Synthesis and biological evaluation of a novel series of aryl S,N-ketene acetals as antileishmanial agents

• Published in: Bioorganic & medicinal chemistry letters 2013-07, Vol.23 (13), p.3979-3982
• Main Authors: Suryawanshi, S.N., Kumar, Santosh, Tiwari, Avinash, Shivahare, Rahul, Chhonker, Yashpal Singh, Pandey, Susmita, Shakya, Nishi, Bhatta, Rabi Sankar, Gupta, Suman
• Format: Article
• Language: English
• Subjects: Acetals - chemical synthesis; Acetals - chemistry; Acetals - pharmacology; amastigotes; animal models; Antileishmanial activity; antileishmanials; Antiparasitic Agents - chemical synthesis; Antiparasitic Agents - chemistry; Antiparasitic Agents - pharmacology; Aryl S,N-ketene acetal; chemistry; Dose-Response Relationship, Drug; drugs; Ethylenes - chemical synthesis; Ethylenes - chemistry; Ethylenes - pharmacology; Hamster; hamsters; inhibitory concentration 50; Ketones - chemical synthesis; Ketones - chemistry; Ketones - pharmacology; Leishmania donovani; Leishmania donovani - drug effects; liver microsomes; Molecular Structure; parasites; Parasitic Sensitivity Tests; Pharmacokinetic studies; sodium; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.04.025

A series of aryl S N ketene acetals 7(a–f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. ·A series of trimethoxy aryl S,N-ketene acetals has been synthesized.·Compounds were evaluated against extracellular promastigotes and intracellular amastigotes of Leishmania donovani.·Of the six screened compounds, 7a and 7b have shown interesting antiamastigote activity with IC50s of 1.2 and 2.1μM and selectivity indices of 34 and 30, respectively.·Compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively, against L. donovani/hamster model.·Compound 7b exhibited moderate metabolic stability with three metabolites (M1, M2 and M3) formed by CYP enzyme. A series of aryl S,N-ketene acetals 7(a–f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. All the 6 compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC50 values ranging from 1.2 to 3.5μM and were found promising as compared with reference drugs, sodium stibogluconate (SSG) and paromomycin. On the basis of good selectivity indices (SI), they were further tested for their in vivo potential against L. donovani/hamster model. Two compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively. These compounds were comparable with SSG and superior to paromomycin. Preliminary in vitro metabolic investigations were also performed to assess the metabolic stability and in vitro hepatic intrinsic clearance (Clint) of compound 7b in hamster liver microsomes.