1. Antileishmanial activity of new thiophene-indole hybrids: Design, synthesis, biological and cytotoxic evaluation, and chemometric studies.
- Author
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Félix MB, de Souza ER, de Lima MDCA, Frade DKG, Serafim VL, Rodrigues KADF, Néris PLDN, Ribeiro FF, Scotti L, Scotti MT, de Aquino TM, Mendonça Junior FJB, and de Oliveira MR
- Subjects
- Antiprotozoal Agents chemistry, DNA Fragmentation drug effects, Drug Discovery, Humans, Indoles chemistry, Inhibitory Concentration 50, Leishmania mexicana genetics, Leishmaniasis, Cutaneous drug therapy, Structure-Activity Relationship, Thiophenes chemistry, Antiprotozoal Agents pharmacology, Indoles pharmacology, Leishmania mexicana drug effects, Thiophenes pharmacology
- Abstract
In the present work, thirty-two hybrid compounds containing cycloalka[b]thiophene and indole moieties (TN5, TN5 1-7, TN6, TN6 1-7, TN7, TN7 1-7, TN8, TN8 1-7) were designed, synthesized and evaluated for their cytotoxic and antileishmanial activity against Leishmania amazonensis promastigotes. More than half of the compounds (18 compounds) exhibited significant antileishmanial activity (IC50 lower than 10.0μg/L), showing better performance than the reference drugs (tri- and penta-valent antimonials). The most active compounds were TN8-7, TN6-1 and TN7 with respective IC50 values of 2.1, 2.3 and 3.2μg/mL. Demonstrating that all of the compounds were less toxic than the reference drugs, even at the highest evaluated concentration (400μg/mL), no compound tested presented human erythrocyte cytotoxicity. Compound TN8-7's effectiveness against a trivalent antimony-resistant culture was demonstrated. It was observed that TN8-7's antileishmanial activity is associated with DNA fragmentation of L. amazonensis promastigotes. Chemometric studies (CPCA, PCA, and PLS) highlight intrinsic solubility/lipophilicity, and compound size and shape as closely related to activity. Our results suggest that hybrid cycloalka[b]thiophene-indole derivatives may be considered as lead compounds for further development of new drugs for the treatment of leishmaniasis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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