Patent Review
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A comprehensive review of patented antileishmanial agents
On 14 October 2010, the WHO reported that more than 1 billion people worldwide who live in remote rural areas are affected by neglected tropical diseases. Leishmaniasis is caused by protozoa of more than 20 different species in humans. The three major forms of disease are cutaneous, mucocutaneous and visceral leishmaniasis (VL). Cutaneous leishmaniasis causes an ulcer on exposed parts of the body and it was estimated that 0.7–1.3 million cases occur worldwide annually. Mucocutaneous leishmaniasis leads to destruction of mucous membranes in various parts of the body and it was reported that it occurs widely in South America. VL is a deadly disease and it is characterized by various symptoms, such as anemia, fever, fatigue and weight loss. The WHO estimated that 200,000–400,000 cases per annum of VL occur worldwide. Although different drugs and drug combinations are used for leishmaniasis, US FDA-approved drugs are limited. Miltefosine is the only drug approved for all forms of leishmaniasis and AmBisome® is approved for VL. Moreover, the drugs used for leishmaniasis have severe side effects. The article summarizes the patents filed between January 2010 and June 2013 for antileishmanial activity. The article covers only the chemical agents and excludes the vaccines and the peptides. A large number of compounds are filed for antileishmanial activity annually, but only a few are more potent than reference drugs such as miltefosine, pentamidine and metronidazole. In addition, most of the compounds are not as efficient as amphotericin B. Therefore, there is a need for novel compounds that are not only potent than the FDA-approved AmBisome and miltefosine, but are also less toxic and more cost effective in humans. This article provides an eclectic compilation of different classes of compounds that are active against amastigotes (the protozoa form found in humans) for the treatment of leishmaniasis.
Leishmania forms, life cycle & geographical distribution Leishmaniasis is a parasitic infection caused by protozoa that are endemic to tropical countries. There are two parasitic forms: promastigotes and amastigotes. Promastigote forms are transferred to humans during the blood meal taken by insect vectors [1] . These promastigotes are transformed into amastigotes inside the human host. Amastigotes multiply by cell division inside the host cells of different tissues. When a sandfly bites an infected host, amastigotes are transferred back to the insect vector. Amastigotes are transformed into promastigotes in the gut of the vector. These are transferred back to
10.4155/PPA.14.55 © 2015 Future Science Ltd
Murugappan Rama1, Nanjangud Venkatesh Anil Kumar*,1 & Seetharaman Balaji2 1 Department of Chemistry, Manipal Institute of Technology, Manipal University, Manipal 576104, India 2 Department of Biotechnology, Manipal Institute of Technology, Manipal University, Manipal 576104, India *Author for correspondence: [email protected]
humans through the same vector and the parasitic life cycle repeats [2] . Depending on the species and also on the susceptibility of the host, leishmaniasis occurs in three different forms: cutaneous, mucocutaneous and visceral. The most common form is cutaneous leishmaniasis (CL). Based on clinical manifestations, CL is further subdivided into localized CL and diffused CL. CL causes an ulcer and leaves life-long scars with serious disability. It occurs widely in Syria, Saudi Arabia, Afghanistan, Brazil, Peru and Iran. Mucocutaneous leishmaniasis causes skin lesions and destruction of mucous membranes in the nose, throat and mouth. This form is common in Bolivia, Brazil and Peru. Visceral leishmaniasis
Pharm. Pat. Anal. (2015) 4(1), 37–56
part of
ISSN 2046-8954
37
Patent Review Rama, Kumar & Balaji
Key terms Endemic: Endemic regions are localized areas which are peculiar in that locality. Promastigote: Promastigotes (with flagellum), are present in insect vectors and transferred to humans during the blood meal. Amastigote: Amastigote (without flagella) parasites are present in humans. They are relevant for the interpretation of antileishmanial activity assays. Structural scaffolds: Structural scaffolds represent a common base structure that is present in a group of similar structures. Macrophages: During the life cycle of Leishmania, as a part of the host defense against infection, macrophages engulf promastigotes and are transformed into amastigotes.
