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.

Silver(I) complexes of 2,4-dihydroxybenzaldehyde–amino acid Schiff bases—Novel noncompetitive α-glucosidase inhibitors

“…We illustrated the predicted binding mode by using compound 18a as an example. Previous research has shown that from the sequence alignment of templates and target proteins, Asp68, Asp214, Phe177 and Phe300 are the key active site residues conserved in α-glucosidase [22][23] , and some other important amino acids Arg212, Asp349, Ser244 and His348 are also present around the active site. We speculate that the oxygen atoms that coordinate with the silver atoms are offered by both the carboxyl and the hydroxyl groups of the amino acid Asp349, and are not offered by the amino acid Schiff base.…”

Quinazolin derivatives as emerging alpha-glucosidase inhibitors

“…Then, we performed Suzuki coupling reactions in Microwave instruments, there we got better results. Results from our initial investigations [29] by using ligand are shown in Table 1.…”

“…With subject to control this particular disease, one of the best-studied therapeutic target is α-glucosidase and its function inhibition. It is located in the brush border of the small intestine [3][4][5][6][7] and involved in breaking down complex carbohydrates such as starch and glycogen into their monomers, it catalyzes the cleavage of individual glucosyl residues from various glycoconjugates including alpha or beta linked polymers of glucose. The body system which is affected by diabetes mellitus needs external regulators to control the insulin balance in the blood, here the α-glucosidase inhibitors come into action, α-glucosidase inhibitors decrease both postprandial hyperglycemia and hyperinsulinemia, and thereby may improve sensitivity to insulin and release the stress on beta cells [7].…”

Advances in Metal-Catalyzed Cross-Coupling Reactions of Halogenated Quinazolinones and Their Quinazoline Derivatives

“…Initial Suzuki-Miyaura cross-coupling of 2-(2-furyl)-6-iodoquinazolin-4(3 H )-one with 4-methoxyphenylboronic in the presence of Pd(OAc) 2 -K 2 CO 3 mixture in dioxane-water (3:1, v/v) and subsequent oxidative-aromatization into the 4-chloroquinazoline followed by amination has also been described in the literature [4]. The Suzuki-Miyaura cross-coupling of 6-bromo/chloro-2-cyclopropyl-3-((pyridin-3-yl)methyl)quinazolin-4(3 H )-one 72 with aryl-, heteroaryl- and alkylboronic acids previously afforded 2-cyclopropyl-6-phenyl-3-((pyridin-3-yl)methyl)quinazolin-4(3 H )-one 73 as potential α-glucosidase inhibitors (Scheme 23) [46]. Several palladium catalysts were used as sources of active Pd(0) species in the presence of K 3 PO 4 in tetrahydropyran (THP) at room temperature and among them, bis-(dicyclohexylphosphino)ferrocene]dichloropalladium(II) [PdCl 2 (dcpf)] and bis(di- tert -butylphosphino) ferrocene]dichloropalladium(II) [PdCl 2 (dtbpf)] were found to be better catalysts that produced the desired products 73 in high yields.…”