Potent non-nucleoside inhibitors of the measles virus RNA-dependent RNA polymerase complex.
Measles virus (MV) is one of the most infectious pathogens known. In spite of the existence of a vaccine, approximately 350000 deaths/year result from MV or associated complications. Antimeasles compounds could conceivably diminish these statistics and provide a therapy that complements vaccine treatment. We recently described a high-throughput screening hit compound 1 (16677) against MV-infected cells with the capacity to eliminate viral reproduction at 250 nM by inhibiting the action of the virus's RNA-dependent RNA polymerase complex (RdRp). The compound, 1-methyl-3-(trifluoromethyl)- N-[4-sulfonylphenyl]-1 H-pyrazole-5-carboxamide, 1 carries a critical CF 3 moiety on the 1,2-pyrazole ring. Elaborating on the preliminary structure-activity (SAR) study, the present work presents the synthesis and SAR of a much broader range of low nanomolar nonpeptidic MV inhibitors and speculates on the role of the CF 3 functionality.
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA. asun2@emory.edu
Aiming
A
Sun
Jeong-Joong
JJ
Yoon
Yan
Y
Yin
Andrew
A
Prussia
Yutao
Y
Yang
Jaeki
J
Min
Richard K
RK
Plemper
James P
JP
Snyder
D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008459:Measles virus / Q000187:drug effects* / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects
D004791:Enzyme Inhibitors; D007093:Imidazoles; D008024:Ligands; D009705:Nucleosides; D010880:Piperidines; D011720:Pyrazoles; C031280:pyrazole; D012324:RNA-Dependent RNA Polymerase