrunculin, a new 2-thiazolidinone macrolide from the marine sponge Latrunculia magnifica. Tetrahedron Lett. 21, 3629–3632 (1980).

43

Amagata T, Johnson TA, Cichewicz RH et al. Interrogating the bioactive pharmacophore of the latrunculin chemotype by investigating the metabolites of two taxonomically unrelated sponges. J. Med. Chem. 51(22), 7234–7242 (2008).

44

White JD, Kawasaki M. Total synthesis of (+)-latrunculin A. J. Am. Chem. Soc. 112, 4991–4993 (1990).

45

Hayot C, Debeir O, Van Ham P et al. Characterization of the activities of actin-affecting drugs on tumor cell migration. Toxicol. Appl. Pharmacol. 211(1), 30–40 (2006).

46

Johnson TA, Sohn J, Inman WD et al. Natural product libraries to accelerate the high-throughput discovery of therapeutic leads. J. Nat. Prod. 74(12), 2545–2555 (2011).

47

Williams BD, Smith AB. Total synthesis of (+)-18-epilatrunculol A. Org. Lett. 15(17), 4584–4587 (2013).

48

Corley DG, Herb R, Moore RE, Scheuer PJ. Laulimalides: new potent cytotoxic macrolides from a marine sponge and a nudibranch predator. J. Nat. Prod. 53(15), 3644–3646 (1988).

49

Quiñoa E, Kakou Y, Crews P. Fijianolides, polyketideheterocycles from a marine sponge. J. Org. Chem. 53(5), 3642–3644 (1988).

50

Mooberry SL, Tien G, Hernandez AH, Plubrukarn A, Davidson BS. Laulimalide and Isolaulimalide, new paclitaxel-like microtubule-stabilizing agents. Cancer Res. 59, 653–660 (1999).

51

Johnson TA, Tenney K, Cichewicz RH et al. The spongederived fijianolide polyketide class: further evaluation of their

27

28

Arcamone F, Bertazzoli C, Ghione M, Scotti T. Melanosporin and elaiophylin, new antibiotics from Streptomyces melanosporus. G. Microbiol. 7, 207–2016 (1959).

29

Kaiser H, Keller-Schierlein W. Metabolites of microorganisms. Part 202. Structure elucidation of elaiophylin: spectroscopic studies and degradation. Helv. Chim. Acta 64(2), 407–424 (1981).

30

31

10.4155/FMC.14.133

Akita H, Yamada H, Matsukura H, Nakata T, Oishi T. Determination of absolute structure of C16-C22 part of irumamycin: chiral synthesis of degradation product. Tetrahedron Lett. 29(49), 6449–6452 (1988).

36

Otoguro K, Iwatsuki M, Ishiyama A et al. In vitro and in vivo antiprotozoal activities of bispolides and their derivatives. J. Antibiot. 63(5), 275–277 (2010). Shoji J, Kozuki S, Okamoto S, Sakazaki R, Otsuka H. Studies on tsushimycin I: isolation and characterization of an acidic acylpeptide containing a new fatty acid. J. Antibiot. 21(7), 439–443 (1968).

32

Shoji J, Otsuka H. Studies on Tsushimycin II: the structures of constituent fatty acids. J. Antibiot. 22(10), 473–479 (1969).

33

Ishiyama A, Otoguro K, Iwatsuki M et al. In vitro and in vivo antitrypanosomal activities of three peptide antibiotics: leucinostatin A and B, alamethicin I and tsushimycin. J. Antibiot. 62(6), 303–308 (2009).

34

Elbein AD. The effect of tsushimycin on the synthesis of lipid-linked saccharides in aorta. BioChem. J. 193(2), 477–484 (1981).

35

Bunkóczi G, Vérstesy L, Sheldrick GM. Structure of the lipopeptide antibiotic tsushimycin. Acta Crystallogr. D. Biol. Crystallogr. D61, 1160–1664 (2005).




in water at physiological pH values. J. Am. Chem. Soc. 126, 823–833 (2004).

structural and cytotoxicity properties. J. Med. Chem. 50(16), 3795–3803 (2007). 52

Ghosh AK, Wang Y. Total synthesis of (-)-laulimalide. J. Am. Chem. Soc. 122(44), 11027–11028 (2000).

53

Gollner A, Mulzer J. Total synthesis of neolaulimalide and isolaulimalide. Org. Lett. 10(20), 4701–4704 (2008).

54

Gollner A, Altmann K-H, Gertsch J, Mulzer J. The laulimalide family: total synthesis and biological evaluation of neolaulimalide, isolaulimalide, laulimalide and a nonnatural analogue. Chem. Eur. J. 15(24), 5979–5997 (2009).

