Exploring biological efficacy of coumarin clubbed thiazolo[3,2-b][1,2,4]triazoles as efficient inhibitors of urease: A biochemical and in silico approach

Abstract

Combating several pathological conditions associated with ureolytic enzyme (urease) remains a formidable challenge because of the lack of effective and safe drug therapies. In this regard, the development of potent inhibitors of urease could be considered as a promising remedy. Herein, we report a new library of structurally diverse hybrid heteroaromatics featuring coumarin and thiazolotriazole motifs in one combined unit. These new chemical scaffolds accessed through the integration approach were shown to inhibit the enzyme urease from jack bean at variable efficacies. An initial structure-activity relationship analysis guided through the variation of several functional groups at the aryl ring connected to the thiazole core revealed compound 6o (IC₅₀ = 4.35 ± 0.18 µM) as the most potent inhibitor. The inhibitory strength of 6o was 5-fold compared to thiourea (standard; IC₅₀ = 20.8 ± 0.59 µM). In the molecular docking analysis, 6o was stabilized in the active pocket through various binding interactions. The presence of an amino moiety at the meta position of the phenyl ring facilitates hydrogen bonding with the sulfhydryl group of Cys322 (2.11 Å) in addition to an interaction observed between the thiazole sulfur and nickel atoms present in the active site. Moreover, this amino group also interacts with the carbonyl oxygen of Ala366 at a distance of 2.75 Å. The chromenone moiety of compound 6o is stabilized by the side chains of various amino acid residues including Ala279, Thr301, Pro303, Thr304, His315 and Met367.

Keywords: Coumarin; Heterocycles; Hybrid scaffold; Molecular docking; Thiazolotriazole; Urease.