Thiourea-functionalized aminoglutethimide derivatives as anti-leishmanial agents

<b>Aim:</b> We aim to develop new anti-leishmanial agents against <i>Leishmania major</i> and <i>Leishmania tropica</i>. <b>Materials &amp; methods:</b> A total of 23 thiourea derivatives of (±)-aminoglutethimide were synthesized and evaluated for <i>in vitro</i> activity against promastigotes of <i>L. major</i> and <i>L. tropica</i>. <b>Results &amp; conclusion:</b> The <i>N</i>-benzoyl analogue <b>7p</b> was found potent (IC₅₀ = 12.7 μM) against <i>L. major</i> and non toxic to normal cells. The docking studies, indicates that these inhibitors may target folate and glycolytic pathways of the parasite. The <i>N</i>-hexyl compound <b>7v</b> was found strongly active against both species, and lacked cytotoxicity against normal cells, whereas compound <b>7r</b>, with a 3,5-bis-(tri-fluoro-methyl)phenyl unit, was active against <i>Leishmania</i>, but was cytotoxic in nature. Compound <b>7v</b> was thus identified as a hit for further studies. Leishmaniasis is a protozoal disease exists in three forms, visceral, cutaneous and mucocutaneous. This disease is responsible of thousands of deaths annually. 23 (<b>7a–w</b>) new thiourea derivatives of (±)aminoglutethimide (<b>5</b>) were synthesized by using simple single chemical transformation. All compounds were purified by column chromatography and characterized by using IR, UV, NMR and MS data. All synthesized compounds were evaluated for <i>in vitro</i> activity against promastigotes of <i>Leishmania major</i>, and <i>Leishmania tropica</i> as well as BJ human normal cell line. The mechanism of anti-leishmanial activity of these compounds was predicted by docking studies, indicating that these inhibitors may target folate and glycolytic pathways of the parasite. The <i>N</i>-benzoyl analogue <b>7p</b> was found potent (IC₅₀ = 12.7 μM) against <i>L. major</i>, with less activity against <i>L. tropica</i>, and nontoxicity to normal human BJ cells. The <i>N</i>-hexyl compound <b>7v</b> was found strongly active against both species, and lacked cytotoxicity against normal cells, whereas compound <b>7r</b>, which contains a 3,5-bis-(tri-fluoro-methyl)phenyl unit, was active against <i>Leishmania</i>, but was cytotoxic in nature. Compound <b>7v</b> was thus identified as a hit for further studies.