Discovery of novel quinazoline-sulfonamide derivatives with promising antidiabetic activity

Five new quinazoline-sulfonamide hybrids 4a (MZ-13), 4b (MZ-20), 4c (MZ-25), 4d (MZ-26), and 6a (MZ-29) were designed, synthesized, and investigated for their in vitro and in vivo antidiabetic activities.

The in vivo screening was conducted in a mouse model of type II diabetes induced by streptozotocin (STZ), using glibenclamide as the positive control. The in vitro model was performed by measuring the activity of these compounds against the PPARγ enzyme. Furthermore, the total antioxidant capacity (TAC) was measured for these compounds to assess their ability to neutralize a wide range of free radicals. A physicochemical study was conducted to demonstrate the drugability of these compounds. Additionally, the in silico ADMET and toxicity studies illustrated good pharmacokinetic properties and a low toxicity profile. Likewise, a comprehensive molecular modeling study was performed to examine the binding modes of the new compounds.

Compound MZ-29 showed 27.1% reduction in blood glucose (BG) levels, and the standard glibenclamide showed 17.2% reduction in BG. The in vitro assay of the compounds MZ-13 and MZ-29 demonstrated superior or comparable activity to the reference glibenclamide.

The study identified MZ-29 and MZ-26 as the most promising candidates in the series. These two compounds achieved docking scores and binding orientations closely mimicking the native ligand.