Effects of intramolecular hydrogen bonds on lipophilicity.

Intramolecular hydrogen bonds (IMHBs) affect the lipophilicity and physicochemical properties of small organic molecules and drug candidates. Considering IMHBs in drug design is an important strategy for improving the lipophilicity and physicochemical properties of drug candidates. However, how IMHBs affect the lipophilicity and partition coefficients are not well understood. Based on the relationship between the effect of IMHBs on the experimental partition coefficients and the H-bonding capabilities of H-bond forming atoms, we explore how IMHBs affect water/n-octanol partition coefficients, water/chloroform partition coefficients, water/hexadecane partition coefficients and lipophilicity. We found that IMHBs may increase or decrease or have no effect on water/n-octanol partition coefficients, but always increase water/chloroform partition coefficients, water/hexadecane partition coefficients and lipophilicity. We introduced ΔHBC, which is the difference between the calculated and actual H-bonding capabilities of molecules, for assessing the propensity of molecules to form IMHBs and the relative strengths of IMHBs. This study may help to improve the physicochemical properties of drug candidates and increase the success of drug design.