Design, Synthesis, and Biological Appraisal of Various Vital Drugs-Linked Heterocyclic Scaffolds and Related Compounds

Abstract

Iminothiazolidinone, aminothiazole, coumarin, sulfonamide, pyrazole and pyrazolone are heterocyclic scaffolds of tremendous importance in medicinal chemistry. Current research in this field suggests that hybridization of biologically-active molecules is a novel strategy to generate robust pharmacophores and to solve resistance problems. In this context, a variety of drugs-linked heterocyclic scaffolds have been synthesized, structurally characterized, and evaluated for elastase, carbonic anhydrase, urease, and a-glucosidase. The reaction of different substituted acyl thioureas and diethyl acetylenedicarboxylate (in methanol) afforded two series of adamantane (347-356) and 3-Ethylphenyl (357-365) clubbed iminothiazolidinones in excellent yield. Adamantane clubbed iminothiazolidinones (347-356) were screened against elastase enzymes. Kinetic studies were caried out to determine the mode of action and molecular docking studies were performed to develop structure-activity relationship. All the test derivatives were highly active against elastase. Among all the compounds (353) displayed highest inhibition with (ICso 0.124 ± 0.022 /lM) A series of 3-Ethylphenyl-linked iminothiazolidinones (357-365) were tested against carbonic anhydrase II. All the tested derivatives showed moderate to good level activity. Among them the derivative (361) exhibited good result with (ICso 1.545 ± 0.016 /lM) closer to the standard acetazolamide. Coumarin and aminothiazole are part of various clinically-approved drugs and found in several bioactive compounds. In view of biological importance of these two heterocyclic cores variety of new coumarin and amantadine linked thiazoles (366-375) & (376-386) were synthesized and characterized. The reaction of a-bromo ketones with differently substituted thioureas in refluxing ethanol afforded two series of coumarin and amantadine linked thiazole (366-375) & (376-386) in good to high yield. A series of amantadine-linked aminothiazoles (376-386) were checked against urease and a-glucosidase enzymes, kinetic studies were exercised to determine the mode of action and molecular docking studies were conducted to develop structure-activity relationship. The derivative (282) was highly active