(VL) is often fatal if not treated. It is characterized by irregular attacks of fever, weight loss, enlargement of the spleen and liver and occasionally causes blindness if it spreads to the eyes. This form is endemic to India, Sudan, Brazil, Bangladesh and Nepal [3] . Among the reported species (∼30) of the genus Leishmania, over 21 species are prominent in humans (Table 1) [4] . Leishmania species that are pathogenic to humans are categorized into ‘old world’ and the ‘new world’ species and they spread through various insect vectors [2,5,6] . Old world species causes various disease forms, such as CL, anthroponotic cutaneous oriental sores, diffused CL, VL or kala-azar, postkala-azar dermal leishmaniasis and infantile VL. The disease forms caused by new world species are VL, CL, mucocutaneous leishmaniasis, localized CL and diffused CL. Leishmaniasis vector control Insect vectors are responsible for VL and are susceptible to malarial insecticides (e.g., dichloro-diphenyl-trichloroethane), as evident from the antimalarial campaign conducted during the 1950s in India. VL completely disappeared due to the use of antimalarial insecticides. The discontinuation of the campaign bought back VL, and resistance of Phlebotomus argentipes to dichlorodiphenyl-trichloroethane was reported in a particular state (Bihar) in India [7] . Therefore, there is a need to prevent such vectors. Treatment The treatment of leishmaniasis differs by species and geographical location. The antileishmanial compounds that target amastigote forms are of particular interest in the treatment of humans. The pentavalent antimonials sodium stibogluconate and meglumine antimoniate have been used as first-line treatments for
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Pharm. Pat. Anal. (2015) 4(1)
leishmaniasis in different geographical locations for more than 70 years. As there was no drug for leishmaniasis until 1996, an alternative treatment was PentostamTM (Glaxo Operations Ltd, Barnard Castle, UK). Only in 1997 was intravenous liposomal amphotericin B (AmBisome®, Gilead Sciences, Inc., CA, USA) approved by the US FDA for the treatment of VL. ThermoMed, (Thermosurgery technologies Inc., AZ, USA) a device that heats the skin with radiowaves, was registered in 2003 for CL [8] . Most of the available drugs have limitations such as ototoxicity and problems with liver function [9,10] . Antimonials have adverse side effects including cardiac arrhythmia and acute pancreatitis. Amphotericin B leads to severe side effects, such as infusion-related fever, chills, hypokalemia (low potassium levels in the blood), nephrotoxicity and anaphylaxis [7] . Researchers have been working to find a better antileishmanial agent with reduced side effects. More recently, miltefosine was approved by the FDA in 2014 for treating all forms of leishmaniasis [11] . Commercially available drugs used for the leishmaniasis are tabulated in Table 2. Antileishmanial agents in patent The literature review revealed that there were 8515 patents granted between 1974 and 2010 having the key word ‘leishmania’. The patented antileishmanial agents from up until 2009 have been reviewed by Monzote and colleagues [20–22] . In addition, these reviews were focused on the patented antileishmanial agents, vaccines and peptides, and so on. In this article, only the granted patents for antileishmanial activity between January 2010 and June 2013 are discussed. This article covers 38 patents as antileishmanial agents by excluding vaccines and peptides. The structural scaffold from the patented antileishmanial compounds is summarized in Supplementary Table 1. An in vitro evaluation of amastigotes and promastigotes has been reported by Sanchez et al. [23] in a patent on oxoisoaporphines derivatives against Leishmania amazonensis, Leishmania infantum, Leishmania braziliensis and Leishmania guyanensis. Among 18 filed compounds, only two (Figure 1) were highly potent for leishmanicidal activity (IC50 :
For reprint orders, please contact [email protected]
A comprehensive review of patented antileishmanial agents
On 14 October 2010, the WHO reported that more than 1 billion people worldwide who live in remote rural areas are affected by neglected tropical diseases. Leishmaniasis is caused by protozoa of more than 20 different species in humans. The three major forms of disease are cutaneous, mucocutaneous and visceral leishmaniasis (VL). Cutaneous leishmaniasis causes an ulcer on exposed parts of the body and it was estimated that 0.7–1.3 million cases occur worldwide annually. Mucocutaneous leishmaniasis leads to destruction of mucous membranes in various parts of the body and it was reported that it occurs widely in South America. VL is a deadly disease and it is characterized by various symptoms, such as anemia, fever, fatigue and weight loss. The WHO estimated that 200,000–400,000 cases per annum of VL occur worldwide. Although different drugs and drug combinations are used for leishmaniasis, US FDA-approved drugs are limited. Miltefosine is the only drug approved for all forms of leishmaniasis and AmBisome® is approved for VL. Moreover, the drugs used for leishmaniasis have severe side effects. The article summarizes the patents filed between January 2010 and June 2013 for antileishmanial activity. The article covers only the chemical agents and excludes the vaccines and the peptides. A large number of compounds are filed for antileishmanial activity annually, but only a few are more potent than reference drugs such as miltefosine, pentamidine and metronidazole. In addition, most of the compounds are not as efficient as amphotericin B. Therefore, there is a need for novel compounds that are not only potent than the FDA-approved AmBisome and miltefosine, but are also less toxic and more cost effective in humans. This article provides an eclectic compilation of different classes of compounds that are active against amastigotes (the protozoa form found in humans) for the treatment of leishmaniasis.
