N1,N3-disubstituted uracils as nonnucleoside inhibitors of HIV-1 reverse transcriptase.
A series of phenyloxyethyl and cinnamyl derivatives of substituted uracils were synthesized and found to exhibit potent activity against HIV-RT and HIV replication in cell culture. In general, the cinnamyl derivatives proved superior to the phenyloxyethyl derivatives, however 1-[2-(4-methylphenoxy)ethyl]-3-(3,5-dimethylbenzyl)uracil (19) exhibited the highest activity (EC(50)=0.27 μM) thus confirming that the 3-benzyluracil fragment in the NNRTI structure can be regarded as a functional analogue of the benzophenone pharmacophore typically found in NNRTIs.
Department of Pharmaceutical & Toxicological Chemistry, Volgograd State Medical University, Pavshikh Bortsov Sq., 1, Volgograd 400131, Russia.
Mikhail S
MS
Novikov
Vladimir T
VT
Valuev-Elliston
Denis A
DA
Babkov
Maria P
MP
Paramonova
Alexander V
AV
Ivanov
Sergey A
SA
Gavryushov
Anastasia L
AL
Khandazhinskaya
Sergey N
SN
Kochetkov
Christophe
C
Pannecouque
Graciela
G
Andrei
Robert
R
Snoeck
Jan
J
Balzarini
Katherine L
KL
Seley-Radtke
D001665:Binding Sites; D002460:Cell Line; D002934:Cinnamates / Q000737:chemistry; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D062105:Molecular Docking Simulation; D009154:Mutation; D017434:Protein Structure, Tertiary; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D002934:Cinnamates; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase