Design, synthesis, and evaluation of trifluoromethyl ketones as inhibitors of SARS-CoV 3CL protease.
A series of trifluoromethyl ketones as SARS-CoV 3CL protease inhibitors was developed. The inhibitors were synthesized in four steps from commercially available compounds. Three different amino acids were explored in the P1-position and in the P2-P4 positions varying amino acids and long alkyl chain were incorporated. All inhibitors were evaluated in an in vitro assay using purified enzyme and fluorogenic substrate peptide. One of the inhibitors showed a time-dependent inhibition, with a K(i) value of 0.3 microM after 4h incubation.
Shao
Yi-Ming
YM
Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 11529, Taiwan.
Yang
Wen-Bin
WB
Kuo
Tun-Hsun
TH
Tsai
Keng-Chang
KC
Lin
Chun-Hung
CH
Yang
An-Suei
AS
Liang
Po-Huang
PH
Wong
Chi-Huey
CH
D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D017611:Fluorine Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006860:Hydrogen Bonding; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008745:Methylation; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D017611:Fluorine Compounds; D007659:Ketones; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases