Identification of antimycobacterial 8-hydroxyquinoline derivatives as in vitro enzymatic inhibitors of Mycobacterium tuberculosis enoyl-acyl carrier protein reductase

• Published in: Bioorganic chemistry 2024-10, Vol.151, p.107705, Article 107705
• Main Authors: Joaquim, Angélica Rocha, Lopes, Marcela Silva, Fortes, Isadora Serraglio, de Bem Gentz, Caroline, de Matos Czeczot, Alexia, Perelló, Marcia Alberton, Roth, Candida Deves, Vainstein, Marilene Henning, Basso, Luiz Augusto, Bizarro, Cristiano Valim, Machado, Pablo, de Andrade, Saulo Fernandes
• Format: Article
• Language: English
• Subjects: 8-Hydroxyquinoline; Antibacterial agents; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Dose-Response Relationship, Drug; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - antagonists & inhibitors; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - metabolism; Enzyme inhibition; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Microbial Sensitivity Tests; Molecular Structure; MtInhA inhibitors; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Oxyquinoline - chemistry; Oxyquinoline - pharmacology; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107705

[Display omitted] •Small library of 8-hydroxyquinoline (8HQ) was evaluated against M. tuberculosis.•9 derivatives were active against the mycobacteria.•5a, 5c, 5d and 5i were active against the mycobacteria and inhibited in vitro MtInhA.•7-substituted 8HQ but not the 5-substituted were able to inhibit in vitro MtInhA.•First report of 8HQ derivatives that inhibit in vitro MtInhA. The increasing prevalence of drug-resistant Mycobacterium tuberculosis strains stimulates the discovery of new drug candidates. Among them are 8-hydroxyquinoline (8HQ) derivatives that exhibited antimicrobial properties. Unfortunately, there is a lack of data assessing possible targets for this class mainly against Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (MtInhA), a validated target in this field. Thus, the main purpose of this study was to identify 8HQ derivatives that are active against M. tuberculosis and MtInhA. Initially, the screening against the microorganism of a small antimicrobial library and its new derivatives that possess some structural similarity with MtInhA inhibitors identified four 7-substituted-8HQ (series 5 – 5a, 5c, 5d and 5i) and four 5-substituted-8HQ active derivatives (series 7 – 7a, 7c, 7d and 7j). In general, the 7-substituted 8-HQs were more potent and, in the enzymatic assay, were able to inhibit MtInhA at low micromolar range. However, the 5-substituted-8-HQs that presented antimycobacterial activity were not able to inhibit MtInhA. These findings indicate the non-promiscuous nature of 8-HQ derivatives and emphasize the significance of selecting appropriate substituents to achieve in vitro enzyme inhibition. Finally, 7-substituted-8HQ series are promising new derivatives for structure-based drug design and further development.