C7‐Halomethylene/methyl‐C3‐thiophenyl‐spirocyclic‐β‐lactams: Synthesis, X‐ray Analysis, Antimicrobial Evaluation, Cytotoxicity Profile and Molecular Docking Interactions

Author:

Yadav Pooja1,Kumari Sumeeta2,Kaur Jaswinder1,Sahoo S. C.1,Reenu 3,Kumar Pinnaka Anil2,Bhalla Aman1ORCID

Affiliation:

1. Department of Chemistry and Centre of Advanced Studies in Chemistry Panjab University Chandigarh 160014 India

2. Microbial Type Culture Collection and Gene Bank CSIR-Microbial Type Culture Collection and Gene Bank Chandigarh 160036 India

3. Department of Chemistry Govt. Home Science College Chandigarh 160011 India

Abstract

AbstractIn the realm of healthcare, the continuous evolution of new alternative antimicrobial agents provides hope in addressing the progressively daunting issue of severe multidrug resistance. In our quest to confront drug resistance, we explored the conjugation of thiophene motif with β‐lactams into single matrix to develop a series of spirocyclic‐β‐lactams. For this, stereoselective synthesis of cisC3‐alkyloxy‐C4‐thiophenyl substituted monocyclic β‐lactams was achieved which were further subjected to intramolecular sulfenyl‐cyclization to furnish C7‐halomethylene/methyl‐C3‐thiophenyl substituted spirocyclic‐β‐lactams. The synthesized compounds were investigated in vitro for their potential activity against six multidrug‐resistant bacterial strains. The most promising C7‐iodomethylene‐C3‐thiophenyl‐spirocyclic‐β‐lactam 7 a appended with 4′‐methoxyphenyl moiety, exhibited acceptable activity against B. cereus and P. aeruginosa with MIC values of 0.75 and 6.25 μg/mL respectively, surpassing ampicillin and vancomycin. Furthermore, this compound demonstrated antifungal effectiveness against C. tropicalis (1.5 μg/mL). On the basis of substituent type and their respective positions, compounds possessing −OCH3 and −C=CHX (halomethylene) groups exhibited more inhibitory potential than others. Active derivatives tested for their cytotoxicity on normal human hepatic (THLE‐2) cell lines confirmed their non‐toxic nature. Further, molecular docking studies predicted the favourable binding interactions of spirocycles within active sites of target proteins. Moreover, several compounds illustrate satisfactory in silico ADME profile. These outcomes provided bright prospect for development of spirocyclic‐β‐lactams as potential solution to combat evolving multidrug resistance.

Publisher

Wiley

Subject

Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology

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