Journal
CHEMICAL & PHARMACEUTICAL BULLETIN
Volume 65, Issue 10, Pages 911-919Publisher
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/cpb.c17-00293
Keywords
thiourea; antileishmanial; in silico evaluation
Funding
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)
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Leishmaniasis is a neglected tropical disease caused by protozoan parasites belonging to the genus Leishmania. Currently, the drugs available for treatment of this disease present high toxicity, along with development of parasite resistance. In order to overcome these problems, efforts have been made to search for new and more effective leishmanicidal drugs. The aim of this study was to synthesize and investigate the leishmanicidal effect of N,N'-disubstituted thioureas against Leishmania amazonensis, with evaluation of their in silico pharmacokinetics and toxicity profiles. Our results showed that different thioureas could be obtained in high to moderate yields using simple reaction conditions. Nine thiourea derivatives (3e, 3i, 3k, 3I, 3p, 3q, 3v, 3x and 3z) were active against parasite promastigotes (IC50 21.48-189.10 mu m), with low cytotoxicity on mice peritoneal macrophages (CC50>200 mu M), except for thiourea 3e (CC50=49.22 mu m). After that, the most promising thioureas (3k, 31, 3p, 3q and 3v) showed IC50 ranging from 70 to 150 mu M against L. amazonensis amastigotes in infected macrophages. Except for thiourea 3p, the leishmanicidal activity of the derivatives were independent of nitric oxide (NO) production. Thioureas 3q and 3v affected promastigotes cell cycle without disturbing the mitochondrial membrane potential. Furthermore, our derivatives showed satisfactory theoretical absorption, distribution, metabolism, excretion, toxicity (ADMET) properties. These data indicate that thiourea derivatives are good candidates as leading compounds for the development of new leishmanicidal drugs.
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