Design, synthesis, and biological evaluation of quinazolinone-dihydropyrimidinone as a potential anti-diabetic agent via GLUT4 translocation stimulation

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL European Journal of Medicinal Chemistry Pub Date : 2025-04-15 Epub Date: 2025-02-06 DOI:10.1016/j.ejmech.2025.117366

Arvind Kumar Jaiswal , Ajay Kishor Kushawaha , Pawan kumar , Alisha Ansari , Nikita Chhikara , Hemlata bhatt , Sarita Katiyar , Ishbal Ahmad , Abhijit Deb Choudhury , Rabi Sankar Bhatta , Akhilesh K. Tamrakar , Koneni V. Sashidhara

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Abstract

A library of 30 novel quinazolinone-dihydropyrimidinone derivatives was synthesized employing a diversity-oriented approach for the identification of potential anti-diabetic therapeutic lead. In vitro evaluation revealed that seven compounds (5d, 5e, 5i, 5j, 5l, 5m and 5s) significantly enhanced the rate of GLUT4 translocation to the cell surface in L6-GLUT4myc myotubes. Out of these, compound, 5m exhibited promising potency to stimulate GLUT4 translocation in skeletal muscle cells via activating AMPK-dependent pathway, but independent to PI-3-K/AKT signaling. Under in vivo conditions, treatment with 5m demonstrated a marked 39.5 % (p < 0.001) reduction in blood glucose levels in a streptozotocin-induced diabetic rat model after 5 h of treatment. Pharmacokinetic analysis indicated compound 5m shows favourable pharmacokinetic properties. Overall, the compound 5m emerged as a promising lead compound for subsequent structural modification and optimization to develop a novel and potent anti-hyperglycemic agent.

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经GLUT4易位刺激的喹唑啉酮-二氢嘧啶酮抗糖尿病药物的设计、合成及生物学评价

采用多样性取向方法合成了30个新型喹唑啉酮-二氢嘧啶酮衍生物库，用于鉴定潜在的抗糖尿病治疗铅。体外评价显示，7种化合物（5d、5e、5i、5j、5l、5m和5s）显著提高了L6-GLUT4myc肌管中GLUT4向细胞表面转运的速率。其中，化合物5m通过激活ampk依赖性通路刺激骨骼肌细胞中的GLUT4易位，但不依赖于PI-3-K/AKT信号。在体内条件下，5m治疗5小时后，链脲佐菌素诱导的糖尿病大鼠模型的血糖水平显著降低39.5% （p<0.001）。药代动力学分析表明，化合物5m具有良好的药代动力学特性。综上所述，化合物5m是一种有前景的先导化合物，可用于后续的结构修饰和优化，从而开发出一种新型有效的抗高血糖药物。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.