Design, synthesis, and biological evaluation of N-alkylated deoxynojirimycin (DNJ) derivatives for the treatment of dengue virus infection.
We recently described the discovery of oxygenated N-alkyl deoxynojirimycin (DNJ) derivative 7 (CM-10-18) with antiviral activity against dengue virus (DENV) infection both in vitro and in vivo. This imino sugar was promising but had an EC(50) against DENV in BHK cells of 6.5 μM, which limited its use in in vivo. Compound 7 presented structural opportunities for activity relationship analysis, which we exploited and report here. These structure-activity relationship studies led to analogues 2h, 2l, 3j, 3l, 3v, and 4b-4c with nanomolar antiviral activity (EC(50) = 0.3-0.5 μM) against DENV infection, while maintaining low cytotoxicity (CC(50) > 500 μM, SI > 1000). In male Sprague-Dawley rats, compound 3l was well tolerated at a dose up to 200 mg/kg and displayed desirable PK profiles, with significantly improved bioavailability (F = 92 ± 4%).
Institute for Hepatitis and Virus Research, Hepatitis B Foundation, Doylestown, PA 18902, USA.
Wenquan
W
Yu
Tina
T
Gill
Lijuan
L
Wang
Yanming
Y
Du
Hong
H
Ye
Xiaowang
X
Qu
Ju-Tao
JT
Guo
Andrea
A
Cuconati
Kang
K
Zhao
Timothy M
TM
Block
Xiaodong
X
Xu
Jinhong
J
Chang
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives*; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001682:Biological Availability; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D003715:Dengue / Q000188:drug therapy / Q000821:virology; D003716:Dengue Virus / Q000187:drug effects*; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014759:Viral Envelope Proteins / Q000032:analysis / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects; D000520:alpha-Glucosidases
D000998:Antiviral Agents; D065089:Glycoside Hydrolase Inhibitors; D014759:Viral Envelope Proteins; D017485:1-Deoxynojirimycin; C034251:4-nitrophenyl-alpha-glucosidase; C042059:glucosidase I; D000520:alpha-Glucosidases