eng Oriental Scientific Publishing Company Biosciences Biotechnology Research Asia 0973-1245 2026-03-30 23 1 233 249 10.13005/bbra/3493 58692 article Vasundhara Sawant 1 Sanjay Sawant 1 Komal Lahoti 1 Shankar Chavan 1 Aditi Pawar 1 Rushikesh Yande 1 Department of Pharmaceutical Chemistry, STES, Smt. Kashibai Navale College of Pharmacy, Savitribai Phule Pune University, Maharashtra, India. Department of Pharmaceutical Quality Assurance, STES, Smt. Kashibai Navale College of Pharmacy, Savitribai Phule Pune University, Maharashtra, India. Human fructose-1,6-bisphosphatase (FBPase), a key regulatory enzyme of hepatic gluconeogenesis, represents an important therapeutic target for the management of type 2 diabetes mellitus. However, classical phosphate-based FBPase inhibitors are often associated with poor pharmacokinetic properties. In the present study, a series of novel quinazolinone–thiazolidin-4-one hybrid derivatives (PT-01 to PT-10) were rationally designed as non-phosphate FBPase inhibitors, synthesized, and structurally confirmed by FT-IR, ¹H NMR, mass spectrometry and elemental analysis. Molecular docking studies were carried out using Auto Dock software against the crystal structure of human FBPase (PDB: 6LS5) to evaluate binding within the allosteric adenine-binding pocket. The synthesized compounds exhibited docking scores ranging from –7.3 to –9.7 kcal/mol, demonstrating stronger predicted binding affinity than the reference inhibitor CS-917 (–6.9 kcal/mol). Key interactions involved residues Val17, Ala24, Leu30, Met177, Arg140, Thr31, and Tyr113. Substituent variation significantly influenced binding, with electron-donating and electron-withdrawing groups enhancing hydrogen bonding and hydrophobic stabilization. Among the series, PT-04 (m-nitrophenyl substituted) showed the highest docking score (–9.7 kcal/mol) and stable multipoint interactions. In a 28-day in vivo evaluation using a diabetic rodent model, the selected compound PT-03 produced a reduction in blood glucose levels from 507 mg/dL to 302 mg/dL, indicating a measurable anti hyperglycaemic effect. The In silico ADMET and drug-likeness analyses suggested acceptable pharmacokinetic properties and compliance with Lipinski’s criteria. Collectively, these findings identify the quinazolinone–thiazolidinone scaffold as a viable non-phosphate framework for further optimization and detailed pharmacological investigation as FBPase-targeted antidiabetic agents. https://www.biotech-asia.org/vol23no1/computationally-guided-design-and-synthesis-of-quinazoline-thiazolidinone-scaffolds-targeting-fructose-1-6-bisphosphatase/ Fructose-1; 6-bisphosphatase; Gluconeogenesis; Quinazoline; Thiazolidinone; Type 2 Diabetes Mellitus