Constants for pi and omega ahve been measured for a miscellaneous group of aromatic substituents of interest to medicinal chemists. Swain and Lupton's gamma and kappa values have been calculated from the omego constants. Values for molar refractivity are also given for each of the substituents.

The highest level of confidence can be placed in calculated log P values when (1) the log P of a parent solute is known, (2) pi constants for the required substituent(s) are available, and (3) the substituents either do not have an effect on groups already present in the parent or else this effect has been previously determined. In some instances there are no values available for any related structures which could serve as a parent; then, rather than substitute groups for hydrogen, it is easier to begin "from scratch", as suggested by Nys and Rekker, and assemble the structure from fragments, each of which has been assigned a hydrophobic value. In the present paper some new log P values for the lower alkanes and the inert gases are analyzed with the view of separating hydrophobic effects according to volume (including branching and flexibility) and polarity. Modified fragment values appear to enable reliable calculations to be made for a wider range of structures than was possible with the originally proposed constants.

Cavity size is the primary determinant of the partition coefficient (P) of apolar solutes between octanol and water. Although the energy of cavity formation would be expected to be related to cavity area, older methods of area calculation give a poorer correlation with log P than does volume. Apolar solutes clearly fall into two classes based on their log P/volume relationship, the distinction possibly being whether the solute exposes mostly hydrogen atoms or unbonded electrons.

A quantitative structure-activity relationship (QSAR) has been formulated for the inhibition of purified E. coli dihydrofolate reductase by 23 5-(substituted benzyl)-2,4-diaminopyrimidines: log 1/C = 1.14MR'3,4,5 + 5.73; r = 0.887; s = 0.285. In this expression, MR'3,4,5 refers to the sum of MR values for X in the 3, 4 and 5 positions of the phenyl moiety. MR' signifies that the effective value of MR is limited to 0.79. Comparison of the QSAR for E. coli enzyme inhibition with that previously obtained for bovine enzyme offers the first general explanation for the great selectivity of the important antibacterial agent trimethoprim. Such QSSR promise to be of value in devising more selective drugs.

Partition coefficients of 32 gaseous anesthetics in the octanol-water system have been determined. It is shown that relative anesthetic potency depends on hydrophobicity of the anesthetic (as defined by log P) and on a polar factor. The presence of a polar hydrogen in the anesthetic greatly increases potency. A quantitative structure-activity relationship is formulated based on these two factors.