Development of Novel Phthalazinone-Triazole Hybrids as Potential Antidiabetic Agents Targeting GLUT4 Translocation in Skeletal Muscle

  • J Med Chem. 2025 Jun 12;68(11):10722-10737. doi: 10.1021/acs.jmedchem.4c02615.
Ajay Kishor Kushawaha  1 ,  Arvind Kumar Jaiswal  1 ,  Pawan Kumar  2  3 ,  Sarita Katiyar  1  3 ,  Rahul Baghel  2  3 ,  Hemlata Bhatt  1  3 ,  Jay Gupta  1 ,  Alisha Ansari  1  3 ,  Poonam Yadav  1  3 ,  Ishbal Ahmad  2 ,  Abhijit Deb Choudhury  4 ,  Rabi Sankar Bhatta  3  4 ,  Akhilesh K Tamrakar  2  3 ,  Koneni V Sashidhara  1  3  5
Affiliations
  • 1. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute BS, 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh 226031, India.
  • 2. Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh 226031, India.
  • 3. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India.
  • 4. Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh 226031, India.
  • 5. Sophisticated Analytical Instrument Facility & Research, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh 226031, India.
PMID: 40383919 DOI: 10.1021/acs.jmedchem.4c02615
Abstract

A series of 38 phthalazinone-triazole compounds were synthesized using Click chemistry to identify potential antidiabetic agents. These compounds were systematically tested for their ability to promote glucose transporter type 4 (GLUT4) translocation in skeletal muscle cells. Among the 38 derivatives, 11 compounds (i.e., 12k, 13a-13c, 13e-13i, 13s, and 13v) showed significant potential to stimulate GLUT4 translocation in skeletal muscle cells, with compound 13a exhibiting most promising activity. Further, treatment with 13a induced a concentration-dependent increase in GLUT4 translocation in L6 skeletal muscle cells through the activation of wortmannin-sensitive PI-3-K-dependent signaling and AMPK-dependent signaling pathways. The in vivo studies further demonstrated that compound 13a effectively lowered blood glucose levels in STZ-induced diabetic rats and displayed favorable pharmacokinetic properties, making it a promising candidate for further development as an antidiabetic agent.

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