title: Design, synthesis, and structure-activity relationships of pyrazolo[3,4-d]pyrimidines: a novel class of potent enterovirus inhibitors.
abstract: A series of pyrazolo[3,4-d]pyrimidines were synthesized and their antiviral activity was evaluated in a plaque reduction assay. It is very interesting that this class of compounds provide remarkable evidence that they are very specific for human enteroviruses, in particular, coxsackieviruses. Some derivatives proved to be highly effective in inhibiting enterovirus replication at nanomolar concentrations. SAR studies revealed that the phenyl group at the N-1 position and the hydrophobic diarylmethyl group at the piperazine largely influenced the in vitro antienteroviral activity of this new class of potent antiviral agents. It was found that the pyrazolo[3,4-d]pyrimidines with a thiophene substituent, such as compounds 20-24, in general exhibited high activity against coxsackievirus B3 (IC(50) = 0.063-0.089 microM) and moderate activity against enterovirus 71 (IC(50) = 0.32-0.65 microM) with no apparent cytotoxic effect toward RD (rhabdomyosarcoma) cell lines (CC(50) > 25 microM).
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Taipei 114, Taiwan, ROC. jhchen@nhri.org.tw
authors.forename: Jyh-Haur
authors.initials: JH
authors.lastname: Chern
authors.forename: Kak-Shan
authors.initials: KS
authors.lastname: Shia
authors.forename: Tsu-An
authors.initials: TA
authors.lastname: Hsu
authors.forename: Chia-Liang
authors.initials: CL
authors.lastname: Tai
authors.forename: Chung-Chi
authors.initials: CC
authors.lastname: Lee
authors.forename: Yen-Chun
authors.initials: YC
authors.lastname: Lee
authors.forename: Chih-Shiang
authors.initials: CS
authors.lastname: Chang
authors.forename: Sung-Nien
authors.initials: SN
authors.lastname: Tseng
authors.forename: Shin-Ru
authors.initials: SR
authors.lastname: Shih
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004770:Enterovirus / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D011743:Pyrimidines