Design, synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors. Issue 15 (1st August 2020)

• Record Type: Journal Article
• Authors: Kronenberger, Thales; Ferreira, Glaucio Monteiro; de Souza, Alfredo Danilo Ferreira; da Silva Santos, Soraya; Poso, Antti; Ribeiro, João Augusto; Tavares, Maurício Temotheo; Pavan, Fernando Rogério; Trossini, Gustavo Henrique Goulart; Dias, Marcio Vinícius Bertacine; Parise-Filho, Roberto
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 15(2020)
• Publication Date: 2020-08-01
• Subjects: Bioisosterism -- Fragment optimization and drug design -- MtDHFR -- Tuberculosis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115600
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The enzyme dihydrofolate reductase from M. tuberculosis ( Mt DHFR) 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 Mt DHFR 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 Mt DHFR, with IC50 values ranging from 7 to 40 μM, where compound 4e not only had the best inhibitory activity (IC50 = 7 μM), 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 Mt DHFR inhibitors and also anti-TB agents.