QSAR Studies, Molecular Docking, Molecular Dynamics, Synthesis, and Biological Evaluation of Novel Quinolinone-Based Thiosemicarbazones against Mycobacterium tuberculosis .

Autor: Valencia J; Grupo de Investigación en Química y Biología, Universidad del Norte, Km 5 vía Puerto Colombia, Barranquilla 081007, Colombia., Rubio V; Grupo de Micobacterias, Red TB Colombia, Dirección de Investigación en Salud Pública, Instituto Nacional de Salud, Bogotá 111321, Colombia., Puerto G; Grupo de Micobacterias, Red TB Colombia, Dirección de Investigación en Salud Pública, Instituto Nacional de Salud, Bogotá 111321, Colombia., Vasquez L; Grupo de Micobacterias, Red TB Colombia, Dirección de Investigación en Salud Pública, Instituto Nacional de Salud, Bogotá 111321, Colombia., Bernal A; Grupo de Investigación en Química y Biología, Universidad del Norte, Km 5 vía Puerto Colombia, Barranquilla 081007, Colombia., Mora JR; Grupo de Química Computacional y Teórica (QCT-USFQ), Departamento de Ingeniería Química, Universidad San Francisco de Quito, Diego de Robles y Vía Interoceánica, Quito 170157, Ecuador., Cuesta SA; Grupo de Química Computacional y Teórica (QCT-USFQ), Departamento de Ingeniería Química, Universidad San Francisco de Quito, Diego de Robles y Vía Interoceánica, Quito 170157, Ecuador.; Department of Chemistry, Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK., Paz JL; Departamento Académico de Química Inorgánica, Facultad de Química e Ingeniería Química, Universidad Nacional Mayor de San Marcos, Cercado de Lima 15081, Peru., Insuasty B; Research Group of Heterocyclic Compounds, Department of Chemistry, Universidad del Valle, A. A., Cali 25360, Colombia., Abonia R; Research Group of Heterocyclic Compounds, Department of Chemistry, Universidad del Valle, A. A., Cali 25360, Colombia., Quiroga J; Research Group of Heterocyclic Compounds, Department of Chemistry, Universidad del Valle, A. A., Cali 25360, Colombia., Insuasty A; Grupo de Investigación en Materiales Funcionales Nanoestructurados, Universidad CESMAG, Pasto 520003, Colombia., Coneo A; Medicine Department, Division of Health Sciences, Universidad del Norte, Barranquilla 081007, Colombia., Vidal O; Medicine Department, Division of Health Sciences, Universidad del Norte, Barranquilla 081007, Colombia., Márquez E; Grupo de Investigación en Química y Biología, Universidad del Norte, Km 5 vía Puerto Colombia, Barranquilla 081007, Colombia., Insuasty D; Grupo de Investigación en Química y Biología, Universidad del Norte, Km 5 vía Puerto Colombia, Barranquilla 081007, Colombia.
Jazyk: angličtina
Zdroj: Antibiotics (Basel, Switzerland) [Antibiotics (Basel)] 2022 Dec 29; Vol. 12 (1). Date of Electronic Publication: 2022 Dec 29.
DOI: 10.3390/antibiotics12010061
Abstrakt: In this study, a series of novel quinolinone-based thiosemicarbazones were designed in silico and their activities tested in vitro against Mycobacterium tuberculosis ( M. tuberculosis ). Quantitative structure-activity relationship (QSAR) studies were performed using quinolinone and thiosemicarbazide as pharmacophoric nuclei; the best model showed statistical parameters of R 2 = 0.83; F = 47.96; s = 0.31, and was validated by several different methods. The van der Waals volume, electron density, and electronegativity model results suggested a pivotal role in antituberculosis (anti-TB) activity. Subsequently, from this model a new series of quinolinone-thiosemicarbazone 11a - e was designed and docked against two tuberculosis protein targets: enoyl-acyl carrier protein reductase (InhA) and decaprenylphosphoryl- β - D -ribose-2'-oxidase (DprE1). Molecular dynamics simulation over 200 ns showed a binding energy of -71.3 to -12.7 Kcal/mol, suggesting likely inhibition. In vitro antimycobacterial activity of quinolinone-thiosemicarbazone for 11a - e was evaluated against M. bovis , M. tuberculosis H37Rv, and six different strains of drug-resistant M. tuberculosis . All compounds exhibited good to excellent activity against all the families of M. tuberculosis . Several of the here synthesized compounds were more effective than the standard drugs (isoniazid, oxafloxacin), 11d and 11e being the most active products. The results suggest that these compounds may contribute as lead compounds in the research of new potential antimycobacterial agents.
Databáze: MEDLINE
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