Introduction
Introducing fluorine atom(s) into bioactive organic compounds has become a leading strategy for drug design and lead optimization. In drug synthesis strategy, fluorine is frequently employed to modify biologically relevant properties such as metabolic stability, basicity, lipophilicity and bioavailability. Additionally, the binding affinity of compounds to biological targets may also improve upon fluorination, therefore fluorine is considered an excellent candidate to serve as a bioisostere of hydroxyl, thiol or amine groups.
Fig 1 Difluoromethyl group
Nowadays, there is a growing interest in organic compounds containing the difluoromethyl group, since it may hold some distinct advantages arising from its unique chemical and physical properties. The difluoromethyl group acts as a lipophilic hydrogen bond donor on a scale similar to that of thiophenol, aniline and amine groups, but not as that of hydroxyl. In particular, replacing a methyl with the difluoromethyl group may lead to a smaller lipophilicity increase relative to trifluoromethyl and provides new hydrogen bonding ability. For example, a series of ArOCF2H compounds exhibit high lipophilicity as well as hydrogen bond acidity (Fig 1).
Fig 2 Physicochemical properties of CF2H group
(J. Med. Chem., 2017, 60 (2), pp 797–804)
Application in drug design
With extraordinary chemical and physical properties, difluoromethyl group can be applied in drug design. More precise design rules may be set for fine tuning of the replacement of OCH3 with OCF2H according to the needed change in the molecule.
