Arefeh Khosravi1, Gholamhassan Vaezi2,3, Vida Hojati1, Khosrou Abdi4. 1. Department of Biology, Damghan branch, Islamic Azad University, Damghan, Iran. 2. Department of Biology, Damghan branch, Islamic Azad University, Damghan, Iran. gh.vaezi@yahoo.com. 3. Department of Chemistry, Islamic Azad University, North Tehran Branch, Tehran, Iran. gh.vaezi@yahoo.com. 4. Department of Medicinal Chemistry and Radiopharmacy, Tehran University of Medical Sciences , Tehran, Iran. khmabdi@tums.ac.ir.
Abstract
PURPOSE: One of the therapeutic approaches in the management of Type 2 diabetes is delaying the absorption of glucose through α-glucosidase enzymes inhibition, which can reduce the incidence of postprandial hyperglycemia. The existence of chronic postprandial hyperglycemia impaired the endogenous antioxidant defense due to inducing oxidative stress induced pancreatic β-cell destruction through uncontrolled free radicals generation such as ROS, which in turn, leads to various macrovascular and microvascular complications. This study aimed to synthesize 2-aryl-4,6-diarylpyrimidine derivatives, screen their α-glucosidase inhibitory activity, perform kinetic and molecular docking studies. METHODS: A series of 3,4,5-triphenyl-4,5-dihydro-1,2,4-oxadiazole derivatives were synthesized and their α-glucosidase inhibitory activity was screened in vitro. Compounds 6a-k were synthesized via a two-step reaction with a yield between 65 and 88%. The structural elucidation of the synthesized derivatives was performed by different spectroscopic techniques. α-Glucosidase inhibitory activity of the oxadiazole derivatives 6a-k was evaluated against Saccharomyces cerevisiae α-glucosidase. RESULTS: Most of the synthesized compounds demonstrated α-glucosidase inhibitory action. Particularly compounds 6c, 6d and 6 k were the most active compounds with IC50 values 215 ± 3, 256 ± 3, and 295 ± 4 μM respectively. A kinetic study performed for compound 6c revealed that the compound is a competitive inhibitor of Saccharomyces cerevisiae α-glucosidase with Ki of 122 μM. The docking study also revealed that the two compounds, 6c and 6 k, have important binding interactions with the enzyme active site. CONCLUSION: The overall results of our study reveal that the synthesized compounds could be a potential candidate in the search for novel α-glucosidase inhibitors to manage the postprandial hyperglycemia incidence. Graphical abstract.
PURPOSE: One of the therapeutic approaches in the management of Type 2 diabetes is delaying the absorption of glucose through α-glucosidase enzymes inhibition, which can reduce the incidence of postprandial hyperglycemia. The existence of chronic postprandial hyperglycemia impaired the endogenous antioxidant defense due to inducing oxidative stress induced pancreatic β-cell destruction through uncontrolled free radicals generation such as ROS, which in turn, leads to various macrovascular and microvascular complications. This study aimed to synthesize 2-aryl-4,6-diarylpyrimidine derivatives, screen their α-glucosidase inhibitory activity, perform kinetic and molecular docking studies. METHODS: A series of 3,4,5-triphenyl-4,5-dihydro-1,2,4-oxadiazole derivatives were synthesized and their α-glucosidase inhibitory activity was screened in vitro. Compounds 6a-k were synthesized via a two-step reaction with a yield between 65 and 88%. The structural elucidation of the synthesized derivatives was performed by different spectroscopic techniques. α-Glucosidase inhibitory activity of the oxadiazole derivatives 6a-k was evaluated against Saccharomyces cerevisiae α-glucosidase. RESULTS: Most of the synthesized compounds demonstrated α-glucosidase inhibitory action. Particularly compounds 6c, 6d and 6 k were the most active compounds with IC50 values 215 ± 3, 256 ± 3, and 295 ± 4 μM respectively. A kinetic study performed for compound 6c revealed that the compound is a competitive inhibitor of Saccharomyces cerevisiae α-glucosidase with Ki of 122 μM. The docking study also revealed that the two compounds, 6c and 6 k, have important binding interactions with the enzyme active site. CONCLUSION: The overall results of our study reveal that the synthesized compounds could be a potential candidate in the search for novel α-glucosidase inhibitors to manage the postprandial hyperglycemia incidence. Graphical abstract.
Authors: Luis R Guerreiro; Elisabete P Carreiro; Luis Fernandes; Teresa A F Cardote; Rui Moreira; Ana T Caldeira; Rita C Guedes; A J Burke Journal: Bioorg Med Chem Date: 2013-01-26 Impact factor: 3.641
Authors: Garrett M Morris; Ruth Huey; William Lindstrom; Michel F Sanner; Richard K Belew; David S Goodsell; Arthur J Olson Journal: J Comput Chem Date: 2009-12 Impact factor: 3.376