Fluorine tweak shows promise for redesigning drug molecules
Researchers have identified a simple chemical modification—adding fluorine atoms—that reshapes how drug candidate molecules fold inside the body. The discovery could help pharmaceutical companies engineer better medicines with improved effectiveness and faster metabolism, potentially accelerating drug development timelines and reducing late-stage clinical failures.
Originaltitel: The effect of <em>gem</em>-difluorination on the conformation and properties of a model macrocyclic system
<p>Conformational control of drug candidates to engineer improved potency and ADME properties is an ongoing area of research. Macrocyclic rings tend to offer a greater degree of rigidity than non-cyclised small molecules, and, as a result they are perfect platforms to instil conformational controls. In this study, the difluoroalkoxyphenyl moiety is examined as a tool to alter the conformation of macrocycles. A fluorinated and non-fluorinated macrocyclic matched pair is compared in terms of conformation preferences and related ADME properties. The synthesised macrocycles are found to give similar major conformations exhibiting a <em>trans</em> amide in the macrocyclic backbone. However, for the fluorinated macrocycle, the major <em>trans</em> amide conformation is in equilibrium with a <em>cis</em> amide minor conformation, seen by <sup>1</sup>H NMR in a 4 : 1 ratio of <em>trans</em>/<em>cis</em>. The conformational fits for the minor fluorinated isomer demonstrate the out of plane preference of the difluoroalkoxy system encouraging the amide within the macrocycle backbone to adopt a <em>cis</em> conformation. The fluorinated macrocycle was less metabolically stable compared to the non-fluorinated, postulated to be a result of the interconversion of <em>trans</em> amide to the <em>cis</em> amide, which potentially could be more readily metabolised.</p>