Zika Virus (ZIKV), a member of the Flaviviridae family of viruses, has recently led to major epidemics in South American countries and has been reported in several other countries as well. ZIKV is the cause of microcephaly and other developmental neuroimmunopