Accepted Manuscript Benzoxazoles and Oxazolopyridines in Medicinal Chemistry Studies Charles S. Demmer , Lennart Bunch PII:
S0223-5234(14)01106-4
DOI:
10.1016/j.ejmech.2014.11.064
Reference:
EJMECH 7557
To appear in:
European Journal of Medicinal Chemistry
Received Date: 22 September 2014 Revised Date:
14 November 2014
Accepted Date: 30 November 2014
Please cite this article as: C.S. Demmer, L. Bunch, Benzoxazoles and Oxazolopyridines in Medicinal Chemistry Studies, European Journal of Medicinal Chemistry (2015), doi: 10.1016/ j.ejmech.2014.11.064. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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*Highlights (for review)
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Crystal structure data and interaction points of benzoxazoles Metabolism of benzoxazoles Medicinal chemistry studies of oxazolopyridines
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Benzoxazoles and Oxazolopyridines in Medicinal
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Chemistry Studies
Charles S. Demmer and Lennart Bunch*
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Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences,
*
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University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark
To whom correspondence should be addressed. (LB), Phone: +45 35336244. Fax: +45
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35336041. E-mail: [email protected]
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Abstract The benzoxazole heterocycle is often found in ligands targeting a plethora of receptors and enzymes. By analysis of published X-ray structures, this review aims at highlighting key
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interactions which the benzoxazole may engage in with its host protein. Furthermore, bioavailability, metabolism and the use of benzoxazole as a bioisostere are discussed. The review is extended to cover structure-activity relationship studies of 2-substituted benzoxazoles, 2-
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substituted oxazolopyridines, and in perspective, application of the recently published novel
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heterocycle oxazolopyrazine in medicinal chemistry studies.
Keywords Drug Design Heterocycle
Oxazolopyrazine
1. Introduction
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Oxazolopyridine
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Benzoxazole
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Planar heterocycles define an important class of chemical entities in life science research.
They are often incorporated as building blocks in medicinal chemistry studies with the purpose of modulating a ligand’s affinity and/or selectivity towards a biological target. Furthermore, they are applied in several other fields of research such as material science and catalysis.
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Amongst the class of planar heterocycles, the benzoxazole parental skeleton is found. The scaffold is a constituent of several natural products (Figure 1) and often incorporated in drug design. In this review, we are will focus on 2-substituted benzoxazoles and their corresponding
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nitrogen analogs (oxazolopyridines) in medicinal chemistry studies. As represented in Figure 2, an increasing number of 2-substituted benzoxazoles have been characterized pharmacologically from 1990 until today. In total, 6418 2-substituted benzoxazoles have been investigated as
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ligands for one or more biological targets, while only 1211 of its nitrogen analogs (the four oxazolopyridines, entry 2-5, Table 1) have been explored. Examples of the use of 2-substituted
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benzoxazoles cover a wide range of research fields, such as antibacterial[1]–[3], antimicrobial[4], antiviral[5], antifungal[3], [6] or antiproliferative[7], [8] activities.
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Boxazomycins A[11]
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Figure 1. Examples of natural products comprising a benzoxazole heterocycle: Calcimycin[9], Nakijinol[10] and
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Figure 2. Total number of instances per year of 2substituted benzoxazoles characterized on biological targets
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from 1960 to 2013.
1000 900 800 700
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600 500
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400 300 200 100
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1962 1965 1968 1971 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 2007 2010 2013
0
Table 1. Number of biologically active 2-substituted
including hydrogena
1 2 3
a
Structure
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Entry
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benzoxazoles and its nitrogen analogs. R= any group
Number of Appearance 6418 733 275
4
125
5
78
Reaxys search performed the 2nd of August 2014.
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2. Binding mode of ligands comprising a benzoxazole The benzoxazole scaffold may engage in a number of distinct energetically favorable interactions with its host protein. Both the 1-oxygen as well as the 3-nitrogen atoms can act as
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hydrogen bond acceptors, and due to its aromatic planar nature both pi-pi stacking and pi-cation interactions are possible. Finally, due to its lipophilic character, hydrophobic interactions with its host protein are possible. We commenced the study by investigating all available x-ray structures
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of 2-substituted benzoxazoles in their respective host proteins. In all five analogs, compounds 1-
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5 (Figure 3) are available from the protein data bank (Figure 4-8).
Figure 3. Biologically active molecules which comprises a
2-substituted benzoxazole or a 2-substituted oxazolo[4,5-
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b]pyridine moiety crystallized in receptors or enzymes
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The protein tyrosine phosphatase (PTP) belongs to a family of enzymes that catalyzes the hydrolysis of phosphorylated tyrosine residues. Amongst them, protein tyrosine phosphatase 1B (PTP1B) is of profound biological importance as it is considered as a negative regulator for
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insulin and leptin.[12] Hence, an important class of drugs for the treatment of type II diabetes and obesity targets this enzyme.[12] Compound 1 is an example of a PTP1B-inhibitor, which comprises a benzoxazole (Figure 3) and inhibits the PTP1B enzyme in the mid-micromolar
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range. A 2D-representation of its binding mode and key interactions with its host protein is depicted in Figure 4.[13] Although the acidic functional groups of 1 engage in extensive
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hydrogen bonding interactions with the polar side chains and backbone of PTP1B, the benzoxazole moiety is surrounded by non-polar amino acids (Figure 4). Not surprisingly, hydrophobic interactions are predominant interactions between the phenyl ring of the benzoxazole and Gly259. Moreover, the crystal structure also reveals that the benzoxazole C4-
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carbon engaged in a weak hydrogen bonding interaction with the backbone carbonyl of Val49.
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Figure 4. Crystal structure of compound 1 with PTP1B
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(PDB code: 4I8N)
A second example of a crystallized protein-ligand complex is compound 2, which is an inhibitor of the channel-activating protease prostasin (CAP1/PRSS8).[14] This enzyme is a key
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player in the severe kidney disease Liddle’s syndrome, which is characterized by malfunction of an epithelial sodium channel (ENaC) due to a genetic mutation. In humans, prostasin is thought
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to be a potential regulator of ENaC function. Compound 2 was successfully crystallized in CAP1/PRSS8 (Figure 5): The nitrogen atom of the oxazole moiety engages in two hydrogen bonds with His57B and Ser195B. Due to the polar receptor residues located in the vicinity of the benzoxazole, no hydrophobic interactions are observed. Moreover, the crystal structure also reveals the presence of explicit water molecules, which would make it interesting to investigate the use of nitrogen analogs of the benzoxazole (oxazolopyridines). On another hand, disruption
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of the water matrix may result in loss of affinity due to the actual hydrogen bonds between the
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Figure 5. Crystal structure of compound 2 with CAP1/PRSS8 (pdb code: 3E0P)
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water molecules (in particular HOH453) and the ligand (Figure 5).
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Transthyretin (TTR) is a protein composed of four distinct subunits and functions as a serum carrier of retinol-binding protein and thyroxine.[15] It is secreted by the liver into the blood stream and therefrom further transported into the cerebrospinal fluid. Protein malfunction or
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mutations within the TTR gene can lead to life-threatening diseases such as transthyretin familial amyloid neuropathy (TTR FAP).[16] A family of 2-substituted benzoxazoles was found to be potent and selective inhibitors of TTR.[17] A hydrogen bond is observed between the phenolic
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alcohol and the SerA117 side chain. Besides from this hydrophobic interactions are predominant,
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involving LysA15, and AlaA108 residues.
Figure 6. X-Ray crystal structure of compound 3 with
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homotetrameric WT-TTR (pdb code: 2QGC)
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Tuberculosis (TB) is a life-threatening disease caused by the bacteria Mycobacterium tuberculosis. Most commonly affected are the lungs. Hence TB is transmitted person to person via air posing a serious health problem. The prevalence is high in poor regions of Africa and
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death numbers are high, due to the lack of treatments.[18] In the year 2010, 1.20–1.45 million people died from TB – the majority from developing countries.[18], [19] Moreover, due to multidrug-resistant tuberculosis (MDR-TB) and extensively-drug-resistant TB (XDR-TB), the
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development of new treatments is essential.[20] Compound 4, a low-nanomolar affinity peptide deformylase inhibitor of Mycobacterium tuberculosis, was reported in 2008 and its crystal
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structure depicted in Figure 7. The crystal structure is a trimer in which the benzoxazole moiety is directed out of the active site. As shown in Figure 7, hydrophobic interactions are observed within a range of 4Ǻ in particular with Leu141 (3.6-3.7 Ǻ) and Val50 (3.6 Ǻ). A hydrogen bond between the nitrogen atom of the benzoxazole and HOH208 (3.0 Ǻ) is also present. Moreover,
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the presence of other water molecules around the phenyl ring might make this inhibitor an interesting target compound for the exploration of oxazolopyridines as isosteres for
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benzoxazoles.
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Figure 7. X-Ray crystal structure of 4 bound to Ni–PDF of
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M. tuberculosis (pdb code: 3E3U)
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The human immunodeficiency virus (HIV) is a retrovirus which infiltrates the immune system eventually leading to its collapse. Todays’ standard treatment is to suppress virus replication by administration of a combination of at least three drugs often referred to “highly active
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antiretroviral therapy” (HAART). A newly synthesized HIV-1 reverse transcriptase inhibitor comprises a benzoxazole heterocycle (compound 5).[21] The inhibitor was co-crystallized with
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two HIV-1 reverse transcriptase mutants (Figure 8). Noteworthy is, that the mutated residues do not engage in direct interactions with the inhibitor (>5 Ǻ). This is an important feature as to avoid loss of drug efficacy as the HIV virus mutates. The HIV inhibitor 5 is buried inside the HIV-1 reverse transcriptase mutants and adopts a butterfly-like conformation.[21] The benzoxazole moiety engages in π-π stacking interactions with both Tyr188 and Tyr181 (dist. 3.63.9 Ǻ, not shown) and moreover, the crystal structure reveals H-π bond interactions with Trp229
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(dist. 3.8 Ǻ, not shown). Classic hydrophobic interactions are present between the side chains of Leu234, Leu100 and Pro95 and the phenyl ring of the heterocycle (dist. 3.7-3.8 Ǻ, not shown). A
oxazolo ring component of the benzoxazole (3.0 Ǻ).
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Figure 8. X-Ray crystal structure of 5 (pdb code: 2YKN)
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water molecule (HOH2162) is making a hydrogen interaction with the oxygen atom of the
Hepatitis is a serious medical condition defined by the inflammation of the liver tissues.
Three different types exist, named hepatitis A, B and C. While vaccines exist for hepatitis A and B, one against the hepatitis C virus (HCV) remains to be developed.[22] Approximately 3% of the world’s population (170 million people) is infected by the HCV.[23] Non-structural proteins 5 (NS5) are viral proteins which are found in the hepatitis C virus[24] and are involved in the replication of the virus RNA. They are divided into two subtype families, NS5A and NS5B. With 12
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the objective of finding new treatments, NS5A and NS5B were pointed out as potential therapeutic targets.[23] Recently, a new quinazolinone-based compound 6 that comprises a oxazolo[4,5-b]pyridine moiety was found to be an inhibitor with low nanomolar efficacy.[25]
following confirmed by X-ray structure (Figure 9).
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The binding mode of compound 6 was first predicted by molecular dynamic protocols and
The crystal structure of the inhibitor 6 with NS5B reveals that the oxazolopyridine
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heterocycle is surrounded by the hydrophobic amino acids Val494, Pro495 and Leu497. Favorable non-conventional hydrogen bonds are observed between the backbone carbonyl of
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Val494 (not shown) and the hydrogen in position 6 of the pyridine ring, and between the side chain of Pro495 and the hydrogen of position 7 (not shown). The two interactions are favorable due to the electronegative character of the nitrogen and oxygen atoms of the oxazolo[4,5-
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b]pyridine heterocycle, which results in a polarization of the C-H bonds of the pyridine ring.
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Figure 9. X-Ray crystal structure of 6 (pdb code: 4JUI)[25]
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3. Bioavailability and metabolism of the benzoxazole heterocycle Looking beyond a ligand’s target affinity, efficacy and selectivity profile, its pharmacokinetic properties are parameters also to be studied and mastered in a successful drug
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discovery program. A detailed study of the metabolism of benzoxazole, 2-methyl benzoxazole and 2-phenyl benzoxazole in rabbits has been conducted (Figure 10).[26] Two groups of metabolites from the benzoxazole and/or the 2-methyl benzoxazole were identified in the rabbits’
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urine. The first originates from the hydrolysis of the oxazolo ring (compounds 7-12). Not surprisingly, phenylglucuronides (compounds 13-15) are also observed as metabolites and
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originate from the glucuronidation of the o-aminophenol. This process assists in the excretion of toxic substances in animals. The second group stems from the oxidation of the benzoxazole (compounds 16 and 17).
On the other hand, when the rabbits were fed with 2-phenyl benzoxazole, this heterocycle was
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not subject to hydrolysis. Only a hydroxy-2-phenylbenzoxazole metabolite could be extracted from the urine, which was thought to be 3-(benzo[d]oxazol-2-yl)phenol (not shown).
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Figure 10. Observed metabolites benzoxazole and/or 2-methyl benzoxazole administered per oral in rabbit.[26]
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In another study, a set of heterocycles were investigated as potential substrates of rabbit liver aldehyde oxidase (Table 2).[27] Amongst the pool of heterocycles, the quinazoline was found to be a good substrate with a Km value in the low micromolar range. The benzoxazole and
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1,2-benzisoxazole were both oxidized at much lower rates. Due to the fact that 2-chloro and 2-
oxidation takes place at the 2-position.
Table 2. Comparison of kinetic data between heterocycles
1
Quinozaline (18)
2
Benzoxazole (19)
3
1,2-Benzisoxazole (20)
5
2-Cl-benzoxazole (21) 2-Me-benzoxazole (22)
(mM)
oxidation rate
0.017
100
2.0
1.5
--
0.3
b
--
b
--
NA NA
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4 a
Compound
Relative
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Entry
Km
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as substrates of aldehyde oxidasea
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methyl benzoxazoles are not substrates for the enzyme, it is reasonable to assume that the
Initial rates were measured at 30°C and pH 6-8. Relative
oxidation rates were measured with a concentration of 0.2
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mM test compound. b No activity.
4. Serving as a bioisostere
The benzoxazole can be regarded as a conformationally restricted N-aryl amide - a functionality which is often incorporated in drugs. Substitution for a benzoxazole provides a conformationally restricted analog which is a well-known strategy to improve ligand affinity
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(reduction in conformational entropic loss). The pharmacokinetic properties of the ligand are also modified and hence this is also a strategy for overcoming problems encountered with bioavailability and/or metabolism.[28] It is indeed true that the benzoxazole cannot engage in
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hydrogen donor activities with the host protein. Thus the strategy of substituting an N-aryl amide for a benzoxazole should only be attempted if it is the hydrogen bond accepting features of the N-aryl amide which is in play. Following this concept the benzoxazole scaffold also offers
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metabolically stable, conformationally restricted analogs of N/O-aryl carbamates, N-aryl urea, and O-aryl esters. The latter functionality is rarely incorporated in drugs due to the fast
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hydrolysis of the aryl ester functionality. Noteworthy is therefore, that the 2-ethoxybenzoxazole proved to be a successful bioisostere of an ethyl benzoate and thus represents an approach to overcome the hydrolysis issue.[29]
chemistry studies
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5. Incorporation of a nitrogen atom into the benzoxazole core structure in medicinal
The replacement with a nitrogen atom(s) for a carbon atom(s) in a heterocycle is an
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attractive strategy in drug discovery for a number of reasons. Firstly, the enhanced polarity will affect the adsorption of the compound and this is at the center of attention for the medicinal
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chemists during the design phase. Secondly, the introduced nitrogen atoms can engage in new hydrogen bond with either a polar receptor residue or a water molecule if present. This may again lead to improved target selectivity. In the following examples of structure-activity relationship studies, the effects of the replacement of the benzoxazole heterocycle by oxazolopyridines are discussed.
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5.1 Example of a positive effect: The fatty acid amide hydrolase (FAAH) inhibitors The endocannabinoid system is defined by a group of neuromodulatory lipids and their receptors, which are found in the brain. It is involved in a wide range of physiological processes
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such as appetite, mood and memory.[30] A breakthrough in its understanding was the isolation of the endogenous fatty acid amides (FAA) named Anamandine.[31] Since then, the enzyme fatty acid amide hydrolase (FAAH) has been a potential therapeutic target for inflammatory pain
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and anxiety.[32], [33] With the objective of discovering new FAAH inhibitors, a set of compounds which comprises the benzoxazole heterocycle and all possible oxazolopyridines were
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synthesized (Table 3). In summary, it was shown that the incorporation of a nitrogen into the benzoxazole core structure resulted in a significant increase of affinity irrespective of the nitrogen atom position (50–200 fold). These results are intriguing as the position of the nitrogen
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does not seem to be critically important for the improvement in affinity.
oxazolopyridines[34]
Compound
1
23
2 3 4 5
R
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Entry
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Table 3. Inhibitors of FAAH comprising benzoxazole and
Ki, nM 370 ± 130
24
2.3 ± 0.1
25
7.2 ± 1.6
26
3.7 ± 1.0
27
11 ± 4.0
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A previous study showed that 3-substituted phenyl propylcarbamates are also FAAH inhibitors. As a part of the structure-activity relationship study, the affinity of a benzoxazole derivate and its nitrogen analogs were compared (Table 4). Accordingly, the use of an
nitrogen atoms resulted in no significant change (Table 4).
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Table 4. 3-Substitued phenyl propylcarbamate as FAAH
FAAH IC50a (µM)
Compd
R
1
28
3.0 ± 0.6
2
29
0.68 ± 0.09
3
30
MGL, % of inhibitionb 26 29
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Entry
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inhibitors[35]
a
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oxazolopyridine increased the inhibitory activity by 4-5 fold, while the incorporation of two
4.5 ± 0.6
18c
Values represent the mean of three independent
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experiments (n=3) performed in duplicate; b Inhibition of enzymatic activity (% of control) at 100 µM (n=2);
c
Lipase.
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Inhibition of human recombinant. MGL: Monoglyceride
5.2 Negative effect
The disease, human African trypanosomiasis (HAT), also referred as sleeping sickness, is
caused by a parasite transported by the Glossina insect, the tsetse fly. The disease is most commonly observed in Equatorial Africa and especially in remote rural areas.[36] In the light of
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finding an irreversible inhibitor of a critical enzyme in the parasite, a preliminary study showed that chloronitrobenzamides exhibit low micromolar inhibitory activity against T. brucei brucei (EC50 =1.5 μM).[37], [38] A further structure-activity relationship led to the synthesis of
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benzoxazole 31, which displays nanomolar inhibitory activity. Interestingly, the use of the
10).[39]
Figure 10. Anti-trypanosomal Activity of 31 and 32 on T.
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brucei brucei
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oxazolo[4,5-b]pyridine heterocycle instead of the benzoxazole led to a loss of affinity (Figure
5.3 No effect
Leukotrienes are a family of inflammatory mediators biosynthesized in leukocytes from
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arachidonic acid by action of the enzyme 5-lipoxygenase (5-LO).[40] A series of aryldienylbenzoxazoles proved to be potent inhibitors of 5-LO (Figure 11, compound 33).[41]
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Interestingly, the use of the oxazolopyridine heterocycle (compound 34) did not lead to an increase in affinity but was equipotent to compound 33. This suggests that the nitrogen atom from the pyridine does not engage in favorable or unfavorable interactions with the enzyme.
Figure 11. Inhibition of 5-lipoxygenase (5-LO) by benzoxazole derivates 33 and 34
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6. Perspectives
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The benzoxazole and its four nitrogen analogs – the oxazolopyridines – find extensive use in drug discovery as they allow the medicinal chemist to fine-tune guest-host interactions and
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furthermore optimize the pharmacokinetic properties of the ligand. It is therefore of particular interest that a synthetic protocol for the oxazolopyrazine scaffold 35 was recently published by us.[42][22] The methodology is based on a robust palladium-catalyzed domino reaction between an amide and 2,3-dichloropyrazine (Scheme 1). An even more detailed fine-tuning of ligand
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properties can now be explored by medicinal chemists.
Scheme 1. Newly developed synthetic route of the
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oxazolopyrazine scaffold (R= aryl)
7. Conclusion
The benzoxazole heterocycle is often incorporated in medicinal chemistry studies but
also found in natural products. By analysis of X-ray structures we have highlighted its potential interactions points with host proteins and discussed the substitution for its nitrogen analogs oxazolopyridines. Furthermore, we have addressed bioavailability/metabolism which highlights 20
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the 2-position as a hot spot, and finally its application as a biosisostere in medicinal chemistry studies.
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8. Acknowledgements
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The authors would like to thank the Lundbeck foundation for financial support.
