| Texto completo | |
| Autor(es): Mostrar menos - |
Kronenberger, Thales
;
Ferreira, Glaucio Monteiro
;
Ferreira de Souza, Alfredo Danilo
;
Santos, Soraya da Silva
;
Poso, Antti
;
Ribeiro, Joao Augusto
;
Tavares, Mauricio Temotheo
;
Pavan, Fernando Rogerio
;
Goulart Trossini, Gustavo Henrique
;
Bertacine Dias, Marcio Vinicius
;
Parise-Filho, Roberto
Número total de Autores: 11
|
| Tipo de documento: | Artigo Científico |
| Fonte: | Bioorganic & Medicinal Chemistry; v. 28, n. 15, p. 10-pg., 2020-08-01. |
| Resumo | |
The enzyme dihydrofolate reductase from M. tuberculosis (MtDHFR) has a high unexploited potential to be a target for new drugs against tuberculosis (TB), due to its importance for pathogen survival. Preliminary studies have obtained fragment-like molecules with low affinity to MtDHFR which can potentially become lead compounds. Taking this into account, the fragment MB872 was used as a prototype for analogue development by bioisosterism/retro-bioisosterism, which resulted in 20 new substituted 3-benzoic acid derivatives. Compounds were active against MtDHFR, with IC50, values ranging from 7 to 40 mu M, where compound 4e not only had the best inhibitory activity (IC50 = 7 mu M), but also was 71-fold more active than the original fragment MB872. The 4e inhibition kinetics indicated an uncompetitive mechanism, which was supported by molecular modeling which suggested that the compounds can access an independent backpocket from the substrate and competitive inhibitors. Thus, based on these results, substituted 3-benzoic acid derivatives have strong potential to be developed as novel MtDHFR inhibitors and also anti-TB agents. (AU) | |
| Processo FAPESP: | 13/15906-5 - Aplicação da técnica "fragment based drug discovery" (FBDD) para duas enzimas da via de biossíntese de folato em Mycobacterium tuberculosis |
| Beneficiário: | João Augusto Ribeiro |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado |
| Processo FAPESP: | 17/25543-8 - Estratégias de Química Medicinal (LBDD e SBDD) na busca de inibidores de Sirtuína 2 de tripanossomatídeos |
| Beneficiário: | Gustavo Henrique Goulart Trossini |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| Processo FAPESP: | 13/18160-4 - Candidatos a novos antineoplásicos: planejamento, síntese e avaliação da atividade antitumoral de análogos capsaicinóides e capsinóides, com vistas à elucidação do mecanismo de ação |
| Beneficiário: | Roberto Parise Filho |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| Processo FAPESP: | 17/00689-0 - Potenciais agentes antineoplásicos: síntese, docking molecular e avaliação da atividade antitumoral de análogos capsaicinoides |
| Beneficiário: | Roberto Parise Filho |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |