Parameters molar refractivity

In this chapter, an attempt has been made to present a total number of 20 QSAR models (12 QSAR models for topo I inhibitors and eight QSAR models for topo II inhibitors) on 11 different heterocyclic compound series (an-thrapyrazoles, benzimidazoles, benzonaphthofurandiones, camptothecins, desoxypodophyllotoxins, isoaurostatins, naphthyridinones, phenanthridines, quinolines, quinolones, and terpenes) as well as on some miscellaneous heterocyclic compounds for their inhibition against topo I and II. They have been found to be well-correlated with a number of physicochemical and structural parameters. The conclusion, from the analysis of these 20 QSAR, has been drawn that the inhibition of topo I is largely dependent on the hydrophobicity of the compounds/substituents. On the other hand, steric parameters (molar refractivity, molar volume, and Verloop s sterimol parameters) are important for topo II inhibition. 

Dearden 1991 Hanch hydrophobic parameter, molar refractivity Substituted anilines... 

Other parameters (molar refractivity of the molecules/substituents, molar volume, Taft s steric constant, and Verio op s sterimol parameters) also appear in several QSAR. In some cases, these parameters correlate all of the observed variations in activity, but they do not seem to play as important a role as hydrophobicity for the data sets that we have examined. 

Parachor is the name (199) of a temperature-independent parameter to be used in calculating physical properties. Parachor is a function of Hquid density, vapor density, and surface tension, and can be estimated from stmctural information. Critical constants for about 100 organic substances have been correlated to a set of equations involving parachors and molar refraction (200). 

In this equation E (R2) is the excess molar refraction, S (tt ) is the solute dipolarity-polarizabiUty, A (2a ) and B(2 3 ) are the solute H-bond acidity and basicity, respectively, and Vis the McGowan characteristic volume (in cm mol /100). The solute size, V, (molecule favors octanol) together with solute H-bond basicity, B, (favors water) are the dominating parameters of this equation. The use of Bo(2P ) resulted in equation... 

Extensive data bases are now available which list lipophilicity, molar refractivity, electronic and steric values for a wide collection of substituents [27,28]. Starting from a particular parent compound one computes the value of a physicochemical parameter (e.g. lipophilicity) for a given drug by adding the contributions... 

A table of correlations between seven physicochemical substituent parameters for 90 chemical substituent groups has been reported by Hansch et al. [39]. The parameters include lipophilicity (log P), molar refractivity MR), molecular weight MW), Hammett s electronic parameters (a and o ), and the field and resonance parameters of Swain and Lupton F and R). 

The behavior of the different amines depends on at least four factors basicity, nucleophilicity, steric hindrance and solvation. In the literature (16), 126 aliphatic and aromatic amines have been classified by a statistical analysis of the data for the following parameters molar mass (mm), refractive index (nD), density (d), boiling point (bp), molar volume, and pKa. On such a premise, a Cartesian co-ordinate graph places the amines in four quadrants (16). In our preliminary tests, amines representative of each quadrant have been investigated, and chosen by consideration of their toxicity, commercial availability and price (Table 1). 

MR, the molar refractivity, which parameterizes polarizability and steric effects and Verloop s parameters, which are steric substituent values calculated from bond angles and distances. 

Using PCA, Cramer found that more than 95% of the variances in six physical properties (activity coefficient, partition coefficient, boiling point, molar refractivity, molar volume, and molar vaporization enthalpy) of 114 pure liquids can be explained in terms of only two parameters which are characteristic of the solvent molecule (Cramer 111, 1980). These two factors are correlated to the molecular bulk and cohesiveness of the individual solvent molecules, the interaction of which depends mainly upon nonspecific, weak intermolecular forces. 

Bioisosteric replacement can be made from a position of knowledge, if the desirable properties of the substituent or substructure to be changed have been characterized. Such properties can include (with typical parameters) (a) size (volume, molar refractivity, surface area, Taft s) (b) shape (Verloop length and breadth, bond angles, interatom distances) (c) lipophilicity (log P, tt,/) (d) solubility (log S) (e) ionization state (pKg, a) ... 

We are forced to reflect that the failure of so many attempts to improve on the DH theory can be attributed to a premature rejection of the DH approach, and a tendency to include extra parameters without proper theoretical foundation. It is surprising that although ionic polarization is emphasized in studies of solvation (36), molten salts (37), and chemistry in general (38), the phenomenon has received little attention in interionic theory. In particular, our attention is drawn to the early work of Fajans and co-workers (39), who first noted the effects of concentration on the ionic molar refractivities of solutions, which were interpreted in terms of a distorting effect on the ions. For various reasons the significance of this work has not been appreciated in the field of electrochemistry. 

Good correlations were also found between molecular connectivity indices of 4//-pyrido[ 1,2-a ]pyrimidin-4-ones and their partition coefficients and chromatographic parameters (83MI7,83MI9). Molar refractions (RM) of five 4//-pyrido[l, 2-a]pyrimidin-4-ones were determined in dioxane, and a good correlation was found between RMs and gas-chromatographic retention indices (/) (87MI2). 

---