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S0223-5234(14)01106-4
DOI:
10.1016/j.ejmech.2014.11.064
Reference:
EJMECH 7557
To appear in:
European Journal of Medicinal Chemistry
Received Date: 22 September 2014 Revised Date:
14 November 2014
Accepted Date: 30 November 2014
Please cite this article as: C.S. Demmer, L. Bunch, Benzoxazoles and Oxazolopyridines in Medicinal Chemistry Studies, European Journal of Medicinal Chemistry (2015), doi: 10.1016/ j.ejmech.2014.11.064. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Graphical Abstract (for review) Click here to download high resolution image
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*Highlights (for review)
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Crystal structure data and interaction points of benzoxazoles Metabolism of benzoxazoles Medicinal chemistry studies of oxazolopyridines
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Benzoxazoles and Oxazolopyridines in Medicinal
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Chemistry Studies
Charles S. Demmer and Lennart Bunch*
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Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences,
*
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University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark
To whom correspondence should be addressed. (LB), Phone: +45 35336244. Fax: +45
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35336041. E-mail: [email protected]
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Abstract The benzoxazole heterocycle is often found in ligands targeting a plethora of receptors and enzymes. By analysis of published X-ray structures, this review aims at highlighting key
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interactions which the benzoxazole may engage in with its host protein. Furthermore, bioavailability, metabolism and the use of benzoxazole as a bioisostere are discussed. The review is extended to cover structure-activity relationship studies of 2-substituted benzoxazoles, 2-
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substituted oxazolopyridines, and in perspective, application of the recently published novel
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heterocycle oxazolopyrazine in medicinal chemistry studies.
Keywords Drug Design Heterocycle
Oxazolopyrazine
1. Introduction
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Oxazolopyridine
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Benzoxazole
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Planar heterocycles define an important class of chemical entities in life science research.
They are often incorporated as building blocks in medicinal chemistry studies with the purpose of modulating a ligand’s affinity and/or selectivity towards a biological target. Furthermore, they are applied in several other fields of research such as material science and catalysis.
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Amongst the class of planar heterocycles, the benzoxazole parental skeleton is found. The scaffold is a constituent of several natural products (Figure 1) and often incorporated in drug design. In this review, we are will focus on 2-substituted benzoxazoles and their corresponding
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nitrogen analogs (oxazolopyridines) in medicinal chemistry studies. As represented in Figure 2, an increasing number of 2-substituted benzoxazoles have been characterized pharmacologically from 1990 until today. In total, 6418 2-substituted benzoxazoles have been investigated as
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ligands for one or more biological targets, while only 1211 of its nitrogen analogs (the four oxazolopyridines, entry 2-5, Table 1) have been explored. Examples of the use of 2-substituted
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benzoxazoles cover a wide range of research fields, such as antibacterial[1]–[3], antimicrobial[4], antiviral[5], antifungal[3], [6] or antiproliferative[7], [8] activities.
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Boxazomycins A[11]
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Figure 1. Examples of natural products comprising a benzoxazole heterocycle: Calcimycin[9], Nakijinol[10] and
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Figure 2. Total number of instances per year of 2substituted benzoxazoles characterized on biological targets
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from 1960 to 2013.
1000 900 800 700
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600 500
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400 300 200 100
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1962 1965 1968 1971 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 2007 2010 2013
0
Table 1. Number of biologically active 2-substituted
including hydrogena
1 2 3
a
Structure
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Entry
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benzoxazoles and its nitrogen analogs. R= any group
Number of Appearance 6418 733 275
4
125
5
78
Reaxys search performed the 2nd of August 2014.
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2. Binding mode of ligands comprising a benzoxazole The benzoxazole scaffold may engage in a number of distinct energetically favorable interactions with its host protein. Both the 1-oxygen as well as the 3-nitrogen atoms can act as
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hydrogen bond acceptors, and due to its aromatic planar nature both pi-pi stacking and pi-cation interactions are possible. Finally, due to its lipophilic character, hydrophobic interactions with its host protein are possible. We commenced the study by investigating all available x-ray structures
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of 2-substituted benzoxazoles in their respective host proteins. In all five analogs, compounds 1-
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5 (Figure 3) are available from the protein data bank (Figure 4-8).
Figure 3. Biologically active molecules which comprises a
2-substituted benzoxazole or a 2-substituted oxazolo[4,5-
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b]pyridine moiety crystallized in receptors or enzymes
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The protein tyrosine phosphatase (PTP) belongs to a family of enzymes that catalyzes the hydrolysis of phosphorylated tyrosine residues. Amongst them, protein tyrosine phosphatase 1B (PTP1B) is of profound biological importance as it is considered as a negative regulator for
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insulin and leptin.[12] Hence, an important class of drugs for the treatment of type II diabetes and obesity targets this enzyme.[12] Compound 1 is an example of a PTP1B-inhibitor, which comprises a benzoxazole (Figure 3) and inhibits the PTP1B enzyme in the mid-micromolar
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range. A 2D-representation of its binding mode and key interactions with its host protein is depicted in Figure 4.[13] Although the acidic functional groups of 1 engage in extensive
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hydrogen bonding interactions with the polar side chains and backbone of PTP1B, the benzoxazole moiety is surrounded by non-polar amino acids (Figure 4). Not surprisingly, hydrophobic interactions are predominant interactions between the phenyl ring of the benzoxazole and Gly259. Moreover, the crystal structure also reveals that the benzoxazole C4-
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carbon engaged in a weak hydrogen bonding interaction with the backbone carbonyl of Val49.
