2. Academic Validation
  3. Design, synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors

Design, synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors

  • Bioorg Med Chem. 2020 Aug 1;28(15):115600. doi: 10.1016/j.bmc.2020.115600.
Thales Kronenberger 1,  Glaucio Monteiro Ferreira 2,  Alfredo Danilo Ferreira de Souza 3,  Soraya da Silva Santos 4,  Antti Poso 1,  João Augusto Ribeiro 5,  Maurício Temotheo Tavares 3,  Fernando Rogério Pavan 6,  Gustavo Henrique Goulart Trossini 7,  Marcio Vinícius Bertacine Dias 8,  Roberto Parise-Filho 9
Affiliations

Affiliations

  • 1 Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Straße 10, DE 72076 Tübingen, Germany; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • 2 Laboratory of Molecular Biology applied to Diagnosis (LBMAD), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
  • 3 Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Faculty of Pharmaceutical Sciences, University of São Paulo, Prof. Lineu Prestes Avenue, 580, Bl.13, São Paulo, SP, Brazil.
  • 4 Laboratory of Design and Synthesis of Chemotherapeutics Potentially Active in Neglected Diseases (LAPEN), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
  • 5 Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
  • 6 Department of Biological Sciences, School of Pharmaceutical Sciences, São Paulo State University, Araraquara (UNESP Araraquara), São Paulo, Brazil.
  • 7 Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, Prof. Lineu Prestes Avenue, 580, Bl.13, São Paulo, SP, Brazil.
  • 8 Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil; Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.
  • 9 Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Faculty of Pharmaceutical Sciences, University of São Paulo, Prof. Lineu Prestes Avenue, 580, Bl.13, São Paulo, SP, Brazil. Electronic address: roberto.parise@usp.br.
PMID: 32631571 DOI: 10.1016/j.bmc.2020.115600
Abstract

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 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 MtDHFR inhibitors and also anti-TB agents.

Keywords

Bioisosterism; Fragment optimization and drug design; MtDHFR; Tuberculosis.

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