1447250-04-5Relevant articles and documents
Development of α-glucosidase inhibitors by room temperature C-C cross couplings of quinazolinones
Garlapati, Ramesh,Pottabathini, Narender,Gurram, Venkateshwarlu,Kasani, Kumara Swamy,Gundla, Rambabu,Thulluri, Chiranjeevi,MacHiraju, Pavan Kumar,Chaudhary, Avinash B.,Addepally, Uma,Dayam, Raveendra,Chunduri, Venkata Rao,Patro, Balaram
, p. 4778 - 4791 (2013/07/26)
Novel quinazolinone based α-glucosidase inhibitors have been developed. For this purpose a virtual screening model has been generated and validated utilizing acarbose as a α-glucosidase inhibitor. Homology modeling, docking, and virtual screening were successfully employed to discover a set of structurally diverse compounds active against α-glucosidase. A search of a 3D database containing 22 500 small molecules using the structure based virtual model yielded ten possible candidates. All ten candidates were N-3-pyridyl-2-cyclopropyl quinazolinone-4-one derivatives, varying at the 6 position. This position was modified by Suzuki-Miyaura cross coupling with aryl, heteroaryl, and alkyl boronic acids. A catalyst screen was performed, and using the best optimal conditions, a series of twenty five compounds was synthesized. Notably, the C-C cross coupling reactions of the 6-bromo-2-cyclopropyl-3- (pyridyl-3-ylmethyl)quinazolin-4(3H)-one precursor have been accomplished at room temperature. A comparison of the relative reactivities of 6-bromo and 6-chloro-2,3-disubstituted quinazolinones with phenyl boronic acid was conducted. An investigation of pre-catalyst loading for the reaction of the 6-bromo-2-cyclopropyl-3-(pyridyl-3-ylmethyl)quinazolin-4(3H)-one substrate was also carried out. Finally, we submitted our compounds to biological assays against α-glucosidase inhibitors. Of these, three hits (compounds 4a, 4t and 4r) were potentially active as α-glucosidase inhibitors and showed activity with IC50 values 50 values 10 μM. These lead compounds have desirable physicochemical properties and are excellent candidates for further optimization.
