Imidazo[1,2-b]pyridazines, Novel Nucleus with Potent and Broad Spectrum Activity against Human Picornaviruses: Design, Synthesis, and Biological Evaluation
- 21 August 2003
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 46 (20), 4333-4341
- https://doi.org/10.1021/jm020583i
Abstract
A novel structural class of picornavirus inhibitors comprising an imidazo[1,2-b]pyridazine nucleus was discovered. 2-Aminoimidazo[1,2-b]pyridazines (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.Keywords
This publication has 7 references indexed in Scilit:
- 2-Amino-3-substituted-6-[(E)-1-phenyl-2-(N-methylcarbamoyl)vinyl]imidazo[1,2-a]pyridines as a Novel Class of Inhibitors of Human Rhinovirus: Stereospecific Synthesis and Antiviral ActivityJournal of Medicinal Chemistry, 1998
- Comparison of Surface Properties of Picornaviruses: Strategies for Hiding the Receptor Site from Immune SurveillanceVirology, 1993
- Virucidal activity of hypericin against enveloped and non-enveloped DNA and RNA virusesAntiviral Research, 1990
- Synthesis and antiviral activity of sulfonamidobenzophenone oximes and sulfonamidobenzamidesJournal of Medicinal Chemistry, 1986
- Controlled trial of enviroxime against natural rhinovirus infections in a communityAntimicrobial Agents and Chemotherapy, 1985
- Synthesis of syn and anti isomers of 6-[[(hydroxyimino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-1H-benzimidazol-2-amine. Inhibitors of rhinovirus multiplicationJournal of Medicinal Chemistry, 1980
- Inhibition of Rhinovirus Replication in Organ Culture by a Potential Antiviral DrugThe Journal of Infectious Diseases, 1980