The emergence and reemergence of pathogenic viruses represent continuous infectious disease threats to public health. Among these, the paramyxoviruses, which include many important human and animal pathogens, also include two excellent examples of emerged, zoonotic viral pathogens of importance: the henipaviruses; Hendra virus (HeV) and Nipah virus (NiV). HeV and NiV have a uniquely broad host tropism capable of infecting at least 18 animal species across 6 orders of mammals. HeV and NiV can also cause a systemic and often fatal respiratory and/or neurological disease in 11 mammalian species including humans. These henipaviruses remain significant biothreats to humans and economically important livestock in Australia and throughout South East Asia. In addition, there are no vaccines or antivirals approved for human use. Thus new treatment options are urgently needed. This application defines a plan to develop potent, small molecule inhibitors, which inhibit henipavirus replication. We have identified compounds that inhibit replication of these viruses, with IC50 values in the nanomolar range. In this application, we propose three specific aims: (1) To optimize the lead (and backup) scaffold and select developmental candidates; (2) Develop the SAR in the henipavirus infectious assay and further investigate the mechanism of action (MOA) of the replication inhibitors; and (3) Select henipavirus inhibitors with in vitro ADME properties suitable for whole animal testing in an infectious animal model.