Background: The frequent use of antibacterial agents leads to antimicrobial resistance,
which is one of the biggest threats to global health today. Therefore, the discovery of novel antimicrobial
agents is still urgently needed to overcome the severe infections caused by these putative
pathogens resistant to currently available drugs.
Objective: The present work was aimed to synthesize and investigate the preliminary structureactivity
relationships (SARs) of isoxazoline and pyrazoline derivatives as antimicrobial agent.
Methods: Target compounds were obtained in a multistep reaction synthesis and the antimicrobial
activity was investigated in several species; two-gram negative (Escherichia coli and Pseudomonas
aeruginosa), two-gram positive (Staphylococcus aureus and Bacillus subtilis) and one fungi
(Candida albicans), using cup-plate agar diffusion method. The most potent compounds were
docked into glucosamine-6-phosphate synthase (GlcN-6-P), the molecular target enzyme for antimicrobial
agents, using Autodock 4.2 program.
Results: Herein, thirteen novel target compounds were synthesized in moderate to good isolated
yield. Based on the SARs, two compounds (2c and 5c) were found to be potent antimicrobial
agents on all tested targets, recording potency higher than amoxicillin, the standard antimicrobial
drug. Compound 2b identified as selective for gram-negative, while compound 7a found to be selective
for gram-positive. The hit compounds (2c, 5a, 5c and 5d) were subjected to a docking
study on glucosamine-6-phosphate synthase (GlcN-6-P). All hits were found to bind to the orthosteric
(active) site of the enzyme, which might represent a competitive mechanism of inhibition.
Conclusion: The newly synthesized heterocyclic compounds could serve as potent leads for the
development of novel antimicrobial agents.