Synthesis and Antimicrobial Evaluation of New 1,2,4-Triazolo[1,5-<i>a</i>]pyrimidine-Based Derivatives as Dual Inhibitors of Bacterial DNA Gyrase and DHFR

Abstract

A series of 1,2,4-triazolo[1,5-<i>a</i>]pyrimidine-based derivatives were developed and prepared by reacting chalcones <b>8a</b>-<b>p</b> with 3-phenyl-1,2,4-triazole-5-amine (<b>5</b>). The novel compounds were analyzed using several spectroscopic techniques, and their antimicrobial efficacies against six pathogens (Gram-negative, Gram-positive, and fungi) were tested. Most of the tested compounds exhibited significant antimicrobial activity compared to ciprofloxacin and fluconazole. Four compounds (<b>9d</b>, <b>9n</b>, <b>9o</b>, and <b>9p</b>) showed promising results. Their minimal inhibitory concentration (MIC) values were between 16 and 102 μM, similar to ciprofloxacin's 10-90 μM values. MIC values against the tested fungal species were between 15.50 and 26.30 μM, higher than fluconazole's 11.50-17.50 μM values. Compounds <b>9n</b> and <b>9o</b>, in particular, showed excellent bactericidal activity. Compounds <b>9n</b> and <b>9o</b>, the most effective antibacterial agents, were further evaluated for their inhibitory effects on bacterial DNA gyrase and DHFR enzymes as possible molecular targets. The results indicated that <b>9n</b> and <b>9o</b> demonstrated a similar level of activity against DNA gyrase and DHFR when compared to the reference drugs ciprofloxacin and trimethoprim. We conducted molecular docking to investigate the binding mechanism and evaluate the reactivity of the intriguing compounds. Compounds <b>9n</b> and <b>9o</b> demonstrated favorable binding interactions with the essential amino acids necessary for the inhibition of <i>E. coli</i> DNA gyrase and DHFR enzymes.