Open AccessChalcone-Thiazole Hybrids: Rational Design, Synthesis, and Lead Identification against 5-Lipoxygenase
Author(s) -
Sanjib Sinha,
S. L. Manju,
Mukesh Doble
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00193
Subject(s) - chalcone , thiazole , pharmacophore , chemistry , ic50 , stereochemistry , chalcone synthase , combinatorial chemistry , rational design , lead compound , biochemistry , in vitro , enzyme , nanotechnology , biosynthesis , materials science
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 (IC 50 = 1.05 ± 0.03 μM). The best compounds in the series, namely, 4k, 4n , and 4v ( 4k : IC 50 = 0.07 ± 0.02 μM, 4n : IC 50 = 0.08 ± 0.05 μM, 4v : 0.12 ± 0.04 μM) are found to be 10 times more active than previously reported 2-amino thiazole ( 2m : IC 50 = 0.9 ± 0.1 μM) 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.