Synthesis and Molecular Docking Studies of Alkoxy- and Imidazole-Substituted Xanthones as α-Amylase and α-Glucosidase Inhibitors
Dolores G. Aguila-Muñoz,
Gabriel Vázquez-Lira,
Erika Sarmiento-Tlale,
María C. Cruz-López,
Fabiola E. Jiménez-Montejo,
Víctor E. López y López,
Carlos H. Escalante,
Dulce Andrade-Pavón,
Omar Gómez-García,
Joaquín Tamariz,
Aarón Mendieta-Moctezuma
Affiliations
Dolores G. Aguila-Muñoz
Centro de Investigación en Biotecnología Aplicada, Instituto Politécnico Nacional, Carretera Estatal Santa Inés Tecuexcomax-Tepetitla, Km 1.5, Tepetitla de Lardizábal, Tlaxcala 90700, Mexico
Gabriel Vázquez-Lira
Centro de Investigación en Biotecnología Aplicada, Instituto Politécnico Nacional, Carretera Estatal Santa Inés Tecuexcomax-Tepetitla, Km 1.5, Tepetitla de Lardizábal, Tlaxcala 90700, Mexico
Erika Sarmiento-Tlale
Centro de Investigación en Biotecnología Aplicada, Instituto Politécnico Nacional, Carretera Estatal Santa Inés Tecuexcomax-Tepetitla, Km 1.5, Tepetitla de Lardizábal, Tlaxcala 90700, Mexico
María C. Cruz-López
Centro de Investigación en Biotecnología Aplicada, Instituto Politécnico Nacional, Carretera Estatal Santa Inés Tecuexcomax-Tepetitla, Km 1.5, Tepetitla de Lardizábal, Tlaxcala 90700, Mexico
Fabiola E. Jiménez-Montejo
Centro de Investigación en Biotecnología Aplicada, Instituto Politécnico Nacional, Carretera Estatal Santa Inés Tecuexcomax-Tepetitla, Km 1.5, Tepetitla de Lardizábal, Tlaxcala 90700, Mexico
Víctor E. López y López
Centro de Investigación en Biotecnología Aplicada, Instituto Politécnico Nacional, Carretera Estatal Santa Inés Tecuexcomax-Tepetitla, Km 1.5, Tepetitla de Lardizábal, Tlaxcala 90700, Mexico
Carlos H. Escalante
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, Mexico City 11340, Mexico
Dulce Andrade-Pavón
Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Av. Wilfrido Massieu S/N, Mexico City 11340, Mexico
Omar Gómez-García
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, Mexico City 11340, Mexico
Joaquín Tamariz
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, Mexico City 11340, Mexico
Aarón Mendieta-Moctezuma
Centro de Investigación en Biotecnología Aplicada, Instituto Politécnico Nacional, Carretera Estatal Santa Inés Tecuexcomax-Tepetitla, Km 1.5, Tepetitla de Lardizábal, Tlaxcala 90700, Mexico
Current antidiabetic drugs have severe side effects, which may be minimized by new selective molecules that strongly inhibit α-glucosidase and weakly inhibit α-amylase. We have synthesized novel alkoxy-substituted xanthones and imidazole-substituted xanthones and have evaluated them for their in silico and in vitro α-glucosidase and α-amylase inhibition activity. Compounds 6c, 6e, and 9b promoted higher α-glucosidase inhibition (IC50 = 16.0, 12.8, and 4.0 µM, respectively) and lower α-amylase inhibition (IC50 = 76.7, 68.1, and >200 µM, respectively) compared to acarbose (IC50 = 306.7 µM for α-glucosidase and 20.0 µM for α-amylase). Contrarily, derivatives 10c and 10f showed higher α-amylase inhibition (IC50 = 5.4 and 8.7 µM, respectively) and lower α-glucosidase inhibition (IC50 = 232.7 and 145.2 µM, respectively). According to the structure–activity relationship, attaching 4-bromobutoxy or 4′-chlorophenylacetophenone moieties to the 2-hydroxy group of xanthone provides higher α-glucosidase inhibition and lower α-amylase inhibition. In silico studies suggest that these scaffolds are key in the activity and interaction of xanthone derivatives. Enzymatic kinetics studies showed that 6c, 9b, and 10c are mainly mixed inhibitors on α-glucosidase and α-amylase. In addition, drug prediction and ADMET studies support that compounds 6c, 9b, and 10c are candidates with antidiabetic potential.