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

• Published in: ChemMedChem Vol. 19; no. 2
• Main Authors: Yadav, Pooja, Kumari, Sumeeta, Kaur, Jaswinder, Sahoo, S. C., Reenu, Kumar Pinnaka, Anil, Bhalla, Aman
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 15.01.2024; Wiley Subscription Services, Inc
• Subjects: Amides; Ampicillin; Antibiotics; Antimicrobial agents; Cell lines; Chemistry, Medicinal; Conjugation; Cytotoxicity; Drug resistance; Fungicides; in silico ADME; Life Sciences & Biomedicine; Molecular docking; molecular docking insights; Multidrug resistance; Pharmacology & Pharmacy; Science & Technology; spirocyclic-β-lactams; Stereoselectivity; Substitutes; Synthesis; Thiophene; Toxicity testing; Vancomycin; in silico ADME; DESIGN; MOIETY; molecular docking insights; Thiophene; AGENT; spirocyclic-beta-lactams; antimicrobial agents; RING; INHIBITORS; DERIVATIVES; BETA-LACTAMS; SPIRO; SCAFFOLD
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202300505

In 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 cis‐C3‐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. New C7‐halomethylene/methyl‐C3‐thiophenyl linked spirocyclic‐β‐lactams were synthesized via halogen‐mediated intramolecular sulfenyl‐cyclization. The target derivatives showed antibacterial and antifungal properties against selected pathogens. Particularly, the C7‐iodomethylene‐C3‐thiophenyl‐spirocyclic‐β‐lactam variant displayed the highest level of bacterial inhibition, outperforming the effectiveness of reference drugs. Molecular docking analysis of representative compounds revealed their specific binding orientations within the active sites of the target proteins.