Design, Synthesis, and Biological Evaluation of novel Alpha Glucosidase Inhibitors

To develop a lead anti-diabetic compound, a series of 21 novel quinazoline derivatives have been synthesized and screened against alpha Glucosidase. The binding mode of the compounds at the active site of alpha Glucosidase was explored using Glide docking method. The binding model suggests one to four hydrogen bonding interactions between quinazoline derivatives and alpha-glucosidase. 6-Bromo-2cyclopropyl quinazoline-4(3H)-one has been modified by C– C cross coupling to obtain nine different aryl scaffolds. These scaffolds further modified at C-4 position using amidation method to generate 21 compounds. These compounds were characterized by elemental analysis, IR, NMR spectral studies and X-ray single-crystal diffraction analysis. Based on the interaction profile and docking score, all these compounds were selected for in vitro enzymatic screening. Seven of the thirty six compounds showed <20 uM activity against alpha Glucosidase and among these, one compound showed the highest inhibition, with an IC50 of 3.4 uM. Insilico analysis was utilized to evaluate the diversity of the set of compounds against shape space, and relevant drug-like properties (Fig. 1).