Structure-activity relationships homologous series

G. S. Estus, J. J. Mieyal, Structure-Activity Relationship for Deacetylation of a Homologous Series of Phenacetin Analogs and Their V-Hydroxy Derivatives , Drug Metab. Dispos. 1983, 11, 471-476. 

Structure-activity relationships are generally applied in the pharmaceutical sciences to drug molecules. The value of any structure-activity correlation is determined by the precision of the biological data. So it is with studies of the interaction of nonionic surfactants and biomembranes. Analysis of results is complicated by the difficulty in obtaining data in which one can discern small differences in the activity of closely related compounds, due to i) biological variability in tissues and animals, ii) potential differential metabolism of the surfactants in a homologous series (2), iii) kinetic and dynamic factors such as different rates of absorption of members of the surfactant homologous series (2) and iv) the typically biphasic concentration dependency of nonionic surfactant action (3 ). 

Regression equations descriptive of multi-dimensional structure/ activity relationships in quantitative terms too frequently are intellectual curiosities developed retrospectively after work in optimization of the biological properties of a series by analog or homolog synthesis has been completed. Retrospective analysis serves well to document that critical factors in the relationship between structural features/physiochemical factors and biological potency are well understood and that optimum compounds have been achieved. Structure/activity understanding developed during the course of a synthesis project, however, lends direction and efficiency to the property optimization effort. 

Lewis, D. F. V., Wiseman, A., and Tarbit, M. H. (1999) Molecular modeling of lanosterol 14-alpha-demethylase (CYP51) from Saccharomyces cerevisiae via homology with CYP102, a unique bacterial cytochrome P450 isoform quantitative structure-activity relationships (QSARs) within two related series of antifungal azole derivatives../. Enz. Inhib. 14, 175-192. 

For the sake of brevity, salient aspects of key structure-activity relationships in one homologous series of twelve mono- and bis-acyl homologated spermine analogues (Fig. 12.8) will be first discussed (Miller et al., 2005). We addressed two questions in this study (i) what is the optimal hydrophobic chain length for effective anti-endotoxic activity, (ii) are symmetrical bis-acyl spermines more effective than mono-acyl compounds We found that a carbon number of 14-16 is optimal in mono-acyl spermines (Fig. 12.9) which are, in general, as potent as... 

Studies on structure-activity relationships between herbicides and homologous series of surfactants indicate that definite relationships exist between the herbicide and surfactant structure for maximum herbicide penetration. The length of the molecular chains (either hydrophilic or lipophilic) of a surfactant molecule appears to have considerable influence on herbicide penetration, and the surfactant concentration also influences this process markedly. 

In keeping with this method, several approaches have been developed to document methods and dose-response relationships for irritation in humans. This work suggests that, at least for nonreactive compounds such esters, aldehydes, ketones, alcohols, carboxylic acids, aromatic hydrocarbons, and pyridine, the percentage of vapor pressure saturation of a compound is a reasonable predictor of its irritant potency. Specific physical properties of molecules predict overall irritation potential. This work is based on the identification of irritant thresholds for homologous series of specific agents. Quantitative structure-activity relationships derived from such work suggests a reasonable model to explain mucosal irritation. 

There is a limited structure-activity relationship (SAR) provided around this series. However, an optimal chain length of three carbon atoms between the phenothiazine and the piperidine is demonstrated. The two-carbon-linked homolog has significantly reduced activity (IC50 < 20% at 30 juM) and the four-carbon tether is at least 3 times less active than (1). 

To find the structure-activity relationships in this series esters of both non-substituted 3-hydroxyquinuclidine and 3-hydroxyquinuclidines having various substituents in the 3-, 6- and other positions have been synthesized. Esters of homologous aminoalcohols 3-hydroxymethyl- and 3-(j8-hydroxyethyl)-qui-nuchdines, esters of isomeric and homologous 1-azabicycloalkanols - 1-aza-bicyclo(3,2,l)-octanol-6 and l-azabicyclo(3,3,2)-nonanole-4 and also esters containing the opened 3-hydroxy-quinuclidine structure, e.g. AT-alkyl-3-hy-... 

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