7-Hydroxy-benzopyran-4-one Derivatives: A Novel Pharmacophore of Peroxisome Proliferator-Activated Receptor α and -γ (PPARα and γ) Dual Agonists

Abstract

Design, synthesis, and in vitro bioevaluation of a new class of potential dual PPARalpha and gamma agonists discovered through a structure-driven design paradigm are described. The 7-hydroxy-benzopyran-4-one moiety (includes flavones, flavanones, and isoflavones) is the key pharmacophore of these novel molecules, exhibiting similarity to the core structure of both fibrates and thiazolidinediones. New lead PPAR ligands were identified from "natraceuticals" and synthetic analogues. In total, 77 molecules, including chalcones, flavones, flavanones, isoflavones, and pyrazole derivatives, were screened and structure-activity relationship studies of the dual agonists undertaken. Compounds 68, 70, 72, and 76 were identified as novel and potent dual PPARalpha and gamma agonists. These novel molecules may have the potential to be the future leads in PPAR-related disorders, including type II diabetes mellitus and metabolic syndrome.

Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice

“…Matin et al have identified some synthetic flavanones, flavones and isoflavones as dual PPAR-α and -γ agonists [34], and further discovered some synthetic isoflavones that can activate three PPAR isoforms in vitro [35]. Here, for the first time, we identified BVC, a natural prenylated isoflavanone, as a potent pan-PPAR agonist.…”

Identification of Benzopyran‐4‐one Derivatives (Isoflavones) as Positive Modulators of GABAA Receptors

“…Recently, we have discovered synthetic analogues of isoflavones as novel templates for potential dual peroxisome proliferator-activated receptor (PPAR)-a and -g agonists. [16] During the course of our ongoing research, we envisioned for the first time, that isoflavones exhibit a potent flumazenil-insensitive positive modulation at human recombinant a 1 b 2 g 2L receptors expressed in Xenopus oocytes. The main goal of this communication is to report the in vitro GABA A activity of the isoflavones and to find correlations between the structure-driven design paradigm and the pharmacological activity.…”

Synthesis and Transformation of Halochromones

“…Bearing in mind the construction of the isoflavone core by a possible scalable synthesis, Felpin and co-workers [161] bed on a solution-phase Suzuki reaction using Pd(0)/C as heterogenous practical and inexpensive catalyst under ligand-free conditions, which was then used by other authors (Scheme 38) [162,163]. Beyond the excellent yields of cross-coupled products 114, the heterogeneous nature of the catalyst is extremely well suited for large-scale applications.…”