Ureidopenicillins are a class of penicillins which are antibiotics active against gram‐negative bacteria. Herein, we report the synthesis of 2‐aminothiophene‐tethered ureidopenicillin analogues and their in vitro antibacterial and antitubercular activity. Intriguingly, unlike the reported ureidopenicillins which are active against gram‐negative bacteria, the synthesised 2‐aminothiophene‐tethered ureidopenicillins were significantly active against Gram‐positive bacterial strains and showed moderate inhibition towards gram‐negative bacterial strains. Among all the analogs, compound 1 b containing 2‐aminothiophene moiety with minimum inhibitory concentration (MIC): 0.29, 0.32, > 10, > 10 μg/ml for Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa, respectively, showed better anti‐bacterial profile as compared to cephalexin and equipotent to ampicillin and amoxicillin on gram‐positive bacterial strains. All the derivatives were also screened for anti‐TB activity against mycobacterium tuberculosis H37Ra. Among the series, cycloocta‐thiophene‐tethered cephalexin analog 3 c displayed excellent antitubercular activity with MIC values 0.78 μg/ml. Low cytotoxicity and high selectivity index indicate the efficacy of 3 c against mycobacterial infections. The results from present study offer a novel approach to modify the existing drug class of ureidopenicillins to yield antimicrobials with promising utility.
A series of ten novel derivatives of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl) benzamide 6a–j were synthesized in good yield from the key compound 4-(benzyloxy)-N′-(substituted benzylidene) benzo hydrazide, called Schiff ’s bases 5a–j, by Staudinger reaction ([2 + 2] ketene-imine cycloaddition reaction) with chloro acetyl chloride in the presence of catalyst tri ethylamine and solvent dimethyl formamide (DMF), by using ultra-sonication as one of the green chemistry tools. All the synthesised compounds were evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) and most of them showed promising activity with an IC50 value of less than 1 µg/mL. To establish the safety, all the synthesized compounds were further tested for cytotoxicity against the human cancer cell line HeLa and all 6a–j compounds were found to be non-cytotoxic in nature. The molecular docking study was carried out with essential enzyme InhA (FabI/ENR) of Mycobacterium responsible for cell wall synthesis which suggests that 6a and 6e are the most active derivatives of the series. The theoretical evaluation of cell permeability based on Lipinski’s rule of five has helped to rationalize the biological results and hence the synthesized azetidinone derivatives 6a–j were also analyzed for physicochemical evaluation that is, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and the results showed that all the derivatives could comply with essential features required for a potential lead in the anti-tubercular drug discovery process.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.