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Sulfonamide derivatives of substituted (piperidin-4-yl)-1H-benzo[d]imidazoles: design, synthesis, antimicrobial and anti-inflammatory activities, and docking studies evaluation and ADME properties

Ravindra Reddy Ummadi, Venkata Nadh Ratnakaram, Subba Rao Devineni, Chennamsetty Subramanyam, and Harnam Singh

Industrial Chemical Product Development and Analysis Centre, Chemistry Department, GITAM School of Science, GITAM Deemed to Be University, Bengaluru, India

E-mail: doctornadh@yahoo.co.in

Abstract:

A novel series of 1-(2-methoxyethyl)-2-(1-(substituted sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazoles, 1-(2-ethoxyethyl)-2-(1-(substituted sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazoles, and 1-benzyl-2-(1-(substituted sulfonyl)piperidin-4-yl)-1H-benzo[d]imidazoles were synthesized from piperidine-4-carboxylic acid through a five-step chemical transformation process. The synthesis involved cyclization of piperidine-4-carboxylic acid with benzene-1,2-diamine to yield a benzimidazole derivative, followed by Boc-protection of the piperidine amine, substitution with methoxyethyl, ethoxyethyl, and benzyl groups on the benzimidazole amine, Boc deprotection, and final substitution with sulfonamides. The structures of all synthesized compounds were confirmed using analytical techniques, including IR, ¹H, and ¹³C NMR, and mass spectrometry. Furthermore, a molecular modelling study was conducted to analyse binding interactions against COX-2 (complexed with the selective inhibitor SC-558(PDB ID: 1CX2), DNA Gyrase-B (PDB ID: 1EI1), and CYP51 (PDB ID: 1EA1). The study provided insights into binding conformations and interactions, aligning well with the in-vitro anti-inflammatory and anti-microbial activities results. The biological activity of the compounds was evaluated for their anti-inflammatory, antibacterial, and antifungal potential. The results indicated promising anti-inflammatory activity, particularly for derivatives substituted (piperidin-4-yl)-1H-benzo[d]imidazoles, which contain a phenyl sulfonamide moiety at the piperidine ring, with inhibition rates ranging from 79.6 to 84.2%. Additionally, derivatives 1-(2-Methoxyethyl)-2-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole (30a), 2-(1-(Ethylsulfonyl)piperidin-4-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole (30b), 1-(2-Ethoxyethyl)-2-(1-(methylsulfonyl) piperidin-4-yl)-1H-benzo[d]imidazole (31a), and 1-Benzyl-2-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole (32a), 1-Benzyl-2-(1-(ethylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole (32b) demonstrated significant antibacterial activity against three tested bacterial strains, while 1-Benzyl-2-(1-tosylpiperidin-4-yl)-1H-benzo[d]imidazole (32d), 1-Benzyl-2-(1-((4-nitrophenyl)sulfonyl) piperidin-4-yl)-1H-benzo[d]imidazole (32e), featuring 4-methylphenyl and 4-nitrophenyl sulfonamide substitutions on the piperidine moiety, showed promising antifungal activity. The findings revealed that the synthesized compounds exhibited higher efficacy against Aspergillus niger (ATCC 16888) and Cladosporium cladosporioides (ATCC 16022), and aliphatic-substituted sulfonamide derivatives displayed stronger antibacterial than antifungal activity.

Graphical abstract

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-025-04533-3

Chemical Papers 80 (3) 2575–2598 (2026)