A New Series of Leishmanicides

Beveridge, Elizabeth; Goodwin, L. G.; Walls, L. P.

doi:10.1038/182316b0

Cited by 12 publications

(4 citation statements)

References 3 publications

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“…The attention and interest of scientists shifted towards the antileishmanial activities of 8-aminoquinolines ever since a series of 6-methoxy-8-alkylpiperazinoalkylaminoquinoline derivatives showed higher antileishmanial activity than pentavalent antimonials [73].…”

Section: -Hydroxyquinoline Derivatives Have Already Been Synthesizedmentioning

confidence: 99%

“…Methyl substitutions were shown to be more active than the methoxy substitutions, which were investigated in a L. tropicamacrophage model in-vitro. Quinoline ring substitutions with a 6-diethyl-aminohexylamino grouping in the 8-position showed antileishmanial activity superior to meglumine antimoniate [73].…”

Section: -Hydroxyquinoline Derivatives Have Already Been Synthesizedmentioning

confidence: 99%

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Chemotherapy of Leishmaniasis: Past, Present and Future

Mishra¹,

Saxena²,

Singh³

2007

CMC

239

138

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Leishmaniasis is a parasitic disease caused by hemoflagellate, Leishmania spp. The parasite is transmitted by the bite of an infected female phlebotomine sandfly. The disease is prevalent throughout the world and in at least 88 countries. Nearly 25 compounds are reported to have anti-leishmanial effects but not all are in use. The pentavalent antimony compounds have remained mainstay for nearly 75 years. Pentavalent antimony is a prodrug that is reduced by glutathione to active trivalent species catalyzed by thiol-dependent-reductase. However, emergence of resistance led to the use of other compounds--amphotericin B, pentamidine, paromomycin, allopurinol etc. Amphotericin B, an antifungal macrolide polyene is characterized by the hydrophilic polyhydroxyl and hydrophobic polyene faces on it long axis. Presently, it is the only drug with highest cure rate. It acts on membrane sterols resulting in parasite cell lysis. Its lipid formulations have been developed to minimize side effects. Other anti-fungals like ketoconazole, fluconazole and terbinafine are found less effective. Recently, anticancer alkylphosphocholines have been found most effective oral compounds. These act as membrane synthetic ether-lipid analogues, and consist of alkyl chains in the lipid portions. Most promising of these are miltefosine (hexadecylphosphocholine), edelfosine (ET-18-OCH(3)) and ilmofosine (BM 41.440). However, the recent focus has been on identifying newer therapeutic targets in the parasite such as DNA topoisomerases. The present review describes the current understanding of different drugs against leishmaniasis, their chemistry, mode of action and the mechanism of resistance in the parasite. Future perspectives in the area of new anti-leishmanial drug targets are also enumerated. However, due to the vastness of the topic main emphasis is given on visceral leishmaniasis.

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Section: -Hydroxyquinoline Derivatives Have Already Been Synthesizedmentioning

confidence: 99%

Section: -Hydroxyquinoline Derivatives Have Already Been Synthesizedmentioning

confidence: 99%

Chemotherapy of Leishmaniasis: Past, Present and Future

Mishra¹,

Saxena²,

Singh³

2007

CMC

239

138

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“…In 1950's 8-aminoquinoline had shown to have antileishmanial activity and oral availability against L. donovani in the hamster model 80 . Later, 8-[[6-(diethylamino) hexyl]amino]-6-methoxy-4-methylquinoline or WR6026, now called sitamaquine was shown to be 708 times more active than meglumine antimoniate (Glucantime®) against L. donovani in hamsters 81 .…”

Section: Investigational Drugsmentioning

confidence: 99%

Investigational drugs for visceral leishmaniasis

Sundar

Chakravarty

2014

Expert Opinion on Investigational Drugs

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Introduction The armamentarium of antileishmanials is small. It is further being threatened by development of resistance and decreasing sensitivity to the available drugs. Development of newer drugs are sorely needed. Areas covered Literature search on investigational drugs for visceral leishmaniasis (VL) was done on PubMed. Those candidates with at least in vitro and in vivo activity against leishmania species causing VL were reviewed. Among the investigational drugs the nitroimidazole compound fexinidazole is the one of the few drugs which has reached phase II trials. Although the (S)-PA-824 is in phase II trials for the treatment of tuberculosis its R enantiomer has shown good antileishmanial activity. Development of sitamaquin, which has completed phase II studies has been stopped for VL due to its low efficacy. Many novel delivery system and oral formulations of Amphotericin B which are cheap and less toxic are in investigational stages, and will go a long way in improving the treatment of VL. Expert opinion Very few new drugs have reached the clinical stage in the treatment of this neglected tropical disease. Thus, there is an urgent need for support from public private partnerships to ensure that drug candidates are promptly taken forward into development.

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“…In fact, the antileishmanial activity of 8-aminoquinoline was revealed more than fifty years ago when a series of 6-methoxy-8-alkylpiperazinoalkylaminoquinoline derivatives were shown to exhibit both a higher activity than pentavalent antimonials and oral availability against L. donovani in the hamster model (Beveridge et al , 1958). Later, a series of 4-methyl-6-methoxy-8-aminoquinolines called lepidines was shown to be several hundred times more active than pentavalent antimonials in a rodent model (Kinnamon et al , 1978).…”

Section: In Vitro and In Vivo Sitamaquine Activities On Leishmaniasismentioning

confidence: 99%

Sitamaquine as a putative antileishmanial drug candidate: from the mechanism of action to the risk of drug resistance

2011

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Sitamaquine is a 8-aminoquinoline in development for the treatment of visceral leishmaniasis by oral route, no activity being observed on the experimental cutaneous leishmaniasis experimental models. Recent data explain how sitamaquine accumulate in Leishmania parasites, however its molecular targets remain to be identified. An advantage of sitamaquine is its short elimination half-life, preventing a rapid resistance emergence. The antileishmanial action of its metabolites is not known. The selection of a sitamaquine-resistant clone of L. donovani in laboratory and the phase II clinical trials pointing out some adverse effects such as methemoglobinemia and nephrotoxicity are considered for a further development decision.

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A New Series of Leishmanicides

Cited by 12 publications

References 3 publications

Chemotherapy of Leishmaniasis: Past, Present and Future

Chemotherapy of Leishmaniasis: Past, Present and Future

Investigational drugs for visceral leishmaniasis

Sitamaquine as a putative antileishmanial drug candidate: from the mechanism of action to the risk of drug resistance

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