ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Design and synthesis of peptide-linked fluorochromane-1,2,3-triazoles via click chemistry for anti-tubercular activity: DFT, docking, and ADMET profiling

Jignesh Hindocha, Jignesh Kamdar, Suresh Odiya, Jyoti Kuchhadiya, and Khushal Kapadiya

Department of Chemistry, School of Science, RK University, Rajkot, India

E-mail: Khushal.kapadiya@rku.ac.in

Received: 12 March 2026  Accepted: 5 June 2026

Abstract:

A novel series of peptide-bond-linked fluorochromane-1,2,3-triazole hybrids was synthesized via copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry. The synthetic strategy involved initial coupling of 6-fluorochromane-2-carboxylic acid with propargylamine, followed by conjugation with various 2-azido-N-phenylacetamide derivatives to yield triazole-linked chromane carboxamides (6a-6j). All final compounds were characterized using MS, IR, ¹H NMR, and ¹³C NMR. The compounds were evaluated for their in vitro anti-tubercular activity against the Mycobacterium tuberculosis H37Rv strain. Notably, compound 6f bearing a 4-CF₃ substituent exhibited the most potent activity with a minimum inhibitory concentration (MIC) of 1.25 μg/mL, followed by 6 g (4-F, 3.12 μg/mL) and 6 h (4-OMe, 6.25 μg/mL). Structure–activity relationship analysis suggested that small lipophilic electron-withdrawing groups, particularly CF₃ and F at the para position, enhanced antimycobacterial efficacy. Molecular docking against M. tuberculosis InhA protein (PDB: 4R9S) showed the strongest binding affinity for 6f with a docking score of -11.3 kcal/mol, followed by 6 g and 6 h, each with docking scores of -10.8 kcal/mol, supporting their superior experimental activity. DFT analysis of the lead compound 6f further indicated favorable electronic characteristics, with calculated HOMO and LUMO energies of -6.216 eV and -4.952 eV, respectively, suggesting a reactive electronic profile that may support ligand-target interactions. ADMET profiling predicted balanced pharmacokinetic parameters and toxicity profiles, indicating potential drug-likeness.

Graphical abstract

Keywords: Fluorochromane; 1,2,3-Triazoles; Click chemistry; Antitubercular activity; Molecular docking; DFT; ADMET

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-026-05180-y

Chemical Papers 80 (11) 13285–13301 (2026)