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

[ Vol. 20 , Issue. 19 ]

Author(s):

Mayara Barbalho Félix, Rodrigo Santos Aquino de Araújo, Renata Priscila Costa Barros, Carlos Alberto de Simone, Raiza Raianne Luz Rodrigues, Thaís Amanda de Lima Nunes, Klinger Antonio da Franca Rodrigues, Francisco Jaime Bezerra Mendonça Junior, Eugene Muratov, Luciana Scotti and Marcus Tullius Scotti*   Pages 1700 - 1715 ( 16 )

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 the 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.

Keywords:

QSAR, drug design, 2-amino-thiophene, indole, leishmaniasis, Leishmania amazonensis.

Affiliation:

Post-Graduation Program in Natural and Synthetic Bioactive Products, Federal University of Paraiba, João Pessoa/PB, 58051-900, Laboratory of Synthesis and Drug Delivery, State University of Paraiba, João Pessoa/PB, 58071-160, Post-Graduation Program in Natural and Synthetic Bioactive Products, Federal University of Paraiba, João Pessoa/PB, 58051-900, Departamento de Física e Informática, Instituto de Física de São Carlos, Universidade de São Paulo - USP, 13560-970 São Carlos/SP, Universidade Federal do Piauí, Campus Ministro Reis Velloso, 64202- 020, São Benedito, Parnaíba/PI, Universidade Federal do Piauí, Campus Ministro Reis Velloso, 64202- 020, São Benedito, Parnaíba/PI, Universidade Federal do Piauí, Campus Ministro Reis Velloso, 64202- 020, São Benedito, Parnaíba/PI, Post-Graduation Program in Natural and Synthetic Bioactive Products, Federal University of Paraiba, João Pessoa/PB, 58051-900, Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, Post-Graduation Program in Natural and Synthetic Bioactive Products, Federal University of Paraiba, João Pessoa/PB, 58051-900, Post-Graduation Program in Natural and Synthetic Bioactive Products, Federal University of Paraiba, João Pessoa/PB, 58051-900



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