Computer-Assisted Design of Thiophene-Indole Hybrids as Leishmanial Agents

Abstract

Background: Chemoinformatics has several applications in the field of drug design, helping to identify new compounds against a range of ailments. Among these are Leishmaniasis, effective treatments for which are currently limited. Objective: To construct new indole 2-aminothiophene molecules using computational tools and to test their effectiveness against Leishmania amazonensis (sp.). Methods: Based on the chemical structure of thiophene-indol hybrids, we built regression models and performed molecular docking, and used these data as bases for design of 92 new molecules with predicted pIC50 and molecular docking. Among these, six compounds were selected for the synthesis and to perform biological assays (leishmanicidal activity and cytotoxicity). Results: The prediction models and docking allowed inference of characteristics that could have positive influences on leishmanicidal activity of the planned compounds. Six compounds were synthesized, one-third of which showed promising antileishmanial activities, with IC50 ranging from 2.16 and 2.97 µM (against promastigote forms) and 0.9 and 1.71 µM (against amastigote forms), with selectivity indexes (SI) of 52 and 75. Conclusion: These results demonstrate the ability of Quantitative Structure-Activity Relationship (QSAR)-based rational drug design to predict molecules with promising leishmanicidal potential, and confirming the potential of thiophene-indole hybrids as potential new leishmanial agents.

Drug Discovery for Cutaneous Leishmaniasis: A Review of Developments in the Past 15 Years

“…Many compound classes have exhibited activity in vitro against promastigotes or amastigotes, including thiophene-indole hybrids [82,83], 2-amino-thiophene derivatives [84], pyrazolothiophene hybrids [85], camphor hydrazone derivatives [86], tetroxanes [87], isoxazole derivatives and tetrahydrofuran neolignans [88], piperine derivatives [89], naphthotriazolyl-4-oxoquinolines [90], furazolidone-based cyclodextrins [91], 2-pyrimidinyl-hydrazone and N-acylhydrazone derivatives [92], piperidine-benzodioxole derivatives [93], and methyl gallate [94]. In vivo studies of these compounds are required to elucidate their activity and safety profiles before clinical development can begin.…”