Novel 5-substituted 2,4-thiazolidinedione and 2,4-oxazolidinedione derivatives as insulin sensitizers with antidiabetic activities

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).     

Synthesis and antidiabetic activity of novel 2,4-thiazolidinedione derivatives containing a thiazole ring

A series of thiazolyl-2,4-thiazolidinediones (Ia-f, IIa-f and IIIa-f) was prepared by Knoevenagel reaction of substituted benzyl-2,4-thiazolidinediones (4a-f) with chlorothiazolecarbaldehydes (2, 3a-b). The prepared compounds were tested for their insulinotropic activities in INS-1 cells. A significant insulinotropic effect was seen with compounds If and IIa.     

Synthesis of furodiketochroman and bis-furocoumarin derivatives and their biological activity

A number of substituted furodiketochroman derivatives (III _a-f ) have been synthesized by fusion of aromatic aldehydes with 5-hydroxybergapten and 5-hydroxyisopimpinellin. On the other hand, when the reaction was carried out in a solvent, the corresponding bis-furocoumarin derivatives (IV _c-n ) were obtained. The anticoagulant effect of compoundsIII _a,b,d andIV _b,c,f,g,i,k , was tested. They failed to demonstrate any significant effect. The effect of the tested compounds on the arterial blood pressure was studied. CompoundsIV _c ,III _d ,III _b ,IV _b ,IV _g ,IV _k andIV _i showed lowering effects on the normal systolic blood pressure of anaesthetized rats in a decreasing manner.     

Synthesis of 2,4-dihalogenofluorobenzenes and their antimicrobial and antifungal activity studies

The aim of this study was to synthesize and identify 2,4-dihalogenofluorobenzene (or trihalogenobenzene) derivatives by spectroscopic means, ¹H-NMR and ¹⁹F-NMR. The 2,4-dihalofluorobenzene derivatives considered were 2,4-dichlorofluorobenzene (1), 2-bromo-4-chlorofluorobenzene (2), 2-iodo-4-chlorofluorobenzene(3), 2,5-dichlorofluorobenzene (4), 2-bromo-5-chlorofluorobenzene (5), 2-iodo-5-chlorofluorobenzene (6). The in vitro antibacterial and antifungal activities of trihalogenobenzene derivatives were studied against the bacteria Staphylococcus aureus ATCC 25923 Gram(+), Bacillus cereus ATCC 6633 Gram(+), Micrococcus flavus (clinical isolate) Gram(+), Morgenella morganii (clinical isolate) Gram(-), Escherichia coli ATCC 27853 Gram(-) and fungus Candida albicans (clinical isolate), obtained from the biology departments of the Pamukkale and Gazi Universities. The antibacterial and antifungal activities were measured by minimum inhibition concentration (MIC) method and the disc-diffusion method used to measure zone diameter against Gram-positive and Gram-negative bacteria and fungi. All these bacteria and fungi were studied against antibiotics to compare the zone diameters with the results from our treatments.     

Synthesis and three-dimensional qualitative structure selectivity relationship of 3,5-disubstituted-2,4-thiazolidinedione derivatives as COX2 inhibitors

In our effort for synthesis of selective COX2 inhibitors, certain new 2,4-thiazolidinedione derivatives were synthesized. It necessitates preparation of potassium salt of 2,4-thiazolidinedione 2, which condensed with intermediate 4a. The resulting 3-[2-(4-methylphenyl)-2-oxo-l-phenylethyl]-2,4-thiazolidinedione 8 was condensed with appropriate aldehyde to afford compounds 10a, 10i-l, 10o and 10p. Compounds (9a-l, 10a-n, 10p, 11 and 12) were obtained through the preparation of 5-arylmethylidene-2,4-thiazolidinediones 6a-p and reaction of its potassium salt 7a-p with compounds 4a, 4b, and 5. Some compounds displayed significant analgesic activity as compared to reference standards. The anti-inflammatory activity of the synthesized compounds revealed that intermediate 8 and compounds 9c, 10c and 10d showed good results. Compound 10c produced no significant mucosal injury. HipHop methodology of Catalyst program was used to build up hypothetical model of selective COX2 inhibitors followed by fitting the synthesized compounds to this model. Compounds 10c and 10d were suspected to be promising selective COX2 inhibitors. Also, compounds (6c, 8, 9a,c,d,k, 10a,c,d,k, 11 and 12) were docked into COX1 and COX2 X-ray structures, using DOCK6 program. Docking results suggested that several of these derivatives are active COX inhibitors with a significant preference for COX2.     

Synthesis and fungicidal activity of pseudo-thiohydantoins, their 5-arylidene derivatives, and 5-arylidene-3-β-aminothiazolid-2,4-one hydrochlorides

A series of pseudo-thiohydantoins and their 5-arylidene derivatives have been synthesized. Reactions of acid hydrolysis of pseudo-thiohydantoins with the formation of the corresponding 5-arylidene-3-β-aminothiazolid-2,4-one hydrochlorides have been performed. The antifungal activity of the synthesized compounds has been evaluated. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 10, pp. 17–19, October, 2006.     

5-(Ethoxymethylene)thiazolidine-2,4-dione derivatives: reactions and biological activities

The 5-(ethoxymethylene)-4-thioxothiazolidin-2-ones 2a-c were synthesized and reacted with acrylonitrile, ethyl acrylate. β-nitrostyrene, N-phenylmaleimide and malononitrile under different conditions, to yield the cycloaddition products 3–14. The antibacterial and antifungal activities of the new products were tested.