Leishmania forms, life cycle & geographical distribution Leishmaniasis is a parasitic infection caused by protozoa that are endemic to tropical countries. There are two parasitic forms: promastigotes and amastigotes. Promastigote forms are transferred to humans during the blood meal taken by insect vectors [1] . These promastigotes are transformed into amastigotes inside the human host. Amastigotes multiply by cell division inside the host cells of different tissues. When a sandfly bites an infected host, amastigotes are transferred back to the insect vector. Amastigotes are transformed into promastigotes in the gut of the vector. These are transferred back to
10.4155/PPA.14.55 © 2015 Future Science Ltd
Murugappan Rama1, Nanjangud Venkatesh Anil Kumar*,1 & Seetharaman Balaji2 1 Department of Chemistry, Manipal Institute of Technology, Manipal University, Manipal 576104, India 2 Department of Biotechnology, Manipal Institute of Technology, Manipal University, Manipal 576104, India *Author for correspondence: [email protected]
humans through the same vector and the parasitic life cycle repeats [2] . Depending on the species and also on the susceptibility of the host, leishmaniasis occurs in three different forms: cutaneous, mucocutaneous and visceral. The most common form is cutaneous leishmaniasis (CL). Based on clinical manifestations, CL is further subdivided into localized CL and diffused CL. CL causes an ulcer and leaves life-long scars with serious disability. It occurs widely in Syria, Saudi Arabia, Afghanistan, Brazil, Peru and Iran. Mucocutaneous leishmaniasis causes skin lesions and destruction of mucous membranes in the nose, throat and mouth. This form is common in Bolivia, Brazil and Peru. Visceral leishmaniasis
Pharm. Pat. Anal. (2015) 4(1), 37–56
part of
ISSN 2046-8954
37
Patent Review Rama, Kumar & Balaji
Key terms Endemic: Endemic regions are localized areas which are peculiar in that locality. Promastigote: Promastigotes (with flagellum), are present in insect vectors and transferred to humans during the blood meal. Amastigote: Amastigote (without flagella) parasites are present in humans. They are relevant for the interpretation of antileishmanial activity assays. Structural scaffolds: Structural scaffolds represent a common base structure that is present in a group of similar structures. Macrophages: During the life cycle of Leishmania, as a part of the host defense against infection, macrophages engulf promastigotes and are transformed into amastigotes.
(VL) is often fatal if not treated. It is characterized by irregular attacks of fever, weight loss, enlargement of the spleen and liver and occasionally causes blindness if it spreads to the eyes. This form is endemic to India, Sudan, Brazil, Bangladesh and Nepal [3] . Among the reported species (∼30) of the genus Leishmania, over 21 species are prominent in humans (Table 1) [4] . Leishmania species that are pathogenic to humans are categorized into ‘old world’ and the ‘new world’ species and they spread through various insect vectors [2,5,6] . Old world species causes various disease forms, such as CL, anthroponotic cutaneous oriental sores, diffused CL, VL or kala-azar, postkala-azar dermal leishmaniasis and infantile VL. The disease forms caused by new world species are VL, CL, mucocutaneous leishmaniasis, localized CL and diffused CL. Leishmaniasis vector control Insect vectors are responsible for VL and are susceptible to malarial insecticides (e.g., dichloro-diphenyl-trichloroethane), as evident from the antimalarial campaign conducted during the 1950s in India. VL completely disappeared due to the use of antimalarial insecticides. The discontinuation of the campaign bought back VL, and resistance of Phlebotomus argentipes to dichlorodiphenyl-trichloroethane was reported in a particular state (Bihar) in India [7] . Therefore, there is a need to prevent such vectors. Treatment The treatment of leishmaniasis differs by species and geographical location. The antileishmanial compounds that target amastigote forms are of particular interest in the treatment of humans. The pentavalent antimonials sodium stibogluconate and meglumine antimoniate have been used as first-line treatments for
38
Pharm. Pat. Anal. (2015) 4(1)
leishmaniasis in different geographical locations for more than 70 years. As there was no drug for leishmaniasis until 1996, an alternative treatment was PentostamTM (Glaxo Operations Ltd, Barnard Castle, UK). Only in 1997 was intravenous liposomal amphotericin B (AmBisome®, Gilead Sciences, Inc., CA, USA) approved by the US FDA for the treatment of VL. ThermoMed, (Thermosurgery technologies Inc., AZ, USA) a device that heats the skin with radiowaves, was registered in 2003 for CL [8] . Most of the available drugs have limitations such as ototoxicity and problems with liver function [9,10] . Antimonials have adverse side effects including cardiac arrhythmia and acute pancreatitis. Amphotericin B leads to severe side effects, such as infusion-related fever, chills, hypokalemia (low potassium levels in the blood), nephrotoxicity and anaphylaxis [7] . Researchers have been working to find a better antileishmanial agent with reduced side effects. More recently, miltefosine was approved by the FDA in 2014 for treating all forms of leishmaniasis [11] . Commercially available drugs used for the leishmaniasis are tabulated in Table 2. Antileishmanial agents in patent The literature review revealed that there were 8515 patents granted between 1974 and 2010 having the key word ‘leishmania’. The patented antileishmanial agents from up until 2009 have been reviewed by Monzote and colleagues [20–22] . In addition, these reviews were focused on the patented antileishmanial agents, vaccines and peptides, and so on. In this article, only the granted patents for antileishmanial activity between January 2010 and June 2013 are discussed. This article covers 38 patents as antileishmanial agents by excluding vaccines and peptides. The structural scaffold from the patented antileishmanial compounds is summarized in Supplementary Table 1. An in vitro evaluation of amastigotes and promastigotes has been reported by Sanchez et al. [23] in a patent on oxoisoaporphines derivatives against Leishmania amazonensis, Leishmania infantum, Leishmania braziliensis and Leishmania guyanensis. Among 18 filed compounds, only two (Figure 1) were highly potent for leishmanicidal activity (IC50 :
