Data_Sheet_3_Design, Synthesis, Antiviral Evaluation, and SAR Studies of New 1-(Phenylsulfonyl)-1H-Pyrazol−4-yl-Methylaniline Derivatives.PDF

A series of N-((3-phenyl-1-(phenylsulfonyl)-1H-pyrazol-4-yl)methyl)anilines 7a-p and 8a-l, structurally related to previously synthesized and tested (N-(1,3-diphenyl-1H-pyrazol-4-yl)methyl)anilines (1a-v), were designed and synthesized. The new derivatives were evaluated in cell-based assays for their cytotoxicity and antiviral activity against a large panel of RNA and DNA viruses of public health significance. Generally, the tested compounds did not display cytotoxicity toward the cell lines used. The majority of derivatives 7a-p were able to interfered with YFV and RSV replication in the micromolar range showing a marked improvement in potency and selectivity with respect to the reference inhibitors 6-azauridine and ribavirin, respectively. The introduction of a p-methoxy substituent on the phenylsulfonyl group (compounds 8a-l) completely abolished the anti-RSV activity and reduced or eliminated the potency against YFV. On the contrary, several p-methoxy analogs were able to interfere with BVDV replication with a comparable (8b, 8c, 8g, and 8k) or better (8a and 8f) potency than the reference inhibitor, ribavirin. Compound 7e, selected for time of addition experiments on BHK-21 cell cultures infected with YFV, achieved the highest reduction of virus titer when added 2 h post infection and maintained up to 4 h post infection.

一系列N-((3-苯基-1-(苯磺酰基)-1H-吡唑-4-基)甲基)苯胺7a-p和8a-l，其结构与先前合成和测试的(N-(1,3-二苯基-1H-吡唑-4-基)甲基)苯胺(1a-v)相关联，经过设计合成。这些新的衍生物在针对公共卫生具有重要意义的大量RNA和DNA病毒的基础细胞实验中，对其细胞毒性及抗病毒活性进行了评估。总体而言，所测试的化合物对所使用的细胞系未表现出细胞毒性。7a-p衍生物中的大多数能够在微摩尔范围内干扰黄病毒(YFV)和呼吸道合胞病毒(RSV)的复制，与参考抑制剂6-氮杂尿苷和利巴韦林相比，显示出显著的效力及选择性提高。在苯磺酰基团上引入对位甲氧基取代基(化合物8a-l)完全消除了对RSV的抗病毒活性，并降低了或消除了对YFV的效力。相反，几种对位甲氧基类似物能够以与参考抑制剂利巴韦林相当(8b、8c、8g和8k)或更优(8a和8f)的效力干扰牛病毒性腹泻病毒(BVDV)的复制。在BHK-21细胞培养中感染黄病毒后，选择7e化合物进行添加时间实验，当在感染后2小时添加时，病毒滴度降低达到最高，并在感染后4小时内保持降低。