QSAR Studies, Molecular Docking, Molecular Dynamics, Synthesis, and Biological Evaluation of Novel Quinolinone-Based Thiosemicarbazones against <i>Mycobacterium tuberculosis</i>

• Main Authors: Jhesua Valencia (Author), Vivian Rubio (Author), Gloria Puerto (Author), Luisa Vasquez (Author), Anthony Bernal (Author), José R. Mora (Author), Sebastian A. Cuesta (Author), José Luis Paz (Author), Braulio Insuasty (Author), Rodrigo Abonia (Author), Jairo Quiroga (Author), Alberto Insuasty (Author), Andres Coneo (Author), Oscar Vidal (Author), Edgar Márquez (Author), Daniel Insuasty (Author)
• Format: Book
• Published: MDPI AG, 2022-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antibiotics12010061; 2079-6382
• Keywords: <i>Mycobacterium tuberculosis</i>; QSAR; docking; quinolinone; thiosemicarbazone; molecular dynamics and cytotoxicity; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 12, Iss 1, p 61 (2022)

In this study, a series of novel quinolinone-based thiosemicarbazones were designed in silico and their activities tested in vitro against <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>). Quantitative structure-activity relationship (QSAR) studies were performed using quinolinone and thiosemicarbazide as pharmacophoric nuclei; the best model showed statistical parameters of R² = 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 <b>11a</b>-<b>e</b> was designed and docked against two tuberculosis protein targets: enoyl-acyl carrier protein reductase (InhA) and decaprenylphosphoryl-<i>β</i>-<i>D</i>-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 <b>11a</b>-<b>e</b> was evaluated against <i>M. bovis</i>, <i>M. tuberculosis</i> H37Rv, and six different strains of drug-resistant <i>M. tuberculosis</i>. All compounds exhibited good to excellent activity against all the families of <i>M. tuberculosis</i>. Several of the here synthesized compounds were more effective than the standard drugs (isoniazid, oxafloxacin), <b>11d</b> and <b>11e</b> being the most active products. The results suggest that these compounds may contribute as lead compounds in the research of new potential antimycobacterial agents.