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

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

  • Eur J Med Chem. 2025 Feb 6:288:117366. doi: 10.1016/j.ejmech.2025.117366.
Arvind Kumar Jaiswal 1,  Ajay Kishor Kushawaha 1,  Pawan Kumar 2,  Alisha Ansari 3,  Nikita Chhikara 2,  Hemlata Bhatt 3,  Sarita Katiyar 3,  Ishbal Ahmad 4,  Abhijit Deb Choudhury 5,  Rabi Sankar Bhatta 6,  Akhilesh K Tamrakar 7,  Koneni V Sashidhara 8
Affiliations

Affiliations

  • 1 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute BS, 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
  • 2 Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India.
  • 3 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute BS, 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India.
  • 4 Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India.
  • 5 Pharmaceutics and Pharmacokinetics Division, CSIR- Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India.
  • 6 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India; Pharmaceutics and Pharmacokinetics Division, CSIR- Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India.
  • 7 Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India. Electronic address: akhilesh_tamrakar@cdri.res.in.
  • 8 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute BS, 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India; Sophisticated Analytical Instrument Facility & Research, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India. Electronic address: kv_sashidhara@cdri.res.in.
PMID: 39954347 DOI: 10.1016/j.ejmech.2025.117366
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.

Keywords

Anti-hyperglycemic agent; Dihydropyrimidinones; GLUT4 translocation; Quinazolinone.

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