The lipophilic behaviour of organic compounds: 1. An updating of the hydrophobic fragmental constant approach

Abstract

In the ®rst part of this paper we brie¯y describe experimental (octanolywater partitioning) as well as computational approaches to quantifying molecular lipophilicity. The central section focuses on the hydrophobic fragmental constant approach (Sf -system) as developed by Rekker and his group, starting in the early seventies. The original approach has been extended and revised a number of times; the most recent updating is presented here. It is followed by a detailed description of how to apply the correction factor C M . The practical procedure of Sf-calculations is described for some examples and the validity of these calculations is veri®ed by comparison with other calculation methods and experimental data.

Tritylamino Aromatic Heterocycles and Related Carbinols as Blockers of Ca 2+-Activated Potassium Ion Channels Underlying Neuronal Hyperpolarization

“…Clotrimazole is a very lipophilic compound having an octanol-water partition coefficient log P = 6.50 (estimated using the revised fragmental constants f of Rekker [20]) (CLOG P [21] = 5.05).The carbinols (2a-d) are also lipophilic, ranging from log P 4.37 (2c) to 6.44 (2d) (CLOG P from 3.89 to 6.02); the most potent of these compounds (2a, 2b), however, have log P = 5.10 (CLOG P = 4.60), i.e. intermediate between these two extreme values.This may suggest that there is an optimum value for log P for the carbinols.…”

QSAR: a abordagem de Hansch

“…Assim, Rekker 9,51,52 considerando este conceito, observou que a aplicação do parâmetro π de Hansch em sistemas contendo cadeias alifáticas resulta em falhas no princípio de aditividade 3,11 . Por esta razão este autor, revendo a contribuição de grupos substituintes individuais para a hidrofobicidade da molécula, definiu o parâmetro ƒ por meio da Equação 14:…”

Prediction of Log P with Substructure‐Based Methods

“…The actual Σ f system [34] lists 13 correction rules and 169 fragment values, including 14 new heterocyclic fragments as well as doubly and triply halogenated methyls. A typical calculation is depicted in Fig.…”