2-Amino-4-aryl thiazole: a promising scaffold identified as a potent 5-LOX inhibitor. Issue 23 (16th February 2016)

• Record Type: Journal Article
• Authors: Sinha, Shweta; Sravanthi, T. V.; Yuvaraj, S.; Manju, S. L.; Doble, Mukesh
• Is Part Of: RSC advances. Volume 6:Issue 23(2016)
• Page Start: 19271
• Page End: 19279
• Publication Date: 2016-02-16
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c5ra28187c
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : Human 5-lipoxygenase (5-LOX) is a target for asthma and allergy treatment. Zileuton is the only marketed drug targeting this enzyme (IC50 ∼ 1 μM). The current study identifies a promising lead molecule which could be improved to match the activity of zileuton. Abstract : Human 5-lipoxygenase (5-LOX) is an important enzyme in the biosynthesis of leukotrienes and is a target for asthma and allergy treatment. Zileuton is the only drug currently marketed that targets this enzyme (IC50 ∼ 1 μM). So, the development of novel lead compounds is highly desirable. A series of 2-aryl indole, thiazolopyrazole acid, oxadiazolobenzothiophene, 1, 4-disubstituted-1, 2, 3-triazole, 2-amino-4-aryl thiazole and 4, 4′-(1, 4-phenylene)bis(1, 3-thiazole) derivatives when tested against this enzyme resulted in the identification of a potent compound (1d ), p -fluoro substituted 2-amino-4-aryl thiazole, with an IC50 of ∼10 μM. Another lead compound identified is (4a ), a thiazolopyrazole acid derivative (IC50 ∼ 40 μM). All the compounds exhibit poor DPPH radical scavenging activity which suggests that their action occurs not due to the disruption of the redox cycle of iron present in the enzyme (unlike zileuton) but through competitive inhibition, since the V max remains constant but the K m increases with an increase in inhibitor concentration. Molecular docking of1d and4a to the active site of 5-LOX also supports the experimental data, and suggests that their possible mechanism of action is through competitive inhibition. The current study identifies a promising lead molecule which could be improved further to match the activity of the commercial drug.