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

Author(s):Show less -

Kronenberger, Thales ^{[1, 2]} ; Ferreira, Glaucio Monteiro ^[3] ; Ferreira de Souza, Alfredo Danilo ^[4] ; Santos, Soraya da Silva ^[5] ; Poso, Antti ^{[1, 2]} ; Ribeiro, Joao Augusto ^[6] ; Tavares, Mauricio Temotheo ^[4] ; Pavan, Fernando Rogerio ^[7] ; Goulart Trossini, Gustavo Henrique ^[8] ; Bertacine Dias, Marcio Vinicius ^{[6, 9]} ; Parise-Filho, Roberto ^[4]

Affiliation

^[1] Univ Eastern Finland, Fac Hlth Sci, Sch Pharm, Kuopio 70211 - Finland

^[2] Univ Hosp Tubingen, Dept Oncol & Pneurnonol, Internal Med 8, Otfried Muller Str 10, DE-72076 Tubingen - Germany

^[3] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, Lab Mol Biol Appl Diag LBMAD, Sao Paulo, SP - Brazil

^[4] Univ Sao Paulo, Fac Pharmaceut Sci, Lab Design & Synth Bioact Subst LAPESSB, Prof Lineu Prestes Ave 580, Bl 13, Sao Paulo, SP - Brazil

^[5] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, Lab Design & Synth Chemotherapeut Potentially Act, Sao Paulo, SP - Brazil

^[6] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Sao Paulo, SP - Brazil

^[7] Sao Paulo State Univ, UNESP Amraquara, Dept Biol Sci, Sch Pharmaceut Sci, Sao Paulo - Brazil

^[8] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, Prof Lineu Prestes Ave 580, Bl 13, Sao Paulo, SP - Brazil

^[9] Univ Warwick, Dept Chem, Coventry CV4 7AL, W Midlands - England

• Document type: Journal article
• Source: Bioorganic & Medicinal Chemistry; v. 28, n. 15 AUG 1 2020.
• Web of Science Citations: 0

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 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)

• FAPESP's process: 13/18160-4 - Novel anticancer candidates: design, synthesis, antitumoral activity and mode of action of novel capsaicinoids and capsinoids analogues
• Grantee: Roberto Parise Filho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/00689-0 - New antineoplastic agents: synthesis, molecular docking and antitumoral activity of capsaicinoids analogues
• Grantee: Roberto Parise Filho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/15906-5 - Fragment based drug discovery (FBDD) applied to two enzymes of folate biosynthetic pathway from Mycobacterium tuberculosis
• Grantee: João Augusto Ribeiro
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/25543-8 - Medicinal Chemistry strategies (LBDD and SBDD) in the search of tripanomatides sirtuin 2 inhibitors
• Grantee: Gustavo Henrique Goulart Trossini
• Support Opportunities: Regular Research Grants