Planejamento, síntese e avaliação do potencial de novos2-aminoselenofenos como candidatos a fármacos leishmanicidas

• Ano de defesa: 2022
• Autor(a) principal: Tibúrcio, Robert da Silva
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal da Paraíba; Brasil; Farmacologia; Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos; UFPB
• Palavras-chave em Português: Reação de Gewald; Bioisosterismo; Hibridização molecular; 2-aminoselenofenos; Atividade leishmanicida; Leishmania spp; Gewald reaction; Bioisosterism; Molecular hybridization; 2-amino selenophenes; Leishmanicidal activity; CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA
• Link de acesso: https://repositorio.ufpb.br/jspui/handle/123456789/23555

Leishmaniasis is a tropical disease caused by protozoa of the genus Leishmania, transmitted by insect phlebotomine and affecting man. The therapy is limited and obsolete with drugs with high toxicity and low therapeutic efficacy, for this reason, there is a growing need for the development and introduction of new drugs. In this context, medicinal chemistry presents as a science that integrates the most diverse areas of the pharmaceutical field, optimizing the planning and synthesis of new bioactive molecules. Previous studies from the Laboratory of Synthesis and Drug Delivery have shown that 2-aminothiophene derivatives are potential candidates for leishmanicidal agents. Thus, and based on the bioisosterism principle, this work aimed to synthesize new 2-aminoselenophenes (2-AS) bioisosteres of 2-aminothiophenes, candidates for leishmanicidal drugs, to evaluate the effects on leishmanicidal activity and toxicity of the bioisosteric substitution of Sulfur by Selenium. Therefore, 12 2-AS derivatives were synthesized based on the Gewald reaction. All compounds were structurally characterized and evaluated for their anti-promastigote activity in vitro against 4 species of the genus Leishmania: Leishmania amazonensis, L. braziliensis, L. infantum, and L. major. It was observed that 4 compounds (6CNSe2, 6CNSe4, 6CNSe9, and 6CNSe11) were capable to inhibit growth at concentrations below 3 μM. Compound 6CNSe2 was the most active of the series, having an IC50 value of 0.16 μM, being lower than the IC50 value of the reference drug Amphotericin B (0.25 μM) against L. braziliensis. All 2-AS derivatives evaluated presented therapeutic safety with selectivity index (SI) values ranging from 20 to 1,181.2. Through comparisons with previous results, it was possible to observe that the bioisosteric modification S ─ Se was favorable for leishmanicidal activity in most compounds. In addition, the influence of bioisosteric modification was positive in the safety profile increasing the SI of candidates for leishmanicidal drugs. These results demonstrate promising the bioisosterism strategy used in the synthesis of 2-aminoselefeno derivatives as potential new leishmanicidal agents.