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

A series of 2-amino-3-substituted-6-[(E)-1-phenyl-2-(N-methylcarbamoyl)viny l] imidazo[1,2-a]pyridines 1a-i, structurally related to Enviroxime and its analogous benzimidazoles, was designed and prepared for testing as antirhi novirus 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 incorpor ation of methyl vinylcarboxamide. The reaction was stereospecific in the su bstrates 5a-f leading exclusively to the desired E-isomer and avoiding the use of reverse-phase preparative HPLC for the separation of both possible i somers before antiviral activity evaluation The isopropylsulfonyl group, kn own as the best substituent at the 1-position in the benzimidazole SAR in t erms of activity, was introduced in this new series of imidazo[1,2-a]pyridi nes via halogen-metal exchange and subsequent treatment with isopropyl isop ropanethiolsulfonate. Compounds 1a-i were evaluated in plaque reduction ass ay and in a cytopathic effect assay. Compounds 1b-d,h exhibited a strong an tirhinovirus activity, and no apparent cellular toxicity was visible. The s ubstitution at the 3-position was required for activity. Surprisingly the i sopropylsulfonyl in this family of compounds did not enhance the activity a s in the case of benzimidazoles. Instead, compound 1i was 4 times less acti ve than its phenyl and sulfide partners. The chemistry as well as the biolo gical evaluation are discussed.