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

Abstract

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.

Inhibitors of glucosamine-6-phosphate synthase as potential antimicrobials or antidiabetics – synthesis and properties

“…The molecular docking studies of 55 and 56 to GlcN-6-P synthase (pdbid: 1moq) showed that obtained inhibitors may bind to the ISOM active site via interactions with Ala602, Ser349 and Thr302 residues. Estimated values of K i for 55 and 56 were 0.769 and 4.21 µM and their binding energies were −8.34 and −7.33 kcal/mol, respectively 73 .…”

“…Ismail and co-workers 73 characterised a series of 1,2-diazole- and 1,2-oxazole-based compounds as potential antimicrobial agents. The synthesis of inhibitors was a two-step procedure, in which p- hydroxy acetophenone was condensed in an aldol manner with 3,3-dimethoxybenzaldehyde or thiophene-2-carbaldehyde, resulting in chalcones 53 and 54 .…”

“…The synthesis of inhibitors was a two-step procedure, in which p- hydroxy acetophenone was condensed in an aldol manner with 3,3-dimethoxybenzaldehyde or thiophene-2-carbaldehyde, resulting in chalcones 53 and 54 . Subsequently, chalcones served as substrates for cyclisation reactions with hydroxylamine or hydrazine hydrochloride that led to final oxazole- and diazole-based compounds 55 and 56 , respectively ( Scheme 13 ) 73 . Derivatives 55 and 56 exhibited the highest antimicrobial potential in disc diffusion tests, actually higher than that of amoxicillin.…”

An Overview on Synthesis and Biological Activity of Chalcone Derived Pyrazolines

“…The synthesized chalcone derivatives ( 1 a – d ) were treated with hydrazine hydrate to obtain pyrazolines ( 2 a – c ). The formed pyrazolines ( 2 a – c ) were further reacted with methyl chloroformate and choloroacetyl chloride to prepare the modified pyrazoline derivatives ( 3 a – b ) and ( 4 a – b ) [46] . (Scheme 3)…”

“…The compound 4‐(5‐Thiophen‐2‐yl)‐4,5‐dihydro‐1H‐pyrazol‐3‐yl) phenol ( 2 c ) was found to possess more potent activity in a concentration ranging from as low as 10 mg/mL to as high as 100 mg/mL when compared to amoxicillin. The compound 2‐Chloro‐N‐(4‐(1‐(2‐chloroacetyl)‐5‐(thiophen‐2‐yl)‐4,5‐dihydro‐1H‐pyrazol‐3‐yl) phenyl acetamide ( 4 a ) was found to be selective for gram‐positive with inhibition zone as 11 mm and 12 mm at 100 mg/mL for S.aureus and B.subtilis respectively [46] …”