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<p>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 <b>12q</b> (IC<sub>50</sub> = 38.89 ± 0.50 µM) with alkyl chain length <i>n</i> = 4 exhibited four-fold superior potency to acarbose (IC<sub>50</sub> = 174.40 ± 2.63 µM) against α-amylase, while compound <b>12t</b> (IC<sub>50</sub> = 41.94 ± 4.76 µM) also with alkyl chain length <i>n</i> = 4 exhibited seven-fold higher activity than acarbose (IC<sub>50</sub> = 282.80 ± 1.46 µM) against α-glucosidase. Enzyme kinetic studies further revealed these compounds (<b>12q</b> and <b>12t</b>) to be mixed inhibitors of the respective enzymes and were extensively engaged in interactions with their targets based on molecular docking simulations.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月6日

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  • Pule Seboletswe,
  • Gobind Kumar,
  • Nontobeko Gcabashe,
  • Sanjeev Dhawan,
  • Neha Manhas,
  • Lungisani Khubone,
  • ALmahi Idris,
  • Md. Shahidul Islam,
  • Parvesh Singh

摘要

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 (IC50 = 38.89 ± 0.50 µM) with alkyl chain length n = 4 exhibited four-fold superior potency to acarbose (IC50 = 174.40 ± 2.63 µM) against α-amylase, while compound 12t (IC50 = 41.94 ± 4.76 µM) also with alkyl chain length n = 4 exhibited seven-fold higher activity than acarbose (IC50 = 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.