Bioactivity profiles of progressively ring-fluorinated cyclohexyl motifs in the WKYMVm peptide as formylpeptide FPR2 agonists and in keto-piperazines as antitrypanosome agents

A series of all-cis-ring-fluorinated cyclohexylalanines with progressively increasing levels of vicinal fluorines, as well as 4-fluorophenylalanine and pentafluoroarylphenylalanine is introduced into the WKYMVm peptide in place of its tyrosine residue, for assays against the G-protein coupled formylpeptide receptor, FPR2. Selected all-cis-ring cyclohexylalanines of this class are also incorporated into a keto-piperazine molecular scaffold to generate sp³-rich derivatives for assays against the parasite Trypanosoma brucei. For these cyclohexylalanine analogs bioactivity trends correlate progressively with the levels of fluorination in each of the case studies. Notably, the all-cis pentafluorocyclohexylalanine analog of the W-peptide is least active perhaps correlating with the well-known polarity of this ‘Janus face’ cyclohexane. Although the trend is also apparent in the anti-trypanosomal assays of the keto-piperazine derivatives, it is less so and some compounds are more active than the previously reported phenylalanine-derived analog.