Design, synthesis and biological evaluation of non-glucosidal based 1,3,4-thiadiazoles as SGLT-2 inhibitors

Type-2 diabetes mellitus (T2DM) is a major metabolic disorder needing insulin-independent treatments; this study developed Schiff base 1,3,4-thiadiazole as Sodium Glucose Co-transporters 2 (SGLT2) inhibitors. The target compounds were synthesized followed by docking studies, in vitro and in vivo analysis. In vitro assay revealed SSS 6 and SSS 2 exhibited high SGLT2 inhibition activity i.e. 78.57% ± 2.8 and 74.60% ± 1.12 compared to dapagliflozin (93.65% ± 4.48) at same dosage in enzyme inhibition assays. In vivo results reveals that SSS 2 significantly improved excretion of urinary glucose (854 ± 46.51 mg/body weight) as compared to dapagliflozin (775 ± 32.68 mg/body weight. SSS 6 and SSS 2 significantly decreased blood glucose levels (137 ± 4.89 mg/dL and 183 ± 15.07 mg/dL) relative to dapagliflozin (158 ± 15.9 mg/dL). Compounds SSS 6 and SSS 2 emerge as a potential candidates for further investigation as SGLT2 inhibitors for treating T2DM.