TAILIEUCHUNG - Pyrazole compound BPR1P0034 with potent and selective anti-influenza virus activity

Influenza viruses are a major cause of morbidity and mortality around the world. More recently, a swineorigin influenza A (H1N1) virus that is spreading via human-to-human transmission has become a serious public concern. Although vaccination is the primary strategy for preventing infections, influenza antiviral drugs play an important role in a comprehensive approach to controlling illness and transmission. In addition, a search for | Shih et al. Journal of Biomedical Science 2010 17 13 http content 17 1 13 I NSC The cost of publication in Journal of Biomedical Science is bourne by the National Science Council Taiwan. JOURNAL OF BIOMEDICAL SCIENCE RESEARCH Open Access Pyrazole compound BPR1P0034 with potent and selective anti-influenza virus activity Shin-Ru Shih1 3 Tzu-Yun Chu2 Gadarla Randheer Reddy4 Sung-Nain Tseng1 3 Hsiun-Ling Chen2 Wen-Fang Tang2 Ming-sian Wu2 Jiann-Yih Yeh4 Yu-Sheng Chao4 John TA Hsu4 5 Hsing-Pang Hsieh 4 and Jim-Tong Horng 2 3 Abstract Background Influenza viruses are a major cause of morbidity and mortality around the world. More recently a swineorigin influenza A H1N1 virus that is spreading via human-to-human transmission has become a serious public concern. Although vaccination is the primary strategy for preventing infections influenza antiviral drugs play an important role in a comprehensive approach to controlling illness and transmission. In addition a search for influenzainhibiting drugs is particularly important in the face of high rate of emergence of influenza strains resistant to several existing influenza antivirals. Methods We searched for novel anti-influenza inhibitors using a cell-based neutralization inhibition of virus-induced cytopathic effect assay. After screening 20 800 randomly selected compounds from a library from ChemDiv Inc. we found that BPR1P0034 has sub-micromolar antiviral activity. The compound was resynthesized in five steps by conventional chemical techniques. Lead optimization and a structure-activity analysis were used to improve potency. Time-of-addition assay was performed to target an event in the virus life cycle. Results The 50 effective inhibitory concentration IC50 of BPR1P0034 was pM when measured with a plaque reduction assay. Viral protein and RNA synthesis of A WSN 33 H1N1 was inhibited by BPR1P0034 and the virus-induced cytopathic effects were thus significantly reduced. BPR1P0034 exhibited .

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