Development of 2-(Trifluoromethyl)pyridine Peptide Derivatives: Synthesis and Computational Studies

Herein we report the synthesis and characterization of pyridine–peptide conjugates containing a trifluoromethyl group by a the acid–amine coupling reaction between (E)-3-[6-(trifluoromethyl)pyridin-3-yl]acrylic acid and various amino acids. The synthetic route involves a straightforward acid–amine coupling reaction. The resulting conjugates were characterized by ¹H and ¹³C NMR spectroscopy and mass spectrometry. To evaluate the antibacterial and antimalarial potentials of the synthesized conjugates, we performed their molecular docking to Mycobacterium tuberculosis enoyl-ACP reductase (PDB ID: 4TZK), Pseudomonas aeruginosa LysR-type transcriptional regulator (PDB ID: 7NBW), and Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PDB ID: 3QG2) was used to elucidate the ligand–protein binding modes, intermolecular interactions, and affinities, which was also used to assess and justify the stability of the ligands in the receptor site. The computational study allowed us to identify the products with potential antimalarial and anti-tubercular properties and favourable ADMET profiles, among which (E)-(N-{3-[6-(Trifluoromethyl)pyridin-3-yl]acryloyl}prolyl)phenylalanine showed strong binding affinities to multiple targets).