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Figure 4. Crystal structure of compound 1 with PTP1B
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(PDB code: 4I8N)
A second example of a crystallized protein-ligand complex is compound 2, which is an inhibitor of the channel-activating protease prostasin (CAP1/PRSS8).[14] This enzyme is a key
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player in the severe kidney disease Liddle’s syndrome, which is characterized by malfunction of an epithelial sodium channel (ENaC) due to a genetic mutation. In humans, prostasin is thought
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to be a potential regulator of ENaC function. Compound 2 was successfully crystallized in CAP1/PRSS8 (Figure 5): The nitrogen atom of the oxazole moiety engages in two hydrogen bonds with His57B and Ser195B. Due to the polar receptor residues located in the vicinity of the benzoxazole, no hydrophobic interactions are observed. Moreover, the crystal structure also reveals the presence of explicit water molecules, which would make it interesting to investigate the use of nitrogen analogs of the benzoxazole (oxazolopyridines). On another hand, disruption
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of the water matrix may result in loss of affinity due to the actual hydrogen bonds between the
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Figure 5. Crystal structure of compound 2 with CAP1/PRSS8 (pdb code: 3E0P)
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water molecules (in particular HOH453) and the ligand (Figure 5).
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Transthyretin (TTR) is a protein composed of four distinct subunits and functions as a serum carrier of retinol-binding protein and thyroxine.[15] It is secreted by the liver into the blood stream and therefrom further transported into the cerebrospinal fluid. Protein malfunction or
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mutations within the TTR gene can lead to life-threatening diseases such as transthyretin familial amyloid neuropathy (TTR FAP).[16] A family of 2-substituted benzoxazoles was found to be potent and selective inhibitors of TTR.[17] A hydrogen bond is observed between the phenolic
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alcohol and the SerA117 side chain. Besides from this hydrophobic interactions are predominant,
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involving LysA15, and AlaA108 residues.
Figure 6. X-Ray crystal structure of compound 3 with
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homotetrameric WT-TTR (pdb code: 2QGC)
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Tuberculosis (TB) is a life-threatening disease caused by the bacteria Mycobacterium tuberculosis. Most commonly affected are the lungs. Hence TB is transmitted person to person via air posing a serious health problem. The prevalence is high in poor regions of Africa and
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death numbers are high, due to the lack of treatments.[18] In the year 2010, 1.20–1.45 million people died from TB – the majority from developing countries.[18], [19] Moreover, due to multidrug-resistant tuberculosis (MDR-TB) and extensively-drug-resistant TB (XDR-TB), the
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development of new treatments is essential.[20] Compound 4, a low-nanomolar affinity peptide deformylase inhibitor of Mycobacterium tuberculosis, was reported in 2008 and its crystal
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structure depicted in Figure 7. The crystal structure is a trimer in which the benzoxazole moiety is directed out of the active site. As shown in Figure 7, hydrophobic interactions are observed within a range of 4Ǻ in particular with Leu141 (3.6-3.7 Ǻ) and Val50 (3.6 Ǻ). A hydrogen bond between the nitrogen atom of the benzoxazole and HOH208 (3.0 Ǻ) is also present. Moreover,
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the presence of other water molecules around the phenyl ring might make this inhibitor an interesting target compound for the exploration of oxazolopyridines as isosteres for
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benzoxazoles.
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Figure 7. X-Ray crystal structure of 4 bound to Ni–PDF of
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M. tuberculosis (pdb code: 3E3U)
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The human immunodeficiency virus (HIV) is a retrovirus which infiltrates the immune system eventually leading to its collapse. Todays’ standard treatment is to suppress virus replication by administration of a combination of at least three drugs often referred to “highly active
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antiretroviral therapy” (HAART). A newly synthesized HIV-1 reverse transcriptase inhibitor comprises a benzoxazole heterocycle (compound 5).[21] The inhibitor was co-crystallized with
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two HIV-1 reverse transcriptase mutants (Figure 8). Noteworthy is, that the mutated residues do not engage in direct interactions with the inhibitor (>5 Ǻ). This is an important feature as to avoid loss of drug efficacy as the HIV virus mutates. The HIV inhibitor 5 is buried inside the HIV-1 reverse transcriptase mutants and adopts a butterfly-like conformation.[21] The benzoxazole moiety engages in π-π stacking interactions with both Tyr188 and Tyr181 (dist. 3.63.9 Ǻ, not shown) and moreover, the crystal structure reveals H-π bond interactions with Trp229
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(dist. 3.8 Ǻ, not shown). Classic hydrophobic interactions are present between the side chains of Leu234, Leu100 and Pro95 and the phenyl ring of the heterocycle (dist. 3.7-3.8 Ǻ, not shown). A
oxazolo ring component of the benzoxazole (3.0 Ǻ).
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Figure 8. X-Ray crystal structure of 5 (pdb code: 2YKN)
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water molecule (HOH2162) is making a hydrogen interaction with the oxygen atom of the
Hepatitis is a serious medical condition defined by the inflammation of the liver tissues.
