Paper
Synthesis and anti-HIV-1 activity of a series of imidazo[1,5-b]pyridazines.
Published Nov 26, 1993 · David Livermore, Bethell Rc, Nicholas Cammack
Journal of medicinal chemistry
71
Citations
0
Influential Citations
Abstract
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.
In Vitro Study
Highly CitedSubstituted imidazo[1,5-b]pyridazines show promising anti-HIV-1 activity, with a 2-imidazolyl-substituted derivative showing exceptional activity against reverse transcriptase and inhibiting HIV-1 replication in MT-4 and C8166 cells.
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