Síntese de novos derivados híbridos contendo 2-aminotiofenos e aminoglicosídeos como potenciais agentes antimicrobianos com ação sob membranas bacterianas, constituintes aniônicos e bombas de efluxo

• Ano de defesa: 2019
• Autor(a) principal: Cruz, Rayssa Marques Duarte da
• Tipo de documento: Tese
• Tipo de acesso: Acesso embargado
• 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: Antibacterianos; 2-aminotiofenos; Aminoglicosídeos; Bombas de efluxo; Composto híbridos; Antibacterial; 2-aminothiophenes; Aminoglycosides; Efflux pumps; Hybrid compounds; CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA
• Link de acesso: https://repositorio.ufpb.br/jspui/handle/123456789/20185

Bacteria are micro-organisms that cause infections, ranging from simple to those that can cause death. The introduction of antibiotics into therapy led to a decline in mortality from these infections, however, the indiscriminate use of antibiotics accelerated the process of natural selection, leading to strains of microorganisms to rapidly developing resistance mechanisms, making many of the antibiotics ineffective, and provoking a need for new antimicrobial agents. In this context, the medicinal chemistry through its tools, allows the drawing and the obtaining of new molecules with potential biological actions. Among these tools, molecular hybridization stands out, being a strategy that combines two or more pharmacophores in the same chemical entity aiming at obtaining molecules with more pronounced biological properties. In this context, this work aimed to plan and synthesize, through the molecular hybridization strategy, new compounds containing as pharmacophores the aminoglycosides and 2-aminothiophenes, which could have their antimicrobial actions potentiated by the action of the compounds under the bacterial membranes , anionic constituents and efflux pumps. The 2-aminothiophenes were synthesized through the Gewald reaction, followed by steps of various reactions of: acetylation, reduction, protection and deprotection, and linker reaction. For the synthesis of the hybrid, a 2-aminothiophene compound was chosen for the coupling reaction with the neamine. 18 compounds were obtained, such as: 17 thiophenes and 1 hybrid neamine + 2- aminothiophene (RMD70). The synthetic routes were simple and effective. The synthetic routes were shown to be simple and effective, resulting in compounds in yields between 8.2% and 89.3%. Some compounds had their cytotoxicity evaluated by the MTT assay, with moderate to low cell viability (64.27 and 82.72%). The compounds had their antibacterial activities evaluated against the different strains of S. aureus (ATCC and mutants that overexpress genes coding for efflux pumps) using two methodologies. Nonody present a direct antibiotic activity, but an antibiotic adjunctive activity. In the methodology A, the compounds RMD70 and 7EST-ACET presented excellent activity, modulating the activity of the antibiotic in 8x. In the methodology B, the 6ME-EST, which modulated the 3 lines studied: 8x for IS-58 (TertK) and SA-1199B (NorA) and 16x for RN-4220 (MrsA). It was observed that the presence of the free amine at C-2, the absence of bulky groups at the C-3 position and in the piperidine amine are important for the biological activity of these compounds. It is concluded that the molecular hybridization performed was a success, resulting in compounds with important antibacterial properties. The further evaluation of the hybrid (and other hybrids), as well as of compounds against other bacterial strains that have other efflux pumps, it is necessary to determine the spectrum of action.