Quantitative structure activity organic compounds

A challenging task in material science as well as in pharmaceutical research is to custom tailor a compound s properties. George S. Hammond stated that the most fundamental and lasting objective of synthesis is not production of new compounds, but production of properties (Norris Award Lecture, 1968). The molecular structure of an organic or inorganic compound determines its properties. Nevertheless, methods for the direct prediction of a compound s properties based on its molecular structure are usually not available (Figure 8-1). Therefore, the establishment of Quantitative Structure-Property Relationships (QSPRs) and Quantitative Structure-Activity Relationships (QSARs) uses an indirect approach in order to tackle this problem. In the first step, numerical descriptors encoding information about the molecular structure are calculated for a set of compounds. Secondly, statistical and artificial neural network models are used to predict the property or activity of interest based on these descriptors or a suitable subset. 

We have developed a quantitative structure-activity model for the variations in potency among the nitrosamines and, more recently, a related model for the variation in target organ for a smaller set of nitrosamines. We are currently developing a model for interspecies variation in susceptibility toward carcinogenic nitrosamines. The model for organ selectivity requires terms for the parent nitrosamine as well as for the hypothesized metabolites while the model for potency variations contains terms only for the unmetabolized parent compound. 

Hu, Q., Wang, X., and Brusseau, M.L. Quantitative structure-activity relationships for evaluating the influence of sorbate structure on sorption of organic compounds by soil, iujFiron. Toxicol. Chem., 14(7) 1133-1140, 1995. 

The lipophilic behaviour of organic compounds 1. An updating of the hydrophobic fragmental constant approach. Quantitative Structure-Activity Relationships, 17, 517-536. 

Rekker, R.F., Mannhold, R., Biljoo, G., de Vries, G. and Dross, K. (1998) The lipophilic behaviour of organic compounds 2. The development of an aliphatic hydrocarbon/water fragmental system via interconnection with octanol-water partitioning data. Quantitative Structure-Activity Relationships, 17, 537-548. 

Quantitative structure-activity relationship studies are of great importance in modern chemistry. From their origin in the study of organic chemistry dating back to the 19th century, these studies have relied on some empirical and qualitative rules about the reactivity similarities of compounds with similar structures. The most significant development in QSARs occurred with the work of Louis Hammett (1894-1987), who correlated some electronic properties of organic acids and bases with their equilibrium constants and reactivity (Johnson, 1973). Hammett postulated that the effect... 

Clearly, molecular structure influences the reaction kinetics of organic compounds during their photocatalytic oxidation. This relationship between degradability and molecular structure may be described using quantitative structure-activity relationship (QSAR) models. QSAR models can be developed to predict kinetic rate constants for organic compounds with similar chemical structures. The following section discusses QSAR models developed by Tang and Hendrix (1998) as well as those developed by other researchers. 

Methods to predict the hydrolysis rates of organic compounds for use in the environmental assessment of pollutants have not advanced significantly since the first edition of the Lyman Handbook (Lyman et al., 1982). Two approaches have been used extensively to obtain estimates of hydrolytic rate constants for use in environmental systems. The first and potentially more precise method is to apply quantitative structure/activity relationships (QSARs). To develop such predictive methods, one needs a set of rate constants for a series of compounds that have systematic variations in structure and a database of molecular descriptors related to the substituents on the reactant molecule. The second and more widely used method is to compare the target compound with an analogous compound or compounds containing similar functional groups and structure, to obtain a less quantitative estimate of the rate constant. 

Systematic studies of the effects of structure on the biological activities of organic compounds and the analysis of the results are comprised in the term Quantitative Structure-Activity Relationships (QSAR). Many of the treatments employed in the correlation analysis of data in this field closely resemble those used for linear free-energy relationships, e.g. the Hammett equation and extensions thereof, and so the study of the biological properties of organic compounds is often regarded as a part of physical organic chemistry. In recent years, some historical study of work in... 

As will be seen, the large amount of quantitative structure-activity relationship (QSAR) modeling that has been carried out for soil sorption has almost exclusively involved nonionic organic compounds. For strongly ionizing and inorganic chemicals, no QSARs are available. However, Bintein and Devillers (1994) developed a soil sorption QSAR that incorporated correction factors for ionization of weak acids and bases. 

Toxicity is measured by the concentration in mg liter-1 of a compound that causes the death of a certain percentage (usually 50 or 100%) of the test population of a chosen organism (e.g., silvery minnows) in a chosen time (e.g., 96 hours). For organic inhibitors, the higher the concentration needed to achieve a lethal dose of 50%, the less toxic the inhibitor. In Table 12.3 the actual lethal concentration (LC50) (at 96 hr) is compared with that calculated by means of a quantitative structure-activity relation (QSAR). The basic calculation is that of the distribution coefficient of the inhibition of the primary alcohol octanol. 

Common unspecific mode of action of all organic compounds has been taken up in quantitative structure-activity relationships (QSARs see Chapter 5) as the concept of baseline toxicity and in toxicokinetics as the body burden concept (see Chapter 2). Baseline toxicity refers to the idea that a minimum toxicity expectation may be formulated for any given organic compound based on considerations of a compound s partition properties between hydrophilic and lipophilic chemicals (e.g., between water and octanol). Commonly, this is expressed in terms of the octanol-water partition coefficient (K0,J of a chemical. The partition coefficient allows estimations of a local concentration or body burden for each individual chemical in the mixture. Assuming that this produces the same toxic effect (disturbances of cell membranes), it is then possible to anticipate joint narcotic action by adding together the respective local concentrations or body burdens for each individual mixture component. 

Other Examples of the Use of Principal Properties Characterization by principal properties has been reported for classes of compounds in applications other than organic synthesis Aminoacids, where principal properties have been used for quantitative structure-activity relations (QSAR) of peptides [64], Environmentally hazardous chemicals, for toxicity studies on homogeneous subgroups [65]. Eluents for chromatography, where principal properties of solvent mixtures have been used for optimization of chromatographic separations in HPLC and TLC [66],... 

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