Novel 4-Bromobenzyl-1H-1,2,3-Triazole Scaffold for Multi-target Enzyme Inhibition in Helicobacter Gastric Injury via Experimental and Computational Approaches

Abstract

Regioselective elaboration of a 4-bromobenzyl-1H-1,2,3-triazole scaffold was achieved through a concise, metal-free sequence that preserves the C-4 carboxylate as a metal-coordinating handle while diversifying the C-5 position. Thermal azide–alkyne cycloaddition between 1-(azidomethyl)-4-bromobenzene and dimethyl but-2-ynedioate furnished the 4,5-diester core, followed by LTBA-mediated, chemoselective reduction of the C-5 ester to an aldehyde at − 10 °C in THF. Modular condensation of the aldehyde delivered three derivatives—Schiff base (a2), hydrazone (a3), and benzimidazole (a1)—in 95–98% yields, with structures confirmed by NMR and HRMS. The regioselective design maximized metal coordination (Ni²+, Zn²+, Fe³+) and produced multi-target inhibition against urease, collagenase, and 15-LOX; the imine derivative a2 was most potent (IC50: 7.21 µM, 27.36 µM, 2.76 µM, respectively), consistent with docking, MD, and MM/GBSA analyses. This synthesis-first strategy establishes a privileged, polypharmacological platform for gastric-injury targets.