Tindara Previtera

3,3′-Di [1,3-thiazolidine-4-one] system. VI. Structural and conformational studies on configurational isomers with antihistaminic activity

Abstract The stereochemistry of the 3,3′-(1,2-ethanediyl)bis[2-(3-fluorophenyl)-1,3-thiazolidine-4-one] configurational isomers ( 2R,2′R 2S,2′ S and 2R,2′S meso ) has been investigated by 1 H-NMR techniques in solution, by X-ray diffraction methods in the solid state and by quantum chemical methods as the free molecule. The racemic compound, which has antagonistic activity at both H 1 and H 2 receptors, is found to prefer a gauche conformation in CDCl 3 solution, in the solid state and in the free molecule. The inactive meso stereoisomer is centrosymmetric in the crystalline state with an antiperiplanar conformation of the ethylene chain, whereas in CDCl 3 solution it exists as a rapidly interconverting mixture of 3 rotamers. The free molecule presents 2 gauche and 1 anti -periplanar conformations (differing by 1.3–2.4 kcal/mol). Some relationships between stereochemistry and activity are discussed.

3,3′-Di [1,3-thiazolidine-4-one] system. II. Anti-inflammatory and anti-histaminic properties in new substituted derivatives

Abstract In pursuing our search on anti-inflammatory dl and meso 3,3′-di[1,3-thiazolidine-4-one] compounds, two series of derivatives have been prepared by modifying the substitution pattern at positions 1 and 2 of the heterocyclic rings and by introducing an ethylene chain between nitrogen atoms. The anti-inflammatory activity of these compounds has been preliminarily assayed against carrageenin-induced rat paw edema: those proven to be active were also tested for analgesic, anti-pyretic and anti-histamine properties. As a whole, the obtained results suggest that some of the new derivatives possess significant anti-histamine activity. The meso forms generally are more active than dl ones in agreement with the previously emphasized SAR of the chiral systems under study.

3,3′-Di(1,3-thiazolidine-4-one) system. V. Synthesis and pharmacological properties of 3,3′(1,2-ethanediyl)bis-(2-heteroaryl-1,3-thiazolidine-4-one) derivatives

A class of anti-inflammatory, analgesic and histamine H1- and H2-receptor antagonists the 2,2′-diheteroarylbisthiazolidinones and their 1,1′-disulfones, obtained as [RR, SS] and [RS, SR] isomers, is described. The heteroaryl substitution at 2 and 2′ carbons generally improves the pharmacological activities with respect to those of the previously studied 2,2′-diaryl analogues. In particular the 2,2′-dithienyl derivatives exhibit analgesic properties and, as [RS, SR] isomers 6b, 11b, 12b H2-histamine receptor antagonism as well. The most effective acute anti-inflammatory agents appear to be the 2,2′-di(3-pyridyl) compounds 8a, 8b, 14a, 14b which also display analgesic activity. Moreover, an H1-histamine receptor antagonism is almost selectively exerted by the 2,2′-di(2-pyridyl) derivatives 7a, 7b, 13a, 13b. The relationships between the assessed activities and the chirality and/or the sulfur oxidation state of the molecules are discussed. The anti-cancer potential was also evaluated against P 388 murine lymphocytic leukemia; however, the results were not significant.

Liquid chromatographic separation of the enantiomers of antihistaminic 3,3′-di(1,3-thiazolidin-4-one) derivatives with two and four stereogenic centres

Abstract The enantiomers of anti-inflammatory and antihistaminic 3,3′-(1,2-ethanediyl)bis(2-aryl-1,3-thiazolidin-4-one) derivatives possessing two stereogenic centres were separated on Chiralcel OD stationary phase without derivatization. The meso form was also well separated from the enantiomers. The good resolution afforded a milligram-scale separation and subsequent measurement of the circular dichroism spectra of an enantiomeric pair. Addition of racemic α-mercaptopropionic acid to the N,N′-dibenzylideneethylenediamine yielded ten possible stereoisomers with four stereogenic centres. Two centres (2 and 2′) bear the same groups; the other two (5 and 5′) also bear the same groups, but these are different from the groups at 2 and 2′. In this situation four enantiomeric pairs and two meso forms exist; all of them were separated and identified using a Chiralpak AD column.

3,3′-di[1,3-thiazolidin-4-one] system. Structural and conformational studies on configurational isomers with anti-inflammatory activity

Abstract3,3′(1,2-Ethanediyl)bis(2-halophenyl-thiazolidin-4-one) derivatives display different pharmacological activities depending on the configuration of the 2,2′ centers and on the oxidation state of the sulfur atoms. Quantum-chemical calculations on the 3-fluorophenyl-substituted configurational isomers are reported here, together with the X-ray structure of the 1∶1 dioxide derivative. This crystallizes in the monoclinic space group P21/c, with four molecules per unit cell and cell dimensions:a=18.917(3),b=9.003(2),c=12.062(2)Å, β=96.20(3)°. The compound, which has an approximate center of symmetry in the middle of the ethylene chain and two asymmetric carbon atoms of opposite chiralities, is the (2R,2′S-meso) (or 2S,2′R-meso) stereoisomer.

Structural and conformational studies on 3,3′-bis [1,3-thiazolidin-4-one] derivatives with biological activity

Abstract 3,3′-(1,2-ethanediyl)bis[2-substituted-1,3-thiazolidin-4-one] derivatives display different biological activities depending on the configuration of the 2,2′ centers and on the substitution at C2, C2′. In this context, 3,3′-(1,2-ethanediyl)bis[2-(2′-(5′-methyl)thienyl)-1,3-thiazolidin-4-one] ( 6b ) and 3,3′-(1,2-ethanediyl)bis[2-(3′-pyridyl)-1,3-thiazolidin-4-one] ( 8b ) have been prepared. Their structural and conformational features, which can be related to the biological activity, have been investigated by X-ray diffraction and molecular modeling techniques.