TY - JOUR
T1 - Synthesis and biological activity of fibrate-based acyl- and alkyl-phenoxyacetic methyl esters and 1,2-dihydroquinolines
AU - Pucheta, Abraham
AU - Mendieta, Aarón
AU - Madrigal, Damián A.
AU - Hernández-Benitez, Roberto I.
AU - Romero, Liseth
AU - Garduño-Siciliano, Leticia
AU - Rugerio-Escalona, Catalina
AU - Cruz-López, María C.
AU - Jiménez, Fabiola
AU - Ramírez-Villalva, Alejandra
AU - Fuentes-Benites, Aydeé
AU - González-Romero, Carlos
AU - Gómez-García, Omar
AU - López, Julio
AU - Vázquez, Miguel A.
AU - Rosales-Acosta, Blanca
AU - Villa-Tanaca, Lourdes
AU - Sequeda-Juárez, Alfonso
AU - Ramón-Gallegos, Eva
AU - Chamorro-Cevallos, Germán
AU - Delgado, Francisco
AU - Tamariz, Joaquín
N1 - Publisher Copyright:
© 2020, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - A series of highly potent antihyperlipidemic agents constituted by a fibrate-based structure was recently reported by our group, whose synthesis started from isovanillin derivatives. In the interest of evaluating the bioisosteric effect of the vanillin-based isomers on their antihyperlipidemic activity, the present study focuses on the synthesis of 5-acyl-1-phenoxyacetic methyl esters 5a–c and their saturated side-chain 5-alkyl-1-phenoxyacetates 6a–c. Their strong in vivo effect was associated with the inhibition of HMG-CoA reductase. Since 1,2-dihydroquinolines inhibit this enzyme, a series of such heterocycles (9a–d) was prepared by our efficient regioselective, one-step, solvent-free method. Apart from showing hypolipidemic activity in vivo, some of the compounds displayed antifungal, antioxidant and cytotoxic activity in vitro. The binding mode of four compounds at the active site of HMGRh was examined with docking simulations, observing an interaction with most of the amino acids targeted by simvastatin.
AB - A series of highly potent antihyperlipidemic agents constituted by a fibrate-based structure was recently reported by our group, whose synthesis started from isovanillin derivatives. In the interest of evaluating the bioisosteric effect of the vanillin-based isomers on their antihyperlipidemic activity, the present study focuses on the synthesis of 5-acyl-1-phenoxyacetic methyl esters 5a–c and their saturated side-chain 5-alkyl-1-phenoxyacetates 6a–c. Their strong in vivo effect was associated with the inhibition of HMG-CoA reductase. Since 1,2-dihydroquinolines inhibit this enzyme, a series of such heterocycles (9a–d) was prepared by our efficient regioselective, one-step, solvent-free method. Apart from showing hypolipidemic activity in vivo, some of the compounds displayed antifungal, antioxidant and cytotoxic activity in vitro. The binding mode of four compounds at the active site of HMGRh was examined with docking simulations, observing an interaction with most of the amino acids targeted by simvastatin.
KW - 1,2-Dihydroquinolines
KW - 2-Acyl-1-hydroxyphenoxyacetic esters
KW - 2-Alkyl-1-hydroxyphenoxyacetic esters
KW - Antihyperlipidemic activity
KW - Antioxidant activity
KW - HMG-CoA reductase
UR - http://www.scopus.com/inward/record.url?scp=85078453761&partnerID=8YFLogxK
U2 - 10.1007/s00044-019-02496-1
DO - 10.1007/s00044-019-02496-1
M3 - Artículo
SN - 1054-2523
VL - 29
SP - 459
EP - 478
JO - Medicinal Chemistry Research
JF - Medicinal Chemistry Research
IS - 3
ER -