Synthesis of and molecular docking studies of azomethine- tethered sulfonamides as carbonic anhydrase II & 15-lipoxygenase inhibitors

Abstract

• A series of hydrazinecarbonyl tethered sulfonamides were synthesized. • Compounds tested for inhibition of II (bCA II), (15-LOX) and antioxidant potential. • Compounds 5i having a furan ring was most potent bCA II inhibitor IC 50 =0.1 µM. • Compounds 5i with N(CH 3 ) 2 was most potent 15-LOX Inhibitor, IC 50 = 0.34 µM. • Most putative binding sites were identified using molecular docking studies. The use of sulfanilamide in organic synthesis has become a classical strategy for the synthesis of several biologically active compounds. In this study, a series of hydrazine-carbonyl tethered sulfonamides derivatives 5(a-j) was synthesized as carbonic anhydrase isoform II ( b CA II) and 15-Lipoxygenase enzyme (15-LOX) inhibitors. The Sulfanilamide ( 1 ) was treated with ethyl acrylate ( 2 ) to yield propanoate ethyl ester ( 3 ) which on reaction with hydrazine hydrate, was successively converted into hydrazide (4). The hydrazide ( 4) on condensation with a variety of substituted aromatic aldehydes, resulted in hydrazinecarbonyl tethered sulfonamides 5(a-j) . The characterization data of the synthesized derivatives confirmed the formation of final products. Against b CA II, all the compounds showed inhibitory effects but derivative 5j exhibited the most potent activity with an value of IC 50 0.11 ± 0.01 μM and it was found more active than standard acetazolamide (IC 50 ). When the inhibitory effects of these compounds were observed against 15-LOX, only two compounds 5 h and 5j exhibited significant inhibitory activity. The molecular docking investigations of the most active inhibitor of both b CA II and 15-LOX enzymes were carried out which further confirmed that the potent derivatives bind well inside the active binding site of the targeted enzyme, respectively. In addition, the free radical scavenging potential of these compounds ( 5a-j) was evaluated and found to have antioxidant potential. Based on our investigations, this study has identified few new scaffolds which may act as dual inhibitor and serve as a core structures for the discovery of effective drugs against carbonic anhydrase-II and 15-Lipoxygenase associated disorders such as inflammation, pancreatic carcinoma, and gastric carcinomas.