Novel imidazo[1,2-b]pyridazine analogues, particularly E-isomer oximes like analogue 7b, exhibited potent broad-spectrum antirhinoviral and antienteroviral activity with no apparent cellular toxicity.
Imidazo[1,2-b]pyridazines, particularly oxime analogues with E geometry like 7b, represent a novel class of potent, broad-spectrum inhibitors against human picornaviruses.
A novel structural class of picornavirus inhibitors comprising an imidazo1,2-bpyridazine nucleus was discovered. 2-Aminoimidazo1,2-bpyridazines (6d, (E/Z)-7b, (E)-7d, (Z)-7d, (E/Z)-8b, (E)-10b, (E)-13a, (Z)-13a, (E)-13b, (Z)-13b, (E)-13c, and (Z)-13c) were designed and synthesized in an effort to identify potent broad spectrum antirhinoviral agents. A practical synthetic route to this chemical scaffold has been developed. The target compounds were evaluated in a plaque reduction assay and in a cytopathic effect assay. Our preliminary SAR studies highlight the minimum structural features required for antirhinovirus activity. Our data suggest that the nature of the linker between the phenyl and the imidazopyridazine moieties has a significant influence on the activity of these compounds. Oximes are slightly better than vinyl carboxamides at this position. The oximes are the most potent analogues against human rhinovirus 14 (HRV-14), and at the concentrations evaluated, no apparent cellular toxicity is noted. Furthermore, the E geometry appears to be a key element for activity; the Z isomer leads to a considerable loss in potency. Of particular interest, analogue 7b exhibits potent broad-spectrum antirhinoviral and antienteroviral activity when evaluated against a panel of seven additional rhino- and enteroviruses. The chemistry and the biological evaluations are discussed.
Hamdouchi et al. (Thu,) conducted a other in Human picornavirus (rhinovirus and enterovirus) infection. 2-Aminoimidazo[1,2-b]pyridazines (e.g., analogue 7b) was evaluated on Antirhinoviral and antienteroviral activity in plaque reduction and cytopathic effect assays. Novel imidazo[1,2-b]pyridazine analogues, particularly E-isomer oximes like analogue 7b, exhibited potent broad-spectrum antirhinoviral and antienteroviral activity with no apparent cellular toxicity.