Developmental Studies of Nucleosidic Anti-RNA Virus Drugs

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The only antiviral drugs which have been licensed for the treatment of respiratory virus infections are amantadine (rimantadine) in the prophylaxis or early therapy of influenza A virus infection and ribavirin in the therapy, by aerosol, of severe respiratory syncytial virus (RSV) infections in children. Ribavirin was described almost two decades ago as a broad-spectrum antiviral agent. It has shown clinical efficacy against influenza A and B virus, RSV, parainfluenza virus infections and Lassa fever. In the treatment of orthomyxo-and paramyxovirus infections, and in particular, RSV infections in children, ribavirin can be administered as a small-particle aerosol.We have designed a new series of imidazole derivatives, namely, 5-alkynyl-1-beta-D-ribofuranosylimdazole-4-carboxamides, which can be viewed as close analogs of ribavirin, whereby the N at position 2 of the triazole ring is replaced by a alkynyl-carbon moiety. 5-Ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR) is … More the prototype of this class of compounds.The 5-alkynyl-1-beta-D-ribofuranosylimidazole-4-carboxamides were synthesized by Pd-catalyzed cross-coupling reaction of terminal alkynes with with 5-iodo derivatieves, which was easily obtained from AICAR in several steps. Other 5-alkyl and derivatives were also synthesized from the corresponding 5-alkynyl derivatives. Among these, EICAR showed the most potent antiviral activity against poxviruses (vaccinia), togaviruses (Sindbis and Semliki forest), arenaviruses (Junin and Tacaribe), reoviruses (type I), orthomyxoviruses (influenza A and B), and paramyxoviruses (parainfluenza type 3, measles, SSPE, and RSV). Although the antiviral activity spectrum of EICAR is similar to that of ribavirin, the potency by EICAR was about 10-to 100-fold greater than that of ribavirin. In vivo antivaccinia virus activity of EICAR was also examined. When administered daily at a dose of either 10 or 25mg/kg, EICAR effected a significant reduction in the number of vaccinia virus tail lesions, without apparent toxicity for the host. Less