Three different types exist, named hepatitis A, B and C. While vaccines exist for hepatitis A and B, one against the hepatitis C virus (HCV) remains to be developed.[22] Approximately 3% of the world’s population (170 million people) is infected by the HCV.[23] Non-structural proteins 5 (NS5) are viral proteins which are found in the hepatitis C virus[24] and are involved in the replication of the virus RNA. They are divided into two subtype families, NS5A and NS5B. With 12
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the objective of finding new treatments, NS5A and NS5B were pointed out as potential therapeutic targets.[23] Recently, a new quinazolinone-based compound 6 that comprises a oxazolo[4,5-b]pyridine moiety was found to be an inhibitor with low nanomolar efficacy.[25]
following confirmed by X-ray structure (Figure 9).
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The binding mode of compound 6 was first predicted by molecular dynamic protocols and
The crystal structure of the inhibitor 6 with NS5B reveals that the oxazolopyridine
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heterocycle is surrounded by the hydrophobic amino acids Val494, Pro495 and Leu497. Favorable non-conventional hydrogen bonds are observed between the backbone carbonyl of
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Val494 (not shown) and the hydrogen in position 6 of the pyridine ring, and between the side chain of Pro495 and the hydrogen of position 7 (not shown). The two interactions are favorable due to the electronegative character of the nitrogen and oxygen atoms of the oxazolo[4,5-
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b]pyridine heterocycle, which results in a polarization of the C-H bonds of the pyridine ring.
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Figure 9. X-Ray crystal structure of 6 (pdb code: 4JUI)[25]
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3. Bioavailability and metabolism of the benzoxazole heterocycle Looking beyond a ligand’s target affinity, efficacy and selectivity profile, its pharmacokinetic properties are parameters also to be studied and mastered in a successful drug
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discovery program. A detailed study of the metabolism of benzoxazole, 2-methyl benzoxazole and 2-phenyl benzoxazole in rabbits has been conducted (Figure 10).[26] Two groups of metabolites from the benzoxazole and/or the 2-methyl benzoxazole were identified in the rabbits’
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urine. The first originates from the hydrolysis of the oxazolo ring (compounds 7-12). Not surprisingly, phenylglucuronides (compounds 13-15) are also observed as metabolites and
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originate from the glucuronidation of the o-aminophenol. This process assists in the excretion of toxic substances in animals. The second group stems from the oxidation of the benzoxazole (compounds 16 and 17).
On the other hand, when the rabbits were fed with 2-phenyl benzoxazole, this heterocycle was
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not subject to hydrolysis. Only a hydroxy-2-phenylbenzoxazole metabolite could be extracted from the urine, which was thought to be 3-(benzo[d]oxazol-2-yl)phenol (not shown).
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Figure 10. Observed metabolites benzoxazole and/or 2-methyl benzoxazole administered per oral in rabbit.[26]
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In another study, a set of heterocycles were investigated as potential substrates of rabbit liver aldehyde oxidase (Table 2).[27] Amongst the pool of heterocycles, the quinazoline was found to be a good substrate with a Km value in the low micromolar range. The benzoxazole and
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1,2-benzisoxazole were both oxidized at much lower rates. Due to the fact that 2-chloro and 2-
oxidation takes place at the 2-position.
Table 2. Comparison of kinetic data between heterocycles
1
Quinozaline (18)
2
Benzoxazole (19)
3
1,2-Benzisoxazole (20)
5
2-Cl-benzoxazole (21) 2-Me-benzoxazole (22)
(mM)
oxidation rate
0.017
100
2.0
1.5
--
0.3
b
--
b
--
NA NA
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4 a
Compound
Relative
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Entry
Km
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as substrates of aldehyde oxidasea
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methyl benzoxazoles are not substrates for the enzyme, it is reasonable to assume that the
Initial rates were measured at 30°C and pH 6-8. Relative
oxidation rates were measured with a concentration of 0.2
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mM test compound. b No activity.
4. Serving as a bioisostere
The benzoxazole can be regarded as a conformationally restricted N-aryl amide - a functionality which is often incorporated in drugs. Substitution for a benzoxazole provides a conformationally restricted analog which is a well-known strategy to improve ligand affinity
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(reduction in conformational entropic loss). The pharmacokinetic properties of the ligand are also modified and hence this is also a strategy for overcoming problems encountered with bioavailability and/or metabolism.[28] It is indeed true that the benzoxazole cannot engage in
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hydrogen donor activities with the host protein. Thus the strategy of substituting an N-aryl amide for a benzoxazole should only be attempted if it is the hydrogen bond accepting features of the N-aryl amide which is in play. Following this concept the benzoxazole scaffold also offers
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metabolically stable, conformationally restricted analogs of N/O-aryl carbamates, N-aryl urea, and O-aryl esters. The latter functionality is rarely incorporated in drugs due to the fast
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hydrolysis of the aryl ester functionality. Noteworthy is therefore, that the 2-ethoxybenzoxazole proved to be a successful bioisostere of an ethyl benzoate and thus represents an approach to overcome the hydrolysis issue.[29]
chemistry studies
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5. Incorporation of a nitrogen atom into the benzoxazole core structure in medicinal
The replacement with a nitrogen atom(s) for a carbon atom(s) in a heterocycle is an
EP
attractive strategy in drug discovery for a number of reasons. Firstly, the enhanced polarity will affect the adsorption of the compound and this is at the center of attention for the medicinal
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chemists during the design phase. Secondly, the introduced nitrogen atoms can engage in new hydrogen bond with either a polar receptor residue or a water molecule if present. This may again lead to improved target selectivity. In the following examples of structure-activity relationship studies, the effects of the replacement of the benzoxazole heterocycle by oxazolopyridines are discussed.
