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Bioorg Med Chem. 2014 Nov 1;22(21):5871-82. doi: 10.1016/j.bmc.2014.09.022. Epub 2014 Sep 19.

Synthesis and highly potent hypolipidemic activity of alpha-asarone- and fibrate-based 2-acyl and 2-alkyl phenols as HMG-CoA reductase inhibitors.

Author information

1
Depto. de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional (IPN), Prol. Carpio y Plan de Ayala S/N, 11340 México, D.F., Mexico.
2
Centro de Investigación en Biotecnología Aplicada, IPN, Carretera Estatal Santa Inés Tecuexcomac-Tepetitla, Km 1.5, Tepetitla de Lardízabal, 90700 Tlaxcala, Mexico.
3
Laboratorio de Toxicología Preclínica, Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala S/N, 11340 México, D.F., Mexico.
4
Laboratorio de Genética Microbiana, Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala S/N, 11340 México, D.F., Mexico.
5
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, 04510 México, D.F., Mexico.
6
Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.
7
Centro de Investigación en Biotecnología Aplicada, IPN, Carretera Estatal Santa Inés Tecuexcomac-Tepetitla, Km 1.5, Tepetitla de Lardízabal, 90700 Tlaxcala, Mexico. Electronic address: carmencruz25@yahoo.com.mx.
8
Depto. de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional (IPN), Prol. Carpio y Plan de Ayala S/N, 11340 México, D.F., Mexico. Electronic address: jtamarizm@gmail.com.

Abstract

In the search for new potential hypolipidemic agents, the present study focused on the synthesis of 2-acyl phenols (6a-c and 7a-c) and their saturated side-chain alkyl phenols (4a-c and 5a-c), and on the evaluation of their hypolipidemic activity using a murine Tyloxapol-induced hyperlipidemic protocol. The whole series of compounds 4-7 greatly and significantly reduced elevated serum levels of total cholesterol, LDL-cholesterol, and triglycerides, with series 6 and 7 showing the greatest potency ever found in our laboratory. At the minimum dose (25mg/kg/day), the latter compounds lowered cholesterol by 68-81%, LDL by 72-86%, and triglycerides by 59-80%. This represents a comparable performance than that shown by simvastatin. Experimental evidence and docking studies suggest that the activity of these derivatives is associated with the inhibition of HMG-CoA reductase.

KEYWORDS:

2-Acyl phenols; 2-Alkyl phenols; Docking; HMG-CoA reductase; Hypolipidemic; Phenoxyacetic

PMID:
25311563
DOI:
10.1016/j.bmc.2014.09.022
[Indexed for MEDLINE]

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