Design, synthetic approach, in silico molecular docking and antibacterial activity of quinazolin-2,4-dione hybrids bearing bioactive scaffolds.

Abstract

Antimicrobial resistance (AMR) is one of ten global public health threats facing humanity. This created the need to identify and develop effective inhibitors as antimicrobial agents. In this respect, quinazolin-2,4-dione hybrids bearing N-heterocyclic cores such as pyrrolidine-2,5-dione, pyrazole and oxadiazole and/or bioactive scaffolds such as hydrazone, amide, sulfonamide, azomethine, and thiourea linkage are described for design, synthesis, antibacterial investigation, and in silico studies. The characterization of the target compounds was accomplished by elemental analysis and various spectroscopic data like FT-IR, 1H-NMR, 13C-NMR and MS. The antibacterial evaluation was achieved for the newly synthesized compounds using two G -ve bacteria (Escherichia coli ATCC 25955 and Pseudomonas aeruginosa ATCC 10145), and two G +ve bacteria (Bacillus subtilis ATCC 6633 and Staphylococcus aureus NRRL B-767). Synthesized compounds exhibited various activities against the tested pathogens, the results revealed that compound 3c exhibited a characteristic antimicrobial efficacy against all the tested pathogenic strains at a concentration lower than the tested standard drug ranging from 2.5 to 10 μg ml-1. Moreover, the molecular docking study against the target S. aureus tyrosyl-tRNA synthetase (PDB ID: 1JIJ) was carried out to investigate the mechanism of action of the prepared compounds, which is in line with an in vitro study. Most new compounds exhibited zero violation of Lipinski's rule (Ro5). These candidate molecules have shown promising antibacterial activity. Among these molecules, compound 3c with di-hydroxyl groups on two phenyl rings at position-4 exhibited a promising potent antibacterial inhibitory effect. Further SAR analysis reveals that a greater number of hydroxyl groups in an organic compound might be crucial for antibacterial efficacy. These findings demonstrate the potential activity of compound 3c as an antibacterial agent.