Synthesis, Antimicrobial Evaluation and Docking Study of Novel 3,5- Disubstituted-2-Isoxazoline and 1,3,5-Trisubstituted-2-Pyrazoline Derivatives

Published: 2019
Medicinal Chemistry 15: 1


Background: The frequent use of antibacterial agents is leading 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 structure-activity 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 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.

Ahmed Hussein Ismail
Ahmed Mutanabbi Abdula
Ivan H.R. Tomi
Ali Hussein R. Al-Daraji
Younis Baqi