title: Antileishmanial activity of new thiophene-indole hybrids: Design, synthesis, biological and cytotoxic evaluation, and chemometric studies.
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.
authors: Departamento de Biologia Molecular, Centro de Ciências Exatas e da Natureza, Universidade Federal da Paraíba, Campus I, Castelo Branco, João Pessoa, Paraíba CEP 58059-900, Brazil.
authors: Mayara B
authors: MB
authors: Félix
authors: Departamento de Antibióticos, Universidade Federal de Pernambuco, Recife, PE 50670-910, Brazil.
authors: Edson R
authors: ER
authors: de Souza
authors: Departamento de Antibióticos, Universidade Federal de Pernambuco, Recife, PE 50670-910, Brazil.
authors: Maria do C A
authors: MDCA
authors: de Lima
authors: Departamento de Biologia Molecular, Centro de Ciências Exatas e da Natureza, Universidade Federal da Paraíba, Campus I, Castelo Branco, João Pessoa, Paraíba CEP 58059-900, Brazil.
authors: Daiana Karla G
authors: DKG
authors: Frade
authors: Departamento de Biologia Molecular, Centro de Ciências Exatas e da Natureza, Universidade Federal da Paraíba, Campus I, Castelo Branco, João Pessoa, Paraíba CEP 58059-900, Brazil.
authors: Vanessa de L
authors: VL
authors: Serafim
authors: Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, João Pessoa, Paraíba 58059-900, Brazil.
authors: Klinger Antonio da F
authors: KADF
authors: Rodrigues
authors: Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, João Pessoa, Paraíba 58059-900, Brazil.
authors: Patrícia Lima do N
authors: PLDN
authors: Néris
authors: Programa de Pós-Graduação em Inovação Terapêutica, Universidade Federal de Pernambuco, Campus I, Recife, PE 50670-901, Brazil.
authors: Frederico F
authors: FF
authors: Ribeiro
authors: Federal University of Paraíba, Campus I, João Pessoa, PB 58051-970, Brazil.
authors: Luciana
authors: L
authors: Scotti
authors: Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, João Pessoa, Paraíba 58059-900, Brazil.
authors: Marcus T
authors: MT
authors: Scotti
authors: Instituto de Quimica e Biotecnologia, Universidade Federal de Alagoas, Maceió, AL 57072-970, Brazil.
authors: Thiago M
authors: TM
authors: de Aquino
authors: Departamento de Ciências Biológicas, Universidade Estadual da Paraíba, CCBSA, João Pessoa, PB 58070-540, Brazil.
authors: Francisco Jaime B
authors: FJB
authors: Mendonça Junior
authors: Departamento de Biologia Molecular, Centro de Ciências Exatas e da Natureza, Universidade Federal da Paraíba, Campus I, Castelo Branco, João Pessoa, Paraíba CEP 58059-900, Brazil. Electronic address: mrosajp@gmail.com.
authors: Márcia R
authors: MR
authors: de Oliveira
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007894:Leishmania mexicana / Q000187:drug effects* / Q000235:genetics; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000981:Antiprotozoal Agents; D007211:Indoles; D013876:Thiophenes
keywords: 2-Aminothiophene; Chemometric studies; Cytotoxicity; Indole; Leishmania amazonensis; Leishmaniasis