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 Activity

Abstract

A series of 2-amino-3-substituted-6-[(E)-1-phenyl-2-(N-methylcarbamoyl)vinyl]+ ++imid azo[1,2-a]pyridines 1a-i, structurally related to Enviroxime and its analogous benzimidazoles, was designed and prepared for testing as antirhinovirus agents. The imidazo ring in this class of compounds was constructed starting from the aminopyridine after tosylation and subsequent treatment with the appropriate acetamides. The key steps in the synthesis include the development and use of a new Horner-Emmons reagent for the direct incorporation of methyl vinylcarboxamide. The reaction was stereospecific in the substrates 5a-f leading exclusively to the desired E-isomer and avoiding the use of reverse-phase preparative HPLC for the separation of both possible isomers before antiviral activity evaluation. The isopropylsulfonyl group, known as the best substituent at the 1-position in the benzimidazole SAR in terms of activity, was introduced in this new series of imidazo[1,2-a]pyridines via halogen-metal exchange and subsequent treatment with isopropyl isopropanethiolsulfonate. Compounds 1a-i were evaluated in plaque reduction assay and in a cytopathic effect assay. Compounds 1b-d,h exhibited a strong antirhinovirus activity, and no apparent cellular toxicity was visible. The substitution at the 3-position was required for activity. Surprisingly the isopropylsulfonyl in this family of compounds did not enhance the activity as in the case of benzimidazoles. Instead, compound 1i was 4 times less active than its phenyl and sulfide partners. The chemistry as well as the biological evaluation are discussed.

2‐Sulfonyliminodihydropyrimidines: A Novel Class of Analgesic Compounds

“…In some cases, compounds 7 were not even detected. These results are in accordance with the literature [14,15].…”

Selective inhibitors of picornavirus replication

“…In this new family the substitution at the 3-position was a key element for activity and both isopropyl sulfonyl and aromatic rings, as well as acyl groups were well tolerated. 213,214 More recently, a series of structurally related imidazo[1,2-b]pyridazine analogues were synthesized and examined for anti-rhinovirus activity. This series was shown to have significant improvement in potency relative to the imidazo[1,2-a]pyridines series, but did not lead to the discovery of more potent enviroxime analogues.…”

2-Amino-3-methylpyridinium 4-methoxybenzoate

“…Pyridine derivatives have been shown to exhibit anticancer (Girgis et al 2006) and antiviral (Hamdouchi et al, 1999) activities. As part of our studies in this area we synthesized the title compound and report herein on its synthesis and crystal structure.…”