Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives

Abstract

A series of 2,3-dihydroquinazolin-4(1H)-one derivatives (3a–3m) was screened for in vitro whole-cell antitubercular activity against the tubercular strain H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 3l and 3m with di-substituted aryl moiety (halogens) attached to the 2-position of the scaffold showed a minimum inhibitory concentration (MIC) of 2 µg/mL against the MTB strain H37Rv. Compound 3k with an imidazole ring at the 2-position of the dihydroquinazolin-4(1H)-one also showed significant inhibitory action against both the susceptible strain H37Rv and MDR strains with MIC values of 4 and 16 µg/mL, respectively. The computational results revealed the mycobacterial pyridoxal-5′-phosphate (PLP)-dependent aminotransferase (BioA) enzyme as the potential target for the tested compounds. In vitro, ADMET calculations and cytotoxicity studies against the normal human dermal fibroblast cells indicated the safety and tolerability of the test compounds 3k–3m. Thus, compounds 3k–3m warrant further optimization to develop novel BioA inhibitors for the treatment of drug-sensitive H37Rv and drug-resistant MTB.

Design and Preparation of Antimicrobial Agents

“…A library of 2,3-dihydroquinazolin-4(1 H )-one derivatives was evaluated for in vitro whole-cell antitubercular activity against the tubercular strain H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains by Venugopala et al [ 8 ]. Compounds with a di-substituted aryl moiety attached to the 2-position of the scaffold showed a minimum inhibitory concentration (MIC) of 2 µg/mL against the MTB strain H37Rv.…”

Molecular and metabolic alterations of 2,3-dihydroquinazolin-4(1H)-one derivatives in prostate cancer cell lines

“…The data presented herein highlight the importance of these compounds as potential anticancer agents particularly C5 which had the most potent cytotoxic effect, exhibited the highest inhibition of wound closure and showed promising anti-adhesive and anti-invasive effects. It is worth mentioning that the safety of these compounds was evaluated against normal fibroblast cells and all compounds showed significantly higher cytotoxicity against PC cell lines compared to fibroblast 34 . The most promising compound, C5, exhibited 15 and 28 times higher IC 50 in fibroblast compared to DU145 and PC3, respectively.…”

“…They are of great interest due to their broad spectrum of pharmacological activities and favorable side effects profile 8 . Quinazoline derivatives have been reported as anticancer, antioxidant, antiviral, anticonvulsant, larvicidal, anti-inflammatory, and antitubercular compounds [8][9][10][11][12] . The Food and Drug Administration (FDA) has approved several quinazoline derivatives for clinical use as anticancer drugs.…”