Substituted (E)-2-(2-benzylidenehydrazinyl)-4-methylthiazole-5-carboxylates as dual inhibitors of 15-lipoxygenase & carbonic anhydrase II: synthesis, biochemical evaluation and docking studies

Abstract

15-Lipoxygenase (15-LOX) plays a major role in many inflammatory lung diseases including chronic obstructive pulmonary disease (COPD), asthma and chronic bronchitis. Over-expression of 15-LOX is related with some specific carcinomas including pancreatic, gastric and brain tumor. Similarly among different isozymes of carbonic anhydrase (CA), CA II is expressed in pancreatic, gastric carcinomas as well as in brain tumors. Therefore, novel potent inhibitors of both 15-LOX and CA II are required to explore the role of these enzymes further and to enable the drug discovery efforts. For this purpose, a series of benzyledinyl-hydrazinyl substituted thiazole derivatives were designed, synthesized and characterized by FTIR, ¹H, &¹³C NMR spectroscopy. The derivatives were then evaluated for their potential to inhibit 15-LOX and bovine carbonic anhydrase II (bCA II). Most of these compounds showed excellent inhibitory potential for 15-LOX with an IC₅₀ of 0.12 ± 0.002 to 0.69 ± 0.5 μM and showed moderate inhibition potency for bCA II with compound 5h (IC₅₀ = 1.26 ± 0.24 μM) being the most active. The most potent compound 5a that emerged as a dual inhibitor of both enzymes, exhibiting 24 times greater selectivity for 15-LOX over bCA II. Compound 5a exhibited dual potent inhibitory activity against both 15-LOX and bCA II enzymes having IC₅₀ values of 0.12 ± 0.002 and 2.93 ± 0.22 μM, respectively. Molecular docking studies of potent as well as dual inhibitors were also carried out to provide an insight into the binding site interactions.

Keywords: 15-Lipoxygenase; Bovine carbonic anhydrase II; Docking studies; Thiazoles.