The design and synthesis of 9-phenylcyclohepta[d]pyrimidine-2,4-dione derivatives as potent non-nucleoside inhibitors of HIV reverse transcriptase.
Novel compounds, which can be considered as conformationally restricted analogues of MKC-442, have been synthesized and tested as inhibitors of the reverse transcriptase of human immunodeficiency virus type-1 (HIV-1). Reaction of urea with a beta-ketoester furnished 6,7,8,9-tetrahydro-9-phenyl-1H-cyclohepta[d]pyrimidine-2,4-(3H,5H)-dione (6a) and 6,7,8,9-tetrahydro-9-p-tolyl-1H-cyclohepta[d]pyrimidine-2,4-(3H,5H)-dione (6b) which were then alkylated at the N-1 position with chloromethyl ether, allyl bromide and benzyl bromide to afford the target compounds 7a-b, 8a-b, 9 and 10, respectively. The seven-membered, annelated compounds have a relatively rigid structures and can lock the orientation of the aromatic ring. Chemical modification at N-1 of the pyrinidine ring and the 9-phenyl ring was attempted, with the aim of improving the antiretroviral activity. In particular, replacement of the aliphatic group with the phenyl moiety at the terminus of N-1 side chain can enhance the activity. The most active compounds showed activity in the low micromolar range with IC50 values comparable to that of nevirapine. The biological activity results are in accordance with the docking results.
Wang
Xiaowei
X
Department of Chemical Biology, School of Pharmaceutical Science, Peking University, Beijing, 100083, China. xiaowei0301@china.com.cn
Lou
Qinghua
Q
Guo
Ying
Y
Xu
Yang
Y
Zhang
Zhili
Z
Liu
Junyi
J
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003508:Cycloheptanes / Q000138:chemical synthesis* / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry*; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D014498:Uracil / Q000031:analogs & derivatives / Q000737:chemistry
C523060:9-phenylcyclohepta(d)pyrimidine-2,4-dione; D019380:Anti-HIV Agents; D003508:Cycloheptanes; D011743:Pyrimidines; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil; C083858:emivirine