Developmental Studies of Nucleosidic Anti-RNA Virus Drugs

唯一获得许可用于治疗呼吸道病毒感染的抗病毒药物是用于预防或早期治疗甲型流感病毒感染的金刚烷胺(金刚烷胺)，以及用于雾化治疗儿童严重呼吸道合胞病毒(RSV)感染的利巴韦林。近20年前，利巴韦林被描述为一种广谱抗病毒药物。对甲型和乙型流感病毒、呼吸道合胞病毒、副流感病毒感染和拉沙热具有临床疗效。在治疗正粘和副粘病毒感染，特别是儿童呼吸道合胞病毒感染时，利巴韦林可以作为一种小颗粒气雾剂给药。我们设计了一系列新的咪唑类衍生物，即5-alkynyl-1-beta-D-ribofuranosylimdazole-4-carboxamides，，它可以被视为利巴韦林的近似物，通过将三唑环上2位的N替换为炔基-碳链。5-Ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide(EICAR)为…这类化合物的原型是通过钯催化末端炔与5-碘衍生物的交叉偶联反应合成的，这一反应很容易从AICAR中得到。由相应的5-炔基衍生物还合成了其他5-烷基及其衍生物。其中，EICAR对痘病毒(牛痘)、托加病毒(辛德比斯和塞姆利基森林病毒)、阿拉伯病毒(Junin和Tacaribe)、呼肠孤病毒(I型)、正粘病毒(A和B流感)和副粘病毒(3型副流感、麻疹、SSPE和RSV)显示出最强的抗病毒活性。虽然EICAR的抗病毒活性谱与利巴韦林相似，但EICAR的效力约为利巴韦林的10-100倍。还检测了EICAR的体内抗痘苗病毒活性。当每天给药剂量为10或25 mg/kg时，EICAR显著减少了痘苗病毒尾部病变的数量，对宿主没有明显的毒性。较少

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