Derivatives of (Phenylsulfanyl)benzoic Acids with Multiple Antileukotrienic Activity

Abstract

A series of derivatives of (phenylsulfanyl)benzoic acids bearing quinoline, 2,4-dihydroxy-3-propylacetophenone and 2,4-difluorobiphenyl moieties were prepared and their antileukotrienic activities evaluated. Some of the compounds were found to display multiple antileukotrienic effect in the inhibition of LTB4biosynthesis, binding to LTD4and LTB4receptors, superior to the standards (zileuton and zafirlukast) used. The compounds had an antiinflammatory effect, manifested with quinoline derivatives by a significant inhibition of bronchospasm induced by LTD4and/or albumin. The results of regression analysis correspond to the observation that the most active compounds belong to quinoline derivatives with the lowest lipophilicity. X-ray analysis of the quinoline compounds revealed that an intramolecular hydrophobic interaction of their aromatic rings does not occur in the solid state.

Characterization of enzymes responsible for biotransformation of the new antileukotrienic drug quinlukast in rat liver microsomes and in primary cultures of rat hepatocytes

“…Quinlukast was prepared in the frame of synthesis of anti-inflammatory compounds with multiple anti-leukotrienic activity (Kuchar et al 1998). It was characterized (Kuchar et al 2000(Kuchar et al , 2001 with significant inhibition of LTB 4 biosynthesis and binding to LTD 4 receptors and its good anti-inflammatory activity was manifested by an antiasthmatic effect in the model of LTD 4 -induced bronchospasm in guinea-pigs. The IC50 value (concentration producing 50% inhibition) for quinlukast in inhibiting binding to leukotriene D 4 receptors is comparable with those of montelukast and zafirlukast, while leukotriene B 4 biosynthesis inhibition by quinlukast is much more effective than that of montelukast and zafirlukast (Kuchar et al 2003).…”

5-Lipoxygenase, Leukotrienes Biosynthesis and Potential Antileukotrienic Agents

“…The structural fragment Q is connected with the other part of the molecule through flexible aliphatic linker. One of the quinoline derivatives (VUFB 19363 -quinlukast, 117) [94] of arylsulfonylbenzoic acid was chosen as a multiple anti-LTs for preclinical development. Quinlukast homologues 118 [94], 119-122 [95,96] quinlukast azaanalogues 123 and 124 [97] were prepared in cooperation with the Research Centre LN00B125.…”

“…In the next series of hydroxyphenylsulfanylbenzoic acids 115 and homologic hydroxyphenylsulfanylphenylacetic acids 116 [94] various moieties were used to carry the lipophilic fragment Q (2,4-dihydoxy-3-propylacetophenonyl or 2,4-difluorobiphenyl or 4-(4-chlorobenzyl)piperazinyl or 2-quinolinyl). The structural fragment Q is connected with the other part of the molecule through flexible aliphatic linker.…”

Inhibition of Aromatic Amino Acid Decarboxylase by a Group of New Potential Nonsteroidal Anti-Inflammatory Drugs with Antileukotrienic Effects

“…Derivatives of phenylsulfanylbenzoic and phenylsulfanylphenylacetic acids were synthetized within the framework of research of anti-inflammatory drugs with a potential antileukotrienic mechanism of action (7). In in vitro experiments, some of the compounds showed a combined antileukotrienic effect via the inhibition of binding of LTD 4 and LTB 4 on the receptors.…”