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 a nd tested for inhibitory activity against the reverse transcriptase of HIV-1 (RT) and their ability to inhibit the growth of infected MT-4 c ells. Crystal data are reported on two compounds, 15c and 33. From the structure-activity relationships developed within this and other seri es, it is proposed that key features of the interaction with RT includ e hydrogen-bond acceptor and aromatic pi-orbital bonding with the imid azopyridazine nucleus and a benzoyl function separated from the hetero cycle by a suitable spacer group. Exceptional activity against the rev erse transcriptase of HIV-1 (IC50 = 0.65 nM) was obtained with a 2-imi dazolyl-substituted derivative, midazo-[1,5-b]pyridazin-7-yl]-1-phenyl -1-heptanone (33) which is attributed to additional binding of the imi dazole sp(2) nitrogen atom. A number of the compounds in this series a lso inhibit the replication of HIV-1 in vitro in MT-4 and C8166 cells at levels observed with the nucleoside AZT.