Quantitative structure-activity substituent effects

The fundamental assumption of SAR and QSAR (Structure-Activity Relationships and Quantitative Structure-Activity Relationships) is that the activity of a compound is related to its structural and/or physicochemical properties. In a classic article Corwin Hansch formulated Eq. (15) as a linear frcc-cncrgy related model for the biological activity (e.g.. toxicity) of a group of congeneric chemicals [37, in which the inverse of C, the concentration effect of the toxicant, is related to a hy-drophobidty term, FI, an electronic term, a (the Hammett substituent constant). Stcric terms can be added to this equation (typically Taft s steric parameter, E,). 

Quantitative structure-activity relationships (QSARs) are important for predicting the oxidation potential of chemicals in Fenton s reaction system. To describe reactivity and physicochemical properties of the chemicals, five different molecular descriptors were applied. The dipole moment represents the polarity of a molecule and its effect on the reaction rates HOMo and LUMO approximate the ionization potential and electron affinities, respectively and the log P coefficient correlates the hydrophobicity, which can be an important factor relative to reactivity of substrates in aqueous media. Finally, the effect of the substituents on the reaction rates could be correlated with Hammett constants by Hammett s equation. 

Sotomatsu, T., Nakagawa, N., Fujita, T. (1987) Quantitative structure-activity studies of benzoylphenylurea larvicides. IV. Benzoyl ortho substituent effects and molecular conformation. Pestic. Biochem. Physiol. 27, 156-164. 

Quantitative structure-activity relationship (QSAR) (Hansch and Klein, 1986 Hansch and Leo, 1995) represents an attempt to correlate structural descriptors of compounds with activities. The physicochemical descriptors include numerical parameters to account for electronic properties, steric effect, topology, and hydrophobicity of analogous compounds. In its simplest form, the biochemical activities are correlated to the numerical substituent descriptors of analogous compounds tested by a linear equation such as... 

The above queries are only a few of the scores which one can readily imagine to be of value in a truly comprehensive quantitative structure-activity system. In addition to structure—activity equations correlating biochemical systems it is important to include in the data bank as many examples as possible of substituent effects in homogeneous organic reac-... 

Halogens (particularly chlorine) can be replaced by other electron-attracting functions snch as trifluoromethyl or cyano groups. In the antibiotic chloramphenicol, both the chlorine atoms of the dichloroacetic moiety and of the para-nitro-phenyl group yielded productive isosteric replacements (Table 15.6). Many other examples of univalent atoms or groups replacements are found in the chapter dealing with substituent effects (Chapter 20) and with quantitative structure-activity relationships (Chapter 23). 

A quantitative structure-activity relationship for the negative inotropic activity of a small series of 1,4-dihydro-pyridines has been developed (47.). For 2,6-dimethyl-3,5-dicarbo-methoxy-4-(substituted phenyl)-1,4-dihydropyridines the effect of the phenyl substituent is determined primarily by steric effects. Thus, for ortho-substituted derivatives,... 

Interestingly, most quantitative structural activity relationship (QSAR) studies usually commence by considering o (Hammett substitution constant) and, in case there exists more than one substituent, the a values are represented in a summed up manner as Za. Keeping in view the enormous quantum of synthetic newer target drug molecules, it has now become almost necessary and possible either to modify/refine or fine tune-up the QSAR equation. In fact, a substituent s resonance effect (R) and inductive effect (F) may be quantified as far as possible with the help of available tables of constants . In certain instances one may evidently observe that ... 

In this chapter, we have developed predictive models based on two well es-tabhshed methods (1) hierarchical quantitative structure-activity (HiQSAR) modeling, and (2) quantitative molecular similarity analysis (QMSA). We have reviewed published work in both of the above areas for important classes of heterocyclic compounds that have therapeutic and toxic effects. Predictive models can be developed based on experimental properties, substituent constants derived from such properties, and also theoretical descriptors which can be calculated directly from molecular structure, hi view of the fact that most potential therapeutic agents and the majority of known drugs and toxicants do not have experimental data available for their evaluation, theoretical descriptors are very useful in the initial screening of compound libraries. 

Linear Free-Energy-Related Model - On the other hand, more emphasis has been placed on the correlation of observed biological activity with measured physicochemical parameters of related compounds than in previous years. Hansch has given the historical development of the use of substituent constants and certain physicochemical parameters in quantitative structure-activity studies of biochemical systems. Specifically, he has dealt with the dependence of biological activity of drug molecules upon partitioning properties, electronic parameters, and steric effects. "... 

The study of structure-reactivity relationships by the organic chemist Hammett showed that there is often a quantitative relationship between the two-dimensional structure of organic molecules and their chemical reactivity. Specifically, he correlated the changes in chemical properties of a molecule that result from a small change in its chemical structure that is, the quantitative linear relationship between electron density at a certain part of a molecule and its tendency to undergo reactions of various types at that site. For example, there is a linear relationship between the effea of remote substituents on the equilibrium constant for the ionization of an acid with the effect of these substituents on the rate or equilibrium constant for many other types of chemical reaction. The relative value of Hammett substituent constants describes the similarity of molecules in terms of electronic properties. Taft expanded the method to include the steric hindrance of access of reagents to the reaction site by nearby substituents, a quantitation of three-dimensional similarity. In addition, Charton, Verloop, Austel, and others extended and refined these ideas. Finally, Hansch and Fujita showed that biological activity frequently is also quantitatively correlated with the hydrophobic character of the substituents. They coined the term QSAR, Quantitative Structure-Activity Relationships, for this type of analysis. 

The alternatives to mathematical descriptors derived from molecular graphs or molecular geometry are the traditional QSAR (quantitative structure-activity relationship) descriptors and quantum chemically computed parameters. The former include the partition coefficient for oil/water (often octanol/water) (log P), the Hammet sigma value (electronic parameter that measures the electron withdrawal from and the electron release to the aromatic ring by a substituent, the Taft s parameters for the electronic effects of substituents in aliphatic compounds (a ), and a steric parameter for the proximity of substituents on reaction sites (Es)- Also selected molecular properties, such as molar refractivity (MR), polarizability (a), molecular weight (MW), and density (d), have been used. 

A series of mono- and dialkylated, chiral 1,2-amino-phosphinamide ligands (752) have been successfully applied in the chiral phosphinamide-Zn(ii) catalysed asymmetric Henry reaction between benzaldehyde and nitromethane (Scheme 210). The effects of the N-substituent sizes of chiral ligands (752) on the enantioselectivities in this reaction have been correlated using a predictive quantitative structure-activity relationship (QSAR) mathematical model. A quantitative correlation model has been also established based on subtractive Sterimol parameters. Ligand optimisation based on the QSAR model led to chiral 1,2-amino-phosphinamide ligand (752a), which produced (R)-p-nitroalcohol (753) in excellent yield (99%) and enantioselectivity (92% ee). ... 

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