5-Lipoxygenase inhibitors: the synthesis and structure-activity relationships of a series of 1-phenyl-3-pyrazolidinones

Abstract

A series of analogues of the 5-lipoxygenase inhibitor 1-phenyl-3-pyrazolidinone (phenidone, 1a) has been prepared via two complementary new synthetic methods. The reaction of various electrophiles with the dianion of 1a or with an N-silylpyrazolidinone anion gave the desired 4-substituted pyrazolidinones (Scheme I and II). A new procedure was developed for the resolution of 4-substituted pyrazolidinones (Scheme V). A regression study on 21 compounds in this series showed a correlation of increased inhibitor potency (pIC50) with increased compound lipophilicity (log P) and with an N-phenyl electronic effect as measured by the 13C NMR chemical shift parameter CNMR1' (R2 = 0.79). The most potent 5-lipoxygenase inhibitor in this series was 4-(ethylthio)-1-phenyl-3-pyrazolidinone (1n) with an IC50 of 60 nM. Another member of this series, 4-(2-methoxyethyl)-1-phenyl-3-pyrazolidinone (1f, IC50 = 0.48 microM), although less potent than 1n, was better tolerated in the whole animal relative to phenidone (1a) and also displayed good oral activity in two models of 5-lipoxygenase inhibition. On the basis of a structure-activity relationship study, a mechanism for the inhibition of 5-lipoxygenase by this class of inhibitors was proposed.

Lipoxygenase inhibitors: A comparative QSAR study review and evaluation of new QSARs

“…[24][25][26][27][28][29][30][31] Hlasta et al 32 prepared a series of 1-phenyl-3-pyrazolidinones and on the basis of a structure activity relationship study, using a multiple linear regression, 33 they proposed a mechanism for the inhibition of LO. For 21 compounds the best model that they found was: The model indicates that two descriptors log P and CNMR1 0 (the 13 C NMR shift at the carbon center C1 0 ) can be used to explain 79% of the total variance of the biological activity.…”

N‐Acylhydrazines: Future Perspectives Offered by New Syntheses and Chemistry

“…of n-butyllithium·N,N,NЈ,NЈ-tetramethylethylenediamine complex Ϫ with various electrophiles [25] (Scheme 9). These compounds inhibit the 5-lipoxygenase enzyme.…”

Inhibition of lipoxygenase affects induction of both direct and indirect plant defences against herbivorous insects

“…Exogenous application of phenidone resulted in a suppression of EFN secretion of nine Acacia species, but treatment with JA could restore the EFN secretion (Heil et al 2004). The inhibitory effect of phenidone is not restricted to LOXs from plants, it also inhibits lipo- and cyclooxygenases from animals (Cucurou et al 1991; Hlasta et al 1991; Li et al 2008). …”