Discovery of novel diarylpyrazolylquinoline derivatives as potent anti-dengue virus agents
- Eur J Med Chem. 2017 Dec 1:141:282-292. doi: 10.1016/j.ejmech.2017.10.001.
- 1. Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan.
- 2. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- 3. Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung, Taiwan; Doctoral Degree Program in Marine Biotechnology, Academia Sinica, Taipei, Taiwan.
- 4. Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung City 807, Taiwan. Electronic address: [email protected].
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.