Novel 5-Substituted 2,4-Thiazolidinedione and 2,4-Oxazolidinedione Derivatives as Insulin Sensitizers with Antidiabetic Activities

Abstract

Two novel classes of 2,4-thiazolidinediones and 2,4-oxazolidinediones with an omega-(azolylalkoxyphenyl)alkyl substituent at the 5-position were prepared and their antidiabetic effects were evaluated in two genetically obese and diabetic animal models, KKA(y) mice and Wistar fatty rats. A large number of the 2,4-thia(oxa)zolidinediones showed potent glucose- and lipid-lowering activities. The antidiabetic activities of the 2,4-oxazolidinediones were superior to those of the 2,4-thiazolidinediones. Among the compounds, both enantiomers of 5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione (64), one of the most interesting compounds in terms of activity, were synthesized by using an asymmetric O-acetylation of the corresponding alpha-hydroxyvalerate (26) with immobilized lipase, followed by cyclization of the oxazolidinedione ring. (R)-(+)-64 showed more potent glucose-lowering activity (effective dose (ED)25 = 0.561 mg/kg/d) than (S)-(-)-64 (ED25 > 1.5 mg/kg/d) or pioglitazone (ED25 = 6 mg/kg/d) in KKA(y) mice. It also exhibited a 10-fold more potent antidiabetic activity (ED25 = 0.05 mg/kg/d) than pioglitazone (ED25 = 0.5 mg/kg/d) in Wistar fatty rats. The antidiabetic effects of this compound are considered to be due to its potent agonistic activity for peroxisome proliferator-activated receptor gamma (EC(50) = 8.87 nM).

Design, Synthesis, Molecular Modelling and Biological Evaluation of Novel α-Naphtholhydroxamate Derivatives as Potential Anticancer Agents

“…IR spectra were recorded Bruker tensor 27, FT-IR Spectrophotometer. All 1 H NMR tyrosine phosphatases (PTP) inhibitors via a structure-based design approach [9]. 2-Phenylnaphthalenoids derivatives represent a novel type of Top II inhibitory scaffold for developing new antitumor chemotherapeutic agents [10].…”

“…The mixture reaction was refluxed overnight and the reaction was checked by TLC. After completion, the reaction mixture was filtered while hot and the solvent was concentrated to produce the title compound (3) [9]. Naphthol amino acid methyl ester derivatives (5 a-m ): Compound (3) (1.5 gm, 7 mmol) was refluxed with thionyl chloride (10 mL) for 3 h and the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (50 mL) and then trimethylamine (3 mL, 30 mmmol) and amino acid methyl ester hydrochloride derivatives (4) were added (10 mmol) and the reaction mixture was stirred for 24 h at room temperature.…”

“…The Lamarckian genetic algorithm (LGA) chosen to confirm maximum of 10 conformers was considered to the docking process with the population size of 150 individuals. The output from AutoDock was further analyzed with PyMOLoftware package [9].…”

“…2-Hydroxymethyl-naphthol diacetate, a naphthol derivative, possesses potent cytotoxic activities in human cancer cell lines [9]. Also (+)-3-(2-(2-fluorobenzyloxy) naphthalen-6-yl)-2-aminopropanoic acid derivatives were identified as reversible and competitive protein by the above observations, we turn our concentration to synthesize a library of novel hybrid compounds comprising hydroxamate moiety with α-naphthol and different linkers of amino acids conjugate.…”

“…α-Naphthol is selectively toxic to short-term organ cultures of human colonic tumor tissue compared to normal intestinal mucosa taken from the same patients and to human colonic cell lines in vitro [9]. 2-Hydroxymethyl-naphthol diacetate, a naphthol derivative, possesses potent cytotoxic activities in human cancer cell lines [9].…”