Design, synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors
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Data
2020-08-01
Autores
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 [UNESP]
Goulart Trossini, Gustavo Henrique
Bertacine Dias, Marcio Vinicius
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Editor
Elsevier B.V.
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.
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Bioisosterism, Fragment optimization and drug design, MtDHFR, Tuberculosis
Como citar
Bioorganic & Medicinal Chemistry. Oxford: Pergamon-elsevier Science Ltd, v. 28, n. 15, 10 p., 2020.