1-Sulfonyl-3-amino-1-1,2,4-triazoles as Yellow Fever Virus Inhibitors: Synthesis and Structure-Activity Relationship.

Yellow fever virus (YFV) transmitted by infected mosquitoes causes an acute viral disease for which there are no approved small-molecule therapeutics. Our recently developed machine learning models for YFV inhibitors led to the selection of a new pyrazolesulfonamide derivative with acceptable activity. We report that the -phenyl-1-(phenylsulfonyl)-1-1,2,4-triazol-3-amine class, which was recently identified as active non-nucleoside reverse transcriptase inhibitors against HIV-1, can also be repositioned as inhibitors of yellow fever virus replication. As compared to other or family viruses tested, both compounds and demonstrate selectivity for YFV over related viruses, with only showing some inhibition of the West Nile virus (EC 7.9 μM, CC 17 μM, SI 2.2). We also describe the absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetics (PK) for in mice. This compound had previously been shown to not inhibit hERG, and we now describe that it has good metabolic stability in mouse and human liver microsomes, low levels of CYP inhibition, high protein binding, and no indication of efflux in Caco-2 cells. A single-dose oral PK study in mice has a of 3.4 h and of 1190 ng/mL, suggesting good availability and stability. We now propose that the -phenyl-1-(phenylsulfonyl)-1-1,2,4-triazol-3-amine class may be prioritized for efficacy testing against YFV.