55

56

Luque-Ortega JR, Cruz LJ, Albericio F, Rivas L. The antitumoral depsipeptide IB-01212 kills Leishmania through an apoptosis-like process involving intracellular targets. Mol. Pharm. 7(5), 1608–1617 (2010). Cruz LJ, Francesch A, Cuevas C, Albericio F. Synthesis and structure-activity relationship of cytotoxic marine cyclodepsipeptide IB-01212 analogues. ChemMedChem. 2(7), 1076–1084 (2007).

57

Cruz LJ, Cuevas C, Cañedo LM, Giralt E, Albericio F. Total solid-phase synthesis of marine cyclodepsipeptide IB-01212. J. Org. Chem. 71(9), 3339–3344 (2006).

58

Cruz LJ, Luque-Ortega JR, Rivas L, Albericio F. Kahalalide F, an antitumor depsipeptide in clinical trials, and its analogues as effective antileishmanial agents. Mol. Pharm. 6(3), 813–824 (2009).

59

Jiménez JC, López-Macià A, Gracia C, Varón S, Carrascal M, Caba JC, Royo M, Francesc AM, Cuevas C, Giralt E, Albericio F. Structure-activity relationship of kahalalide F synthetic analogues. J. Med. Chem. 51(16), 4920–4931 (2008).

60

López-Macià A, Jiménez JC, Royo M, Giralt E, Albericio F. Synthesis and structure determination of kahalalide F (1,2). J. Am. Chem. Soc. 123(46), 11398–11401 (2001).

61

dos Santos AR, Falcão CAB, Muzitano MF, Kaiser CR, Rossi-Bergmann B, Férézou J-P. Ivermectin-derived leishmanicidal compounds. Bioorg. Med. Chem. 17(2), 496–502 (2009).

62

Mrozik H, Eskola P, Arison BH, Albers-Schönberg G, Fisher MH. Avermectin aglycons. J. Org. Chem. 47(3), 489–492 (1982).

63

Hanessian H, Dubé D, Hodges PJ. Studies on the deconjugation-epimerization strategy en route to avermectin B1a: problems and solutions. J. Am. Chem. Soc. 109(23), 7063–7067 (1987).

64

65

66

Sánchez-Moreno M, Marín C, Navarro P et al. In vitro and in vivo trypanosomicidal activity of pyrazole-containing macrocyclic and macrobicyclic polyamines: their action on acute and chronic phases of Chagas disease. J. Med. Chem. 55(9), 4231–4243 (2012). Arán VJ, Kumar M, Molina J et al. Synthesis and protonation behavior of 26-membered oxaaza- and polyazamacrocycles containing two heteroaromatic units of 3,5-disubstituted pyrazole or 1-benzylpyrazole: a potentiometric and 1H and 13C NMR study. J. Org. Chem. 64(17), 6135–6146 (1999). Miranda C, Escartí F, Lamarque L et al. New 1H-pyrazolecontaining polyamine receptors able to complex L-glutamate


Review

67

Lamarque L, Navarro P, Miranda C et al. Dopamine interaction in the absence and in the presence of Cu2+ ions with macrocyclic and macrobicyclic polyamines containing pyrazole units: crystal structure of [Cu2(L1)(H2O)2] (ClO4)4 and [Cu2(H−1L3)](ClO4)3·2H2O. J. Am. Chem. Soc. 123, 10560–10570 (2001).

68

Arán VJ, Kumar M, Molina J et al. Synthesis and protonation behavior of 26-membered oxaaza- and polyazamacrocycles containing two heteroaromatic units of 3,5-disubstituted pyrazole or 1-benzylpyrazole: a potentiometric and 1H and 13C NMR study. J. Org. Chem. 64(17), 6135–6146 (1999).

69

Clares MP, Blasco S, Inclán M et al. Manganese(II) complexes of scorpiand-like azamacrocycles as MnSOD mimics. Chem. Commun. 47, 5988–5990 (2011).

70

Portmann C, Blom JF, Gademann K, Jüttner F. Aerucyclamides A and B: isolation and synthesis of toxic ribosomal heterocyclic peptides from the cyanobacterium Microcystis aeruginosa PCC 7806. J. Nat. Prod. 71(7), 1193–1196 (2008).

71

Portmann C, Blom JF, Kaiser M, Brun R, Jüttner F, Gademann K. Isolation of aerucyclamides C and D and structure revision of microcyclamide 7806A: heterocyclic ribosomal peptides from Microcystis aeruginosa PCC 7806 and their antiparasite evaluation. J. Nat. Prod. 71(11), 1891–1896 (2008).

72

Peña S, Scarone L, Manta E et al. Synthesis of a Microcystis aeruginosa predicted metabolite with antimalarial activity. Bioorg. Med. Chem. Lett. 22(15), 4994–4997 (2012).

