Synthesis and anti-HIV-1 activity of a series of imidazo[1,5-b]pyridazines.
A series of substituted imidazo[1,5-b]pyridazines have been prepared and tested for inhibitory activity against the reverse transcriptase of HIV-1 (RT) and their ability to inhibit the growth of infected MT-4 cells. Crystal data are reported on two compounds, 15c and 33. From the structure-activity relationships developed within this and other series, it is proposed that key features of the interaction with RT include hydrogen-bond acceptor and aromatic pi-orbital bonding with the imidazopyridazine nucleus and a benzoyl function separated from the heterocycle by a suitable spacer group. Exceptional activity against the reverse transcriptase of HIV-1 (IC50 = 0.65 nM) was obtained with a 2-imidazolyl-substituted derivative, 7-[2-(1H-imidazol-1- yl)-5-methylimidazo-[1,5-b]pyridazin-7-yl]-1-phenyl-1-heptanone (33) which is attributed to additional binding of the imidazole sp2 nitrogen atom. A number of the compounds in this series also inhibit the replication of HIV-1 in vitro in MT-4 and C8166 cells at levels observed with the nucleoside AZT.
Livermore
D G
DG
Medical Chemistry II Department, Glaxo Group Research Ltd., Greenford, Middlesex, U.K.
Bethell
R C
RC
Cammack
N
N
Hancock
A P
AP
Hann
M M
MM
Green
D V
DV
Lamont
R B
RB
Noble
S A
SA
Orr
D C
DC
Payne
J J
JJ
D000998:Antiviral Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003460:Crystallization; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D015394:Molecular Structure; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D007093:Imidazoles; D011724:Pyridazines; D018894:Reverse Transcriptase Inhibitors; C084737:7-(2-(1H-imidazol-1-yl)-5-methylimidazo(1,5-b)pyridazin-7-yl)-1-phenyl-1-heptanone; D015215:Zidovudine; D054303:HIV Reverse Transcriptase