Abstract
A series of novel [1,2,4]triazolo[4,3-a]quinoxaline derivatives were synthesized and evaluated for their antimicrobial inhibiting activity. Compound 6e chalcone derivative (IC50 = 54.1 nM and 7.62 µM against both DHFR and DNA gyrase dual mechanism) is the best antibacterial hit analogue for further structural optimization and drug development.
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•A series of novel triazoloquinoxaline-based scaffold compounds.•Different rigid or flexible linkers were utilized for design of these derivatives.•In vitro antimicrobial screening and DHFR and DNA gyrase enzymes.•Computational pharmacokinetic profile was done for the novel triazoloquinoxalines.•Convenient molecular docking calculations were introduced for SAR analyses.
A novel series of [1,2,4]triazolo[4,3-a]quinoxaline derivatives of different heteroaromatization members were synthesized. The newly synthesized molecules were explored for their potential antimicrobial activities against a panel of pathogenic organisms. Among these derivatives, the chalcone compound 6e with a methoxy substituent exhibited broad potent antimicrobial activity against most of the bacterial and fungal strains. Furthermore, the analysis of the SAR disclosed that the linker and terminal aromatic fragments perform critical roles in exerting antibacterial activity. The molecular docking calculations were executed on two of the most bacterial targets, ATP-binding sites of DNA gyrase B, and the folate-binding site of DHFR enzymes. The results presented good binding data to the pockets of both enzymes showing different linkers contributions through the hydrogen-bonding and aromatic stacking interactions that stabilize the compounds in their pockets taking 6e compound as representative of most active analogs. In addition, good pharmacokinetic profiling data for the 6e compound was obtained and compared to reference drugs. Accordingly, our findings suggest that [1,2,4]triazolo[4,3-a]quinoxaline scaffold is an interesting precursor for the design of potent antimicrobial agents with multitarget inhibition.