73

Ziemert N, Ishida K, Quillardet P et al. Microcyclamide biosynthesis in two strains of Microcystis aeruginosa: from structure to genes and vice versa. Appl. Environ. Microbiol. 74(6), 1791–1797 (2008).

74

Peña S, Scarone L, Manta E, Serra G. First total synthesis of aerucyclamide B. Tetrahedron Lett. 54, 2806–2808 (2013).

75

Peña S, Scarone L, Medeiros A, Manta E, Comini M, Serra G. Synthesis of precursors and macrocycle analogs of aerucyclamides as anti-trypanosomal agents. MedChemComm 3(11), 1443–1448 (2012).

76

Peña S, Fagundez C, Medeiros A et al. Synthesis of cyclohexapeptides as antimalarial and anti-trypanosomal agents. MedChemComm 5, 1309-1316 (2014).

77

Otoguro K, Iwatsuki M, Ishiyama A et al. In vitro and in vivo antiprotozoal activities of bispolides and their derivatives. J. Antibiot. 63(5), 275–277 (2010).

78

Nobutaka T, Curtis RW. Isolation and characterization of malformin. Plant Physiol. 36, 30–61 (1961).

79

Bodanszky M, Stahl GL. Structure and synthesis of malformin A. Proc. Nat. Acad. Sci. USA 71(7), 2791–2794 (1974).

80

Kojima Y, Sunazuka T, Nagai K, Julfakyan K. Total synthesis of Malformin C: an Inhibitor of bleomycin- induced G2 arrest. J. Antibiot. (Tokyo) 61(5), 297–302 (2008).

81

Takeuchi S, McLafferty FW, Senn M, Curtis RW. Chemical studies on Malformin-V. * Malformin B1 and B2. Phytochemistry 6(1961), 287–292 (1967).

10.4155/FMC.14.133

Review Peña, Scarone & Serra 82

Anderegg RJ, Biemann K, Buechi G, Cushman M. Malformin C: a new metabolite of Aspergillus niger. J. Am. Chem. Soc. 98(11), 3365–3370 (1976).

83

Kojima Y, Sunazuka T, Nagai K et al. Solid-phase synthesis and biological activity of malformin C and its derivatives. J. Antibiot. 62(12), 681–686 (2009).

84

85

Reid CM, Ebikeme C5, Barrett MP et al. Synthesis and anti-protozoal activity of C2-substituted polyazamacrocycles. Bioorg. Med. Chem. Lett. 18(7), 2455–2458 (2008).

86

Reid CM, Ebikeme C, Barrett MP et al. Synthesis of novel benzamidine- and guanidine-derived polyazamacrocycles: selective anti-protozoal activity for human African trypanosomiasis. Bioorg. Med. Chem. Lett. 18(20), 5399–5401 (2008).

87

Oyelere A K, Chen P C, Guerrant W et al. Non-peptide macrocyclic histone deacetylase inhibitors. J. Med. Chem. 52(2), 456–468 (2009).

•

Article of interest of macrolides as histone deacetylase inhibitors.

88

Guerrant W, Mwakwari SC, Chen PC, Khan SI, Tekwani BL, Oyelere AK. A structure-activity relationship study of the antimalarial and antileishmanial activities of nonpeptide macrocyclic histone deacetylase inhibitors. ChemMedChem 5(8), 1232–1235 (2010).

89

90

Linington RG, Gonzalez J, Ureña L-D, Romero LI, OrtegaBarría E, Gerwick WH. Venturamides A and B: antimalarial constituents of the panamanian marine Cyanobacterium Oscillatoria sp. J. Nat. Prod. 70(3), 397–401 (2007).

95

Tao H, Peng L, Zhang Q. Synthesis of azole-enriched cyclic peptides by a clean solid-phase-based cyclization-cleavage strategy. ACS Comb. Sci. 15(9), 447–451 (2013).

96

Asakawa Y, Toyota M, Bischler H, Campbell EO, Hattori S. Comparative study of chemical constituents of Marchantia species. J. Hatfori Bat. Lub. 57, 383–389 (1984).

97

Jensen S, Omarsdottir S, Bwalya AG, Nielsen MA, Tasdemir D, Olafsdottir ES. Marchantin A: a macrocyclic bisbibenzyl ether, isolated from the liverwort Marchantia polymorpha, inhibits protozoal growth in vitro. Phytomedicine 19(13), 1191–1195 (2012).

98

Brockmann H, Schmidt-Kastner G. Valinomycin I, XXVII. Mitteilung über antibiotikaaus actinomyceten. Chember 88, 57–61 (1955).

