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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses
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Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses

机译：新型Pleconaril衍生物：异恶唑中取代基的影响和苯环对肠病病毒的抗病毒活性

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摘要

Today, there are no medicines to treat enterovirus and rhinovirus infections. In the present study, a series of novel pleconaril derivatives with substitutions in the isoxazole and phenyl rings was synthesized and evaluated for their antiviral activity against a panel of pleconaril-sensitive and -resistant enteroviruses. Studies of the structure-activity relationship demonstrate the crucial role of the N,N-dimethylcarbamoyl group in the isoxazole ring for antiviral activity against pleconaril-resistant viruses. In addition, one or two substituents in the phenyl ring directly impact on the spectrum of antienteroviral activity. The 3-(3-methyl-4-(3-(3-N,N-dimethylcarbamoyl-isoxazol-5-yl)propoxy)phenyl)-5-trifluoromethyl-1,2,4- oxadiazole 10g was among the compounds exhibiting the strongest activity against pleconaril-resistant as well as pleconaril-susceptible enteroviruses with IC50 values from 0.02 to 5.25 mu M in this series. Compound 10g demonstrated markedly less CYP3A4 induction than pleconaril, was non-mutagenic, and was bioavailable after intragastric administration in mice. These results highlight compound 10g as a promising potential candidate as a broad spectrum enterovirus and rhinovirus inhibitor for further preclinical investigations. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：今天，没有药物治疗肠道病毒和鼻病毒感染。在本研究中，合成了一系列具有异恶唑和苯环的取代的新型Pleconaril衍生物，并评估其针对抗病肠道肠病患者的抗病毒活性。结构 - 活性关系的研究证明了N，N-二甲基氨基酰基在异恶唑环中的关键作用，用于对抗抗质子抗性病毒的抗病毒活性。此外，苯环中的一个或两个取代基直接影响辅病毒活性的光谱。 3-（3-甲基-4-（3-（3-N-（3-N-二甲基氨基甲酰基 - 异恶唑-5-基）丙氧基）苯基）-5-三氟甲基-1,2,4-二甲唑10g在表现出的化合物中对该系列中的0.02至5.25 mu m的IC50值，对抗pleconaril的最强的活性以及易肠道病毒。化合物10G显着较少的CYP3A4诱导比Pleconaril，是非致突变性的，并且在小鼠中胃内给药后生物可利用。这些结果突出了化合物10g作为广泛的潜在候选的潜在候选者，作为广谱肠道病毒和鼻病毒抑制剂，以进一步临床前研究。 （c）2019年Elsevier Masson SAS。版权所有。

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