Synthesis, Characterization, Computational Studies and In Vitro Biological Effects of Novel Pyrazoles, Pyridazines, Thiazoles Containing a Quinazoline Scaffold

A novel series of 3‐methylquinazolin‐4‐ones 3 , 5 , 7 , 8 , and 10 linked to aryl hydrazone, pyrazole, pyridazine, and thiazole through thio linker was generated and described in the present work, starting from quinazoline acetonitrile 1 . Spectroscopic and microanalytical data were used to investigate the newly generated materials. The antimicrobial efficacy of these molecules was tested using amoxicillin and ketoconazole, which are standard antimicrobial agents. The new compounds were examined against several bacterial and fungal microorganisms. Pyrazole analogue 5b showed excellent potency rather than 5a , resembling that of the reference amoxicillin (MIC = 1.95, 3.9, 0.98, and 0.49 µM against S. aureus , E. faecalis , K. pneumoniae , and P. aeruginosa , respectively). Also, derivative 5b gave moderate activity against fungi A. niger and C. albicans (MIC = 15.63 and 125 µM, respectively) comparing with the standard ketoconazole (MIC = 7.81 and 62.5 µM, respectively). The above derivatives were evaluated for inhibition of DNA gyrase and topoisomerase IV of S. aureus in relation to the common drug ciprofloxacin. Although the tested derivatives 5a , b had a potential suppressive effect against S. aureus DNA gyrase when compared to the standard used (IC 50 = 8.15 ± 0.55, 6.44 ± 0.30 and 5.72 ± 0.13 µM, respectively), they revealed a significant decrease in the suppressive effect on topoisomerase IV compared to standard drugs, with (IC 50 range 61.58–95.40 µM, IC 50 ciprofloxacin = 14.88 ± 0.25 µM). Utilizing molecular docking technology, the more potent molecules, 5a and 5b , were further examined for the ability to attach to the required DNA gyrase of S. aureus . Hydrogen bonding interactions between their structures and protein residues such as Pro1080 and His1081 were observed in the DNA gyrase active pocket of S. aureus . Both pyrazoles 5a and 5b appear to have good prospects for further research progress and improvement, according to computational evaluation of physicochemical parameters and ADMET.