99

Pimentel-Elardo SM, Kozytska S, Bugni TS, Ireland CM, Moll H, Hentschel U. Anti-parasitic compounds from Streptomyces sp. strains isolated from Mediterranean sponges. Mar. Drugs 8(2), 373–380 (2010).

100 Santos VAFFM, Regasini LO, Nogueira CR et al. Anti

protozoal sesquiterpene pyridine alkaloids from Maytenus ilicifolia. J. Nat. Prod. 75(5), 991–995 (2012). 101 Corsino J, Bolzani VDS, Pereira AMS, Franca SC, Furlan

M. Bioactive sesquiterpene pyridine alkaloids from Maytenus aquifolium. Phytochemistry 48(1), 137–140 (1998).

Linington RG, Edwards DJ, Shuman CF, McPhail KL, Matainaho T, Gerwick WH. Symplocamide A: a potent cytotoxin and chymotrypsin inhibitor from the marine Cyanobacterium Symploca sp. J. Nat. Prod. 71(1), 22–27 (2008).

102 Marín C, Clares MP, Ramírez-Macías I et al. In vitro activity

Portmann C, Sieber S, Wirthensohn S et al. Balgacyclamides: antiplasmodial heterocyclic peptides from Microcystis aeruguinosa EAWAG 251. J. Nat. Prod. 77(3), 557–562 (2014).

103 Richman JE, Atkins TJ. Nitrogen analogs of crown ethers.

91

Volk CA, Köck M. Viscosamine: the first naturally occurring trimeric 3-alkyl pyridinium alkaloid. Org. Lett. 5(20), 3567–3569 (2003).

92

Timm C, Köck M. First total synthesis of the marine natural product viscosamine. Synthesis 15, 2580–2584 (2006).

93

10.4155/FMC.14.133

Wilson JM, Giordani F, Farrugia LJ, Barrett MP, Robins DJ, Sutherland A. Synthesis, characterization and anti-protozoal activity of carbamate-derived polyazamacrocycles. Org. BioMol. Chem. 5(22), 3651–3656 (2007).

94

Rodenko B, Al-Salabi MI, Teka I a et al. Synthesis of marine-derived 3-alkylpyridinium alkaloids with potent antiprotozoal activity. Med. Chem. Lett. 2(12), 901–906 (2011).


of scorpiand-like azamacrocycle derivatives in promastigotes and intracellular amastigotes of Leishmania infantum and Leishmania braziliensis. Eur. J. Med. Chem. 62, 466–477 (2013). J. Am. Chem. Soc. 96(7), 2268–2270 (1974). 104 Inclán M, Albelda M T, Frías J C, Blasco S, Verdejo B,

Serena C, Salat-Canela C, Díaz M L, García-España A, García-España E. Modulation of DNA binding by reversible metal-controlled molecular reorganizations of scorpiand-like ligands. J. Am. Chem. Soc. 134(23), 9644–9656 (2012). 105 Olmo F, Marín C, Clares MP et al. Scorpiand-like

azamacrocycles prevent the chronic establishment of Trypanosoma cruzi in a murine model. Eur. J. Med. Chem. 70, 189–198 (2013). •

Article of considerable interest about promising compounds as antichagasics.


Therapeutic Potential of Spirooxindoles as Antiviral Agents.

Therapeutic potential of chalcones as cardiovascular agents.

Cytoprotective pyridinol antioxidants as potential therapeutic agents for neurodegenerative and mitochondrial diseases.

Investigation of Stilbenoids as Potential Therapeutic Agents for Rotavirus Gastroenteritis.

Therapeutic potential of hydrazones as anti-inflammatory agents.

Therapeutic potential of psychedelic agents.

Rethinking Nuclear Receptors as Potential Therapeutic Targets for Retinal Diseases.

Phytonutrients as therapeutic agents.

Oligonucleotides as therapeutic agents.

Therapeutic potential of natural pharmacological agents in the treatment of human diseases.

Therapeutic potential of curcumin in digestive diseases.

Potential therapeutic agents for circulatory diseases from Bauhinia glauca Benth.subsp. pernervosa. (Da Ye Guan Men).

Engineered bacteria as therapeutic agents.

Potential future application with therapeutic agents.

Neglected tropical diseases: becoming less neglected.

anti-TNF agents as therapeutic choice in immune-mediated inflammatory diseases: focus on adalimumab.

Selenium compounds as therapeutic agents in cancer.

Therapeutic potential of PACAP for neurodegenerative diseases.

Therapeutic potential of berberine against neurodegenerative diseases.

Tackling neglected diseases.

Neglected diseases, delinquent diagnostics.

Advocacy for identifying certain animal diseases as "neglected".

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Bacteriocins as Potential Anticancer Agents.