International Journal of Drug Delivery Technology
Volume 15, Issue 3

Design, Synthesis, and Evaluation of Novel C-Aryl Glycoside-Based Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors for Improved Antidiabetic Therapy 

Pooja Dhembare, Vijay Wakale*, Sachin Datkhile, Kuldeep Ramteke

Samarth Institute of Pharmacy, Belhe, Tal.-Junnar, Dist.-Pune, Affiliated to Dr. Babasaheb Ambedkar Technological University, Lonere, Dist.-Raigad, Maharashtra, India 

Received: 11th Jun, 2025; Revised: 26th Aug, 2025; Accepted: 5th Sep, 2025; Available Online: 25th Sep, 2025 

ABSTRACT

Currently, SGLT2 inhibitors have established themselves as an efficacious class of agents to treat type-2 diabetes mellitus with main action of increasing glucose excretion through urine. This report describes the design, synthesis & assessment of innovative C-aryl glycoside-based SGLT2 inhibitors with an enhanced binding affinity and dual inhibition potential. For rational drug design, enhanced H-bonding, π-π stacking, and hydrophobic interactions were derived from critical key heterocyclic phenols and alcohols so as to rope in SGLT2 inhibitors against C-aryl glycosides-based SGLT2 inhibitors. As per molecular docking analysis, QPB-1 was found to be having the best affinity (Vina score: -10.7) compared with dapagliflozin (-10.0) and empagliflozin (-8.7) against a panel of key residues in Pocket C2 (ASP21, ASP25, ILE26, PHE33, and TRP172). On the other side, biological assessment with α-amylase inhibition assays showed that QPB-1 (85% inhibition, IC₅₀ = 25 µM) was comparable to acarbose (85%, IC₅₀ = 24 µM) and superior to dapagliflozin (78%, IC₅₀ = 32 µM) and empagliflozin (74%, IC₅₀ = 40 µM). Other promising derivatives, QPB-9 (80%, IC₅₀ = 30 µM) and QPB-6 (77%, IC₅₀ = 35 µM), also exhibited strong inhibitory activity. This indicates that our novel C-aryl glycoside-based inhibitors have enhanced stability, stronger inhibition, and dual glucose-lowering mechanisms, qualifying them as promising candidates for next-generation antidiabetic therapy. Further studies, including preclinical evaluation and pharmacokinetic profiling, are being planned to test the therapeutic prospect of these agents.

Keywords: SGLT2 inhibitors, C-aryl glycosides, type 2 diabetes mellitus, molecular docking, α-amylase inhibition, structure-based drug design, quinoline derivatives, glycoside scaffolds

How to cite this article: Pooja Dhembare, Vijay Wakale, Sachin Datkhile, Kuldeep Ramteke. Design, Synthesis, and Evaluation of Novel C-Aryl Glycoside-Based Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors for Improved Antidiabetic Therapy. International Journal of Drug Delivery Technology. 2025;15(3):1220-27. doi: 10.25258/ijddt.15.3.42

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