Quantitative structure—Activity relationship of fluridone derivatives with phytoene desaturase

Abstract

Structure-activity investigations were carried out with fluridone analogs which are inhibitors of the enzyme phytoene desaturase. The chemical modifications of the 21 bleaching compounds used were all positioned at the pyridinone ring. Inhibition of carotenoid biosynthesis was determined either with intact cells of the cyanobacterium Aphanocapsa or with isolated Aphanocapsa thylakoid membranes assaying inhibition of phytoene desaturation. Methyl was found to be a favorable N-substituent, and the aromatic nature of the heterocycle is not essential although the resulting piperidinone showed lower bleaching activity. Replacement of the keto group by either methoxy or dimethylamine resulted in lowered but still substantial inhibition. The corresponding thione or chloro derivatives were more or less inactive. Quantitative structure-activity correlations were calculated between inhibitory activity and physicochemical properties of the substituents at position 3 of the pyridinone ring. Regression analysis showed a significant correlation between cellular I 50 values and lipophilicity π and σ p. Using in vitro data the contribution of σ p to the regression was not significant.