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5.1 Example of a positive effect: The fatty acid amide hydrolase (FAAH) inhibitors The endocannabinoid system is defined by a group of neuromodulatory lipids and their receptors, which are found in the brain. It is involved in a wide range of physiological processes
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such as appetite, mood and memory.[30] A breakthrough in its understanding was the isolation of the endogenous fatty acid amides (FAA) named Anamandine.[31] Since then, the enzyme fatty acid amide hydrolase (FAAH) has been a potential therapeutic target for inflammatory pain
SC
and anxiety.[32], [33] With the objective of discovering new FAAH inhibitors, a set of compounds which comprises the benzoxazole heterocycle and all possible oxazolopyridines were
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synthesized (Table 3). In summary, it was shown that the incorporation of a nitrogen into the benzoxazole core structure resulted in a significant increase of affinity irrespective of the nitrogen atom position (50–200 fold). These results are intriguing as the position of the nitrogen
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does not seem to be critically important for the improvement in affinity.
oxazolopyridines[34]
Compound
1
23
2 3 4 5
R
AC C
Entry
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Table 3. Inhibitors of FAAH comprising benzoxazole and
Ki, nM 370 ± 130
24
2.3 ± 0.1
25
7.2 ± 1.6
26
3.7 ± 1.0
27
11 ± 4.0
17
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A previous study showed that 3-substituted phenyl propylcarbamates are also FAAH inhibitors. As a part of the structure-activity relationship study, the affinity of a benzoxazole derivate and its nitrogen analogs were compared (Table 4). Accordingly, the use of an
nitrogen atoms resulted in no significant change (Table 4).
SC
Table 4. 3-Substitued phenyl propylcarbamate as FAAH
FAAH IC50a (µM)
Compd
R
1
28
3.0 ± 0.6
2
29
0.68 ± 0.09
3
30
MGL, % of inhibitionb 26 29
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Entry
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inhibitors[35]
a
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oxazolopyridine increased the inhibitory activity by 4-5 fold, while the incorporation of two
4.5 ± 0.6
18c
Values represent the mean of three independent
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experiments (n=3) performed in duplicate; b Inhibition of enzymatic activity (% of control) at 100 µM (n=2);
c
Lipase.
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Inhibition of human recombinant. MGL: Monoglyceride
5.2 Negative effect
The disease, human African trypanosomiasis (HAT), also referred as sleeping sickness, is
caused by a parasite transported by the Glossina insect, the tsetse fly. The disease is most commonly observed in Equatorial Africa and especially in remote rural areas.[36] In the light of
18
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finding an irreversible inhibitor of a critical enzyme in the parasite, a preliminary study showed that chloronitrobenzamides exhibit low micromolar inhibitory activity against T. brucei brucei (EC50 =1.5 μM).[37], [38] A further structure-activity relationship led to the synthesis of
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benzoxazole 31, which displays nanomolar inhibitory activity. Interestingly, the use of the
10).[39]
Figure 10. Anti-trypanosomal Activity of 31 and 32 on T.
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brucei brucei
SC
oxazolo[4,5-b]pyridine heterocycle instead of the benzoxazole led to a loss of affinity (Figure
5.3 No effect
Leukotrienes are a family of inflammatory mediators biosynthesized in leukocytes from
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arachidonic acid by action of the enzyme 5-lipoxygenase (5-LO).[40] A series of aryldienylbenzoxazoles proved to be potent inhibitors of 5-LO (Figure 11, compound 33).[41]
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Interestingly, the use of the oxazolopyridine heterocycle (compound 34) did not lead to an increase in affinity but was equipotent to compound 33. This suggests that the nitrogen atom from the pyridine does not engage in favorable or unfavorable interactions with the enzyme.
Figure 11. Inhibition of 5-lipoxygenase (5-LO) by benzoxazole derivates 33 and 34
19
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6. Perspectives
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The benzoxazole and its four nitrogen analogs – the oxazolopyridines – find extensive use in drug discovery as they allow the medicinal chemist to fine-tune guest-host interactions and
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furthermore optimize the pharmacokinetic properties of the ligand. It is therefore of particular interest that a synthetic protocol for the oxazolopyrazine scaffold 35 was recently published by us.[42][22] The methodology is based on a robust palladium-catalyzed domino reaction between an amide and 2,3-dichloropyrazine (Scheme 1). An even more detailed fine-tuning of ligand
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properties can now be explored by medicinal chemists.
Scheme 1. Newly developed synthetic route of the
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oxazolopyrazine scaffold (R= aryl)
7. Conclusion
The benzoxazole heterocycle is often incorporated in medicinal chemistry studies but
also found in natural products. By analysis of X-ray structures we have highlighted its potential interactions points with host proteins and discussed the substitution for its nitrogen analogs oxazolopyridines. Furthermore, we have addressed bioavailability/metabolism which highlights 20
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the 2-position as a hot spot, and finally its application as a biosisostere in medicinal chemistry studies.
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8. Acknowledgements
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The authors would like to thank the Lundbeck foundation for financial support.
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