Antidiabetic evaluation of novel thienopyrimidinone-thiazolidinedione hybrids complemented with kinetic and computational investigations

Abstract

Diabetes mellitus (DM) is a complex disease, and its treatment/management frequently requires the use of different drugs with distinct modes of action. Unfortunately, many of the current medications come with an increasing plethora of adverse effects. Consequently, DM poses a significant challenge to the global health system. Carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase have emerged as well-known therapeutic targets for the regulation of postprandial glucose levels. Herein, we report the design and synthesis of 20 novel molecular hybrids encompassing thienopyrimidinone and thiazolidinedione pharmacophores that can inhibit α-amylase and α-glucosidase and prevent oxidative stress. Several derivatives showed more potency than the standard drug acarbose. Compound 12q (IC 50 = 38.89 ± 0.50 µM) with alkyl chain length n = 4 exhibited four-fold superior potency to acarbose (IC 50 = 174.40 ± 2.63 µM) against α-amylase, while compound 12t (IC 50 = 41.94 ± 4.76 µM) also with alkyl chain length n = 4 exhibited seven-fold higher activity than acarbose (IC 50 = 282.80 ± 1.46 µM) against α-glucosidase. Enzyme kinetic studies further revealed these compounds ( 12q and 12t ) to be mixed inhibitors of the respective enzymes and were extensively engaged in interactions with their targets based on molecular docking simulations.

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