Solvation enthalpies as descriptors of structure - in vitro percutaneous permeation relationship of benzoxazinones regioisomers

The aim of this work was to correlate the in vitro human skin permeability, expressed as the permeability coefficient (K-p), and some physicochemical parameters of a new series of benzoxazinones. The in vitro human skin perme ability of 14 substances, including regioisomers with CH3, OH, OCH3, and Cl groups in different positions on the aromatic ring, was determined. The mo dified Franz diffusion cell method was used. The K-p values were in the ran ge 0.14-8.24 cm/h, showing a strong dependence on the position and type of substituent. Physicochemical descriptors usually referred in literature, su ch as log P, molecular weight and volume (MV), hydrogen bond donor (H-d) an d acceptor activity (H-a), and molecular refractivity were considered, with the addition of solvation enthalpy (Delta DeltaH(solv)). Delta DeltaH(solv ) is defined as the difference between formation enthalpies in water and oc tanol. The algorithm with the best correlation between K-p and physicochemi cal descriptors was calculated, taking into account the differences observe d among the regioisomers. The algorithm obtained with Delta DeltaH(solv) ha d a good correlation (r(2) = 0.749, F = 16.43, P = 0.0005), comparable with the equation, proposed by Potts and Guy, based on MV, H-d and H-a (r(2) = 0.830, F = 16.3, P = 0.0004). (C) 2000 Elsevier Science S.A. All rights res erved.