Synthesis of 4-oxotetrahydropyrimidine-1(2H)-carboxamides derivatives as capsid assembly modulators of hepatitis B virus
Nicky Hwang # 1 , Haiqun Ban # 1 2 , Junjun Chen 1 , Julia Ma 1 , Hui Liu 1 3 , Patrick Lam 1 , John Kulp 1 , Stephan Menne 4 , Jinhong Chang 1 , Ju-Tao Guo 1 , Yanming Du 1
Affiliations
Affiliations
1
Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902 USA.
2
Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai, 200127 Pudong New District China.
3
Department of Pathogen Biology, Peking University Medical Center, Beijing, China.
4
Georgetown University Medical Center, 3900 Reservoir Road, Washington, DC 20057 USA.
We report herein the synthesis and evaluation of phenyl ureas derived from 4-oxotetrahydropyrimidine as novel capsid assembly modulators of hepatitis B virus (HBV). Among the derivatives, compound 27 (58031) and several analogs showed an activity of submicromolar EC50 against HBV and low cytotoxicities (>50 μM). Structure-activity relationship studies revealed a tolerance for an additional group at position 5 of 4-oxotetrahydropyrimidine. The mechanism study indicates that compound 27 (58031) is a type II core protein allosteric modulator (CpAMs), which induces core protein dimers to assemble empty capsids with fast electrophoresis mobility in native agarose gel. These compounds may thus serve as leads for future developments of novel antivirals against HBV.
Keywords: 4-Oxotetrahydropyrimidine; Capsid assembly; Hepatitis B virus; Phenyl ureas.