TY - JOUR
T1 - Synthesis, antimicrobial evaluation and docking study of novel 3,5-disubstituted-2-isoxazoline and 1,3,5-trisubstituted-2-pyrazoline derivatives
AU - Ismail, Ahmed H.
AU - Abdula, Ahmed M.
AU - Tomi, Ivan H.R.
AU - Al-Daraji, Ali H.R.
AU - Baqi, Younis
N1 - Funding Information:
This project received support from the Arab-German Young Academy of Sciences and Humanities (AGYA) that has been funded under the German Ministry of Education and Research (BMBF) grant 01DL16002.
Publisher Copyright:
© 2021 Bentham Science Publishers.
PY - 2021/5/24
Y1 - 2021/5/24
N2 - 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.
AB - 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.
KW - Antimicrobial
KW - Chalcone
KW - Docking
KW - Isoxazoline
KW - Pyrazoline
KW - Synthesis
KW - Catalytic Domain
KW - Pyrazoles/chemical synthesis
KW - Bacteria/drug effects
KW - Candida albicans/drug effects
KW - Anti-Bacterial Agents/chemical synthesis
KW - Structure-Activity Relationship
KW - Isoxazoles/chemical synthesis
KW - Microbial Sensitivity Tests
KW - Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/antagonists & inhibitors
KW - Protein Binding
KW - Molecular Docking Simulation
KW - Molecular Structure
KW - Enzyme Inhibitors/chemical synthesis
KW - Antifungal Agents/chemical synthesis
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UR - http://www.scopus.com/inward/citedby.url?scp=85102917077&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/f433a607-b30f-3d97-b4d8-90e8b19aa65d/
U2 - 10.2174/1573406415666191107121757
DO - 10.2174/1573406415666191107121757
M3 - Article
C2 - 31702515
AN - SCOPUS:85102917077
SN - 1573-4064
VL - 17
SP - 462
EP - 473
JO - Medicinal Chemistry
JF - Medicinal Chemistry
IS - 5
ER -