European Journal of Medicinal Chemistry
European Journal of Medicinal Chemistry
5 years ago

Discovery of novel diarylpyrazolylquinoline derivatives as potent anti-dengue virus agents

Discovery of novel diarylpyrazolylquinoline derivatives as potent anti-dengue virus agents
A number of diarylpyrazolylquinoline derivatives were synthesized and evaluated for their anti-dengue virus (DENV) activity. Among them, 6-fluoro-2-(1-(4-fluorophenyl)-3- (4-methoxyphenyl)-1H-pyrazol-5-yl)quinoline (11c), 2-[1,3-bis(4-methoxyphenyl)-1H-pyrazol- 5-yl]-6-fluoroquinoline (12c), and 4-[5-(6-fluoroquinolin-2-yl)-3-(4-methoxyphenyl)-1H-pyrazol- 1-yl]benzenesulfonamide (13c) exhibited approximately 10-folds more active anti-DENV-2 activity (IC50 of 1.36, 1.09 and 0.81 μM, respectively) than that of ribavirin (IC50 = 12.61 μM). Compound 13c was also potent inhibited other sero-types of DENV. It reduced DENV replication in both viral protein and mRNA levels, and no significant cell cytotoxicity was detected, with greater than 50% viability of Huh-7-DV-Fluc cells at a concentration of 200 μM. Furthermore, compound 13c can effectively protect mice from DENV infection by reducing disease symptoms and mortality of DENV-infected mice. It represents a potential antiviral agent to block DENV replication in vitro and in vivo. Structural optimization of the initial lead compound, 13c, and the detailed molecular mechanism of action are ongoing.

Publisher URL: www.sciencedirect.com/science

DOI: S0223523417307936

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