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

A series of N -((3-phenyl-1-(phenylsulfonyl)-1 H -pyrazol-4-yl)methyl)anilines 7a-p and 8a-l , structurally related to previously synthesized and tested ( N -(1,3-diphenyl-1 H -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.