Stereoselective Synthesis of Peptidyl Trifluoromethyl Alcohols and Ketones: Inhibitory Potency Against Human Leucocyte Elastase,Cathepsin G,Porcine Pancreatic Elastase and HIV-1 Protease

New fluorinated inhibitors have been designed to target two major proteases—human leucocyte elastase and HIV-1 protease. Two series of β-peptidyl trifluoromethyl alcohols (TFMAs) Z-L-Val-NH-*CH(Y)-*CH(OH)-CF₃, where *C is the chiral centre, varied in the nature of the substituent Y, a phenylethyl [-(CH₂)₂-C₆H₅] or an isopropyl [-CH(CH₃)₂] group. These TFMAs were first synthesized as two pairs of the syn and anti diastereoisomers. The inhibitory effects of these mixtures were then assessed on three serine proteases chosen on the basis of the aromatic and aliphatic nature of the substituents—human leucocyte elastase (HLE), human cathepsin G (HCG) and porcine pancreatic elastase (PPE). In the presence of detectable inhibition, each epimer at C2 was separated to determine its inhibition constant (K_i) towards HLE, HCG and PPE. The stereoisomerically pure TFMAs were then oxidized into peptidyl trifluoromethyl ketones = 5·65 × 10^?4 M). The tested compounds also had structural properties compatible with recognition by HIV-1 protease. The inhibition of the enzyme was observed with TFMK only (IC50 = 15–200 μM). The phenylethyl substituent promoted inhibition by a factor of 10 (IC50 = 15μM) compared with the isopropyl substituent (IC50 = 200 μM) leading to selective inhibition of HIV-1 protease. Isomerically pure TFMKs were more potent towards HLE than the alcohols from which they were obtained. However, an enantiomerically pure TFMA selectively inhibited HLE unlike its TFMK analogue which also inhibited PPE. This last result together with the selective inhibition of HIV-1 protease by TFMK with a phenylethyl substituent might be relevant to the design of specific HLE and HIV-1 inhibitors as therapeutic agents.