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

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. In vitro biological evaluation showed that most of the compounds were better 5-LOX inhibitors than the positive control, Zileuton (IC50 = 1.05 +/- 0.03 mu M). The best compounds in the series, namely, 4k, 4n, and 4v (4k: IC50 = 0.07 +/- 0.02 mu M, 4n: IC50 = 0.08 +/- 0.05 mu M, 4v: 0.12 +/- 0.04 mu M) are found to be 10 times more active than previously reported 2-amino thiazole (2m: IC50 = 0.9 +/- 0.1 mu M) by us. Further, 4k has redox (noncompetitive) while 4n and 4v 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.