Improved Delivery through Biological Membranes. Synthesis and Antiviral Activity of a Series of Ribavirin Chemical Delivery Systems: 2′ and 3′ Derivatives

Abstract

Ribavirin was chemically manipulated to provide a number of derivatives in which a 1,4-dihydrotrigonellinate species was attached to either the 2′ or 3′-position. In addition, a variety of other modifications was used to augment the lipophilicity and stability of the ribavirin redox systems. Prepared compounds were tested in a murine model of viral encephalitis. Intravenous administration of an isomeric pair of derivatives (1-[3′-O-(N-methyl-3-carbonyl-1,4-dihydropyridine)-2′-O-benzoyl-β-D-ribofuranosyl]-1,2,4-triazole-3-carboxamide/1-[2′-O-(N-methyl-3-carbonyl-1,4-dihydropyridine)-3′-O-benzoyl-β-D-ribofuranosyl]-1,2,4-triazole-3-carboxamide) resulted in 43% survival compared with 0% for vehicle treatment and resulted in a decrease in brain viral titres by 10-fold.