New 1-phenyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides inhibit hepatitis C virus replication via suppression of cyclooxygenase-2

作者：Manvar Dinesh; Pelliccia Sveva; La Regina Giuseppe; Famiglini Valeria; Coluccia Antonio; Ruggieri Anna; Anticoli Simona; Lee Jin Ching; Basu Amartya; Cevik Ozge; Nencioni Lucia; Palamara Anna Teresa; Zamperini Claudio; Botta Maurizio; Neyts Johan; Leyssen Pieter; Kaushik Basu Neerja^*; Silvestri Romano

来源：European Journal of Medicinal Chemistry, 2015, 90: 497-506.

DOI：10.1016/j.ejmech.2014.11.042

• HCV
• Subgenomic replicon 1b genotype
• Cyclooxigenase-2
• Pyrazolecarboxamide

We report here the synthesis and mechanism of inhibition of pyrazolecarboxamide derivatives as a new class of HCV inhibitors. Compounds 6, 7, 8 and 16 inhibited the subgenomic HCV replicon lb genotype at EC50 values between 5 and 8 mu M and displayed an even higher potency against the infectious Jc1 HCV 2a genotype. Compound 6 exhibited an EC50 of 6.7 mu M and selectivity index of 23 against HCV 1b, and reduced the RNA copies of the infectious Jc1 chimeric 2a clone by 82% at 7 mu M. Evaluation of the mode of anti-HCV activity of 6 revealed that it suppressed HCV-induced COX-2 mRNA and protein expression, displaying an IC50 of 3.2 mu M in COX-2 promoter-linked luciferase reporter assay. Conversely, the anti-HCV activity of 6 was abrogated upon over-expression of COX-2. These findings suggest that 6 as a representative of these pyrazolecarboxamides function as anti-HCV agents via targeting COX-2 at both the transcription and translation levels.

• 出版日期2015-1-27
• 单位rutgers; 河北医科大学