Design, synthesis, and antidiabetic evaluation of Hantzsch's 1,4-dihydropyridine-pyrazole scaffolds as stimulator of skeletal-muscle GLUT4 translocation

  • Bioorg Chem. 2026 Jun 17:180:110110. doi: 10.1016/j.bioorg.2026.110110.
Sarita Katiyar  1 ,  Shadab Ahmad  2 ,  Hemlata Bhatt  1 ,  Amol Chhatrapati Bisen  3 ,  Arvind Kumar Jaiswal  4 ,  Ishbal Ahmad  5 ,  Ajay Kishor Kushawaha  4 ,  Nikita Chhikara  2 ,  Rahul Baghel  2 ,  Pawan Kumar  2 ,  Rabi Sankar Bhatta  6 ,  Akhilesh K Tamrakar  7 ,  Koneni V Sashidhara  8
Affiliations
  • 1. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India.
  • 2. Division of Biochemistry and Structural Biology, 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, U.P., India.
  • 3. Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India; ICMR- National Institute for Pre-Clinical Research (NIPCR), Hyderabad, Telangana 500101, India.
  • 4. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
  • 5. Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.
  • 6. Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India.
  • 7. Division of Biochemistry and Structural Biology, 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, U.P., India. Electronic address: [email protected].
  • 8. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India. Electronic address: [email protected].
PMID: 42330847 DOI: 10.1016/j.bioorg.2026.110110
Abstract

In the quest for new antidiabetic agents, a library of twenty-three 1,4-dihydropyridine-pyrazole derivatives was synthesized via an efficient green multicomponent Hantzsch reaction. The compounds were screened in vitro for GLUT4 translocation stimulatory activity in L6-GLUT4myc myotubes, and subsequently evaluated in vivo for anti-hyperglycemic effects in a streptozotocin-induced diabetic rat model. Several compounds, particularly 6c, 6 h, 6j, 6 l, and 6 m, significantly enhanced GLUT4 translocation to cell surface in L6-GLUT4myc myotubes, suggesting improved glucose uptake potential. Among them, compound 6c exhibited the highest activity and produced a significant reduction in blood glucose levels (23.9%, p < 0.01) in diabetic rats. The observed biological activity highlights the therapeutic relevance of the 1,4-dihydropyridine-pyrazole scaffold and identifies compound 6c as a promising lead for further structure-activity relationship studies aimed at the development of novel antidiabetic agents.

Keywords
1,4-dihydropyridine–pyrazole hybrids; Antidiabetic agent; GLUT4 translocation; Green multicomponent reaction; Hantzsch dihydropyridine synthesis.
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