Chalcone-Thiazole Hybrids: Rational Design, Synthesis, and Lead Identification against 5-Lipoxygenase

Abstract

A hybrid pharmacophore approach is used to design and synthesize novel chalcone-thiazole hybrid molecules. Herein, thiazole has been hybridized with chalcone to obtain a new class of 5-LOX inhibitors. <i>In vitro</i> biological evaluation showed that most of the compounds were better 5-LOX inhibitors than the positive control, Zileuton (IC₅₀ = 1.05 ± 0.03 μM). The best compounds in the series, namely, <b>4k, 4n</b>, and <b>4v</b> (<b>4k</b>: IC₅₀ = 0.07 ± 0.02 μM, <b>4n</b>: IC₅₀ = 0.08 ± 0.05 μM, <b>4v</b>: 0.12 ± 0.04 μM) are found to be 10 times more active than previously reported 2-amino thiazole (<b>2m</b>: IC₅₀ = 0.9 ± 0.1 μM) by us. Further, <b>4k</b> has redox (noncompetitive) while <b>4n</b> and <b>4v</b> act through a competitive inhibition mechanism. SAR indicated that the presence of methoxy/methyl either in the vicinity of chalcone or both thiazole and chalcone contributed to the synergistic inhibitory effect.