title: Development of α-glucosidase inhibitors by room temperature C-C cross couplings of quinazolinones.
abstract: 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 <20 μM. Based on structural novelty and desirable drug-like properties, 4a was selected for structure-activity relationship study, and thirteen analogs were synthesized. Nine out of thirteen analogs acted as α-glucosidase inhibitors with IC50 values <10 μM. These lead compounds have desirable physicochemical properties and are excellent candidates for further optimization.
authors.affiliation: Medicinal Chemistry Division, GVK Biosciences Pvt. Ltd, Plot 28A, IDA Nacharam, Hyderabad, India.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Garlapati
authors.forename: Narender
authors.initials: N
authors.lastname: Pottabathini
authors.forename: Venkateshwarlu
authors.initials: V
authors.lastname: Gurram
authors.forename: Kumara Swamy
authors.initials: KS
authors.lastname: Kasani
authors.forename: Rambabu
authors.initials: R
authors.lastname: Gundla
authors.forename: Chiranjeevi
authors.initials: C
authors.lastname: Thulluri
authors.forename: Pavan Kumar
authors.initials: PK
authors.lastname: Machiraju
authors.forename: Avinash B
authors.initials: AB
authors.lastname: Chaudhary
authors.forename: Uma
authors.initials: U
authors.lastname: Addepally
authors.forename: Raveendra
authors.initials: R
authors.lastname: Dayam
authors.forename: Venkata Rao
authors.initials: VR
authors.lastname: Chunduri
authors.forename: Balaram
authors.initials: B
authors.lastname: Patro
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013696:Temperature; D000520:alpha-Glucosidases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D052999:Quinazolinones; D000520:alpha-Glucosidases