Antileishmanial drug discovery: comprehensive review of the last 10 years

Sangshetti, Jaiprakash N.; Khan, Firoz A. Kalam; Kulkarni, Abhishek; Arote, Rohidas; Patil, Rajendra

doi:10.1039/c5ra02669e

Cited by 133 publications

(99 citation statements)

References 244 publications

(256 reference statements)

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“…meglumine antimoniate and sodium stibogluconate) are old and toxic drugs administered intramuscularly that still constitute, for a large part, the first‐line of intervention. Liposomal amphotericin B, pentamidine salts, paromomycin sulfate, and oral miltefosine are the available second‐line drugs in case of antimonial treatment failure . As for antimonials, these second‐line drugs also have several drawbacks including toxicity, high costs, long‐term treatments and repeated doses, emergence of resistance, and need of constant medical care (which is difficult to afford in areas strongly related to poverty and lack of health services).…”

Section: Introductionmentioning

confidence: 99%

Discovery of benzimidazole‐based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis

et al. 2018

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Chemotherapy is currently the only effective approach to treat all forms of leishmaniasis. However, its effectiveness is severely limited due to high toxicity, long treatment length, drug resistance, or inadequate mode of administration. As a consequence, there is a need to identify new molecular scaffolds and targets as potential therapeutics for the treatment of this disease. We report a small series of 1,2-substituted-1H-benzo[d]imidazole derivatives (9a-d) showing affinity in the submicromolar range (K = 0.15-0.69 μM) toward Leishmania mexicanaCPB2.8ΔCTE, one of the more promising targets for antileishmanial drug design. The compounds confirmed activity in vitro against intracellular amastigotes of Leishmania infantum with the best result being obtained with derivative 9d (IC = 6.8 μM), although with some degree of cytotoxicity (CC = 8.0 μM on PMM and CC = 32.0 μM on MCR-5). In silico molecular docking studies and ADME-Tox properties prediction were performed to validate the hypothesis of the interaction with the intended target and to assess the drug-likeness of these derivatives.

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Section: Introductionmentioning

confidence: 99%

Discovery of benzimidazole‐based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis

et al. 2018

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“…[1] The first-line drugs are antimonial (Sb V ) derivatives (sodium stibogluconate and meglumine antimonate) developed more than 60 years ago that produce serious side-effects. Currently, chemotherapy is limited by the high cost, the emergence of resistance, and the toxicity of the available drugs.…”

Section: Introductionmentioning

confidence: 99%

Ensemble‐based ADME–Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2.8ΔCTE

et al. 2017

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In an effort to identify novel molecular warheads able to inhibit Leishmania mexicana cysteine protease CPB2.8ΔCTE, fused benzo[b]thiophenes and β,β'-triketones emerged as covalent inhibitors binding the active site cysteine residue. Enzymatic screening showed a moderate-to-excellent activity (12%-90% inhibition of the target enzyme at 20 μm). The most promising compounds were selected for further profiling including in vitro cell-based assays and docking studies. Computational data suggest that benzo[b]thiophenes act immediately as non-covalent inhibitors and then as irreversible covalent inhibitors, whereas a reversible covalent mechanism emerged for the 1,3,3'-triketones with a Y-topology. Based on the predicted physicochemical and ADME-Tox properties, compound 2b has been identified as a new drug-like, non-mutagen, non-carcinogen, and non-neurotoxic lead candidate.

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“…157 Another approach examined the role played by known active molecules in medicinal plants traditionally used against leishmaniasis, as well as in documented plants that have yet to be explored. [158][159][160][161] Several active agents from different chemical classes are also reported to have in vitro antileishmanial activity. The more promising candidates appear to be the nitroimidazoles, quinoline scaffold-based derivatives such as indolyl quinoline analogs, naphthoquinones, the cytotoxic drug doxorubicin, and also antimicrobial peptides.…”

Section: Novel Products With Antileishmanial Activity Combined Into Nmentioning

confidence: 99%

Nanostructured delivery systems with improved leishmanicidal activity: a critical review

Bruni¹,

Stella²,

Giraudo³

et al. 2017

IJN

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Leishmaniasis is a vector-borne zoonotic disease caused by protozoan parasites of the genus Leishmania , which are responsible for numerous clinical manifestations, such as cutaneous, visceral, and mucocutaneous leishmaniasis, depending on the site of infection for particular species. These complexities threaten 350 million people in 98 countries worldwide. Amastigotes living within macrophage phagolysosomes are the principal target of antileishmanial treatment, but these are not an easy target as drugs must overcome major structural barriers. Furthermore, limitations on current therapy are related to efficacy, toxicity, and cost, as well as the length of treatment, which can increase parasitic resistance. Nanotechnology has emerged as an attractive alternative as conventional drugs delivered by nanosized carriers have improved bioavailability and reduced toxicity, together with other characteristics that help to relieve the burden of this disease. The significance of using colloidal carriers loaded with active agents derives from the physiological uptake route of intravenous administered nanosystems (the phagocyte system). Nanosystems are thus able to promote a high drug concentration in intracellular mononuclear phagocyte system (MPS)-infected cells. Moreover, the versatility of nanometric drug delivery systems for the deliberate transport of a range of molecules plays a pivotal role in the design of therapeutic strategies against leishmaniasis. This review discusses studies on nanocarriers that have greatly contributed to improving the efficacy of antileishmaniasis drugs, presenting a critical review and some suggestions for improving drug delivery.

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Antileishmanial drug discovery: comprehensive review of the last 10 years

Abstract: This review covers the current aspects of leishmaniasis including marketed drugs, new antileishmanial agents, and possible drug targets of antileishmanial agents.

Cited by 133 publications

References 244 publications

Discovery of benzimidazole‐based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis

Discovery of benzimidazole‐based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis

Ensemble‐based ADME–Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2.8ΔCTE

Nanostructured delivery systems with improved leishmanicidal activity: a critical review

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