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

被引:1
|
作者
Joaquim, Angelica Rocha [1 ,2 ,3 ]
Lopes, Marcela Silva [1 ,2 ]
Fortes, Isadora Serraglio [1 ,2 ]
Gentz, Caroline de Bem [1 ,2 ]
Czeczot, Alexia de Matos [5 ,6 ]
Perello, Marcia Alberton [5 ]
Roth, Candida Deves [5 ]
Vainstein, Marilene Henning [7 ]
Basso, Luiz Augusto [5 ,6 ]
Bizarro, Cristiano Valim [5 ,8 ]
Machado, Pablo [5 ,6 ,8 ]
de Andrade, Saulo Fernandes [1 ,2 ,4 ]
机构
[1] Univ Fed Rio Grande Do Sul, Pharmaceut Synth Grp PHARSG, BR-90610000 Porto Alegre, RS, Brazil
[2] Univ Fed Rio Grande Do Sul, Programa Posgrad Ciencias Farmaceut, BR-90610000 Porto Alegre, RS, Brazil
[3] Univ Fed Santa Maria, Ctr Ciencias Saude, BR-97105900 Santa Maria, RS, Brazil
[4] Univ Fed Rio Grande Do Sul, Programa Posgrad Microbiol Agr & Ambiente, BR-90035003 Porto Alegre, RS, Brazil
[5] Pontificia Univ Catolica Rio Grande Do Sul, Ctr Pesquisas Biol Mol & Func, Inst Nacl Ciencia & Tecnol TB, BR-90616900 Porto Alegre, RS, Brazil
[6] Pontificia Univ Catol Rio Grande Do Sul, Programa Posgrad Med & Ciencias Saude, Porto Alegre, RS, Brazil
[7] Univ Fed Rio Grande Do Sul, Ctr Biotecnol, Porto Alegre, RS, Brazil
[8] Pontificia Univ Catolica Rio Grande Do Sul, Programa Posgrad Biol Celular & Mol, Porto Alegre, RS, Brazil
关键词
8-Hydroxyquinoline; Mycobacterium tuberculosis; Antibacterial agents; Enzyme inhibition; MtInhA inhibitors; ANTITUBERCULOSIS; RESISTANCE; RING;
D O I
10.1016/j.bioorg.2024.107705
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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), Mt InhA), 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 Mt InhA. Initially, the screening against the microorganism of a small antimicrobial library and its new derivatives that possess some structural similarity with Mt InhA 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 Mt InhA at low micromolar range. However, the 5substituted-8-HQs that presented antimycobacterial activity were not able to inhibit Mt InhA. 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.
引用
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页数:12
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