Here we describe a rapid and divergent synthetic route toward structurally novel αHTs functionalized with either one or two thioether or sulfonyl appendages. Evaluation of this library against hepatitis B and herpes simplex virus, as well as the pathogenic fungus Cryptococcus neoformans, revealed complementary biological profiles and new lead compounds with sub-micromolar activities against each pathogen and high selectivities when compared to mammalian cell lines.