Antileishmanial activity of new thiophene-indole hybrids: Design, synthesis, biological and cytotoxic evaluation, and chemometric studies
| Autor: | Daiana Karla G. Frade, Mayara Barbalho Félix, Marcus Tullius Scotti, Luciana Scotti, Vanessa de Lima Serafim, Francisco Jaime Bezerra Mendonça Junior, Márcia Rosa de Oliveira, Thiago Mendonça de Aquino, Maria do Carmo Alves de Lima, Frederico Fávaro Ribeiro, Klinger Antonio da Franca Rodrigues, Patrícia Lima do Nascimento Néris, Edson Rubhens de Souza |
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| Rok vydání: | 2016 |
| Předmět: |
Indoles
Stereochemistry Clinical Biochemistry Leishmania mexicana Antiprotozoal Agents Pharmaceutical Science Leishmaniasis Cutaneous DNA Fragmentation Thiophenes 01 natural sciences Biochemistry chemistry.chemical_compound Inhibitory Concentration 50 Structure-Activity Relationship Drug Discovery Thiophene Structure–activity relationship Humans Cytotoxicity Molecular Biology IC50 Indole test biology 010405 organic chemistry Organic Chemistry biology.organism_classification Combinatorial chemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Lipophilicity Molecular Medicine DNA fragmentation |
| Zdroj: | Bioorganicmedicinal chemistry. 24(18) |
| ISSN: | 1464-3391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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