Effect of the solvent-dependent conformational system of hydroxyureas on predicted vs. observed log P

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Abstract
Calculated and observed log P values are reported and compared with in vivo and in vitro biological action (L1210 leukemia [mouse] ILS% and ribonucleotide reductase ID50 [median inhibitory dose]) for hydroxyurea, the 1-N methyl and ethyl, and the 3-N ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl and p-chlorophenyl analogues. The log P values were calculated via the method of Hansch and Leo from literature f values and the observed log P values were obtained by direct determination after equilibration between octanol and water. Calculations of log P for hydroxyurea were found to be appreciably more hydrophilic than the values obtained experimentally. Differences in calculated and observed log P (.DELTA. log P) for the substituted analogues were lowest with the 1-N and the bulky 3-N substituents and greatest with the 3-N-substituted straight-chain analogues (.DELTA. log P = 0.70). Different structural species were observed by IR spectroscopy in dry octanol vs. octanol after water equilibration and drying, and this is proposed as due to changes in conformational equilibrium in the hydroxyurea systems. Differences between calculated and observed log P are explained via the stabilization of internally H-bonded conformers in the case of 1-N or bulky 3-N analogues or destabilization of various conformers allowing maximal interactions with solvent or water which is the case with straight chain 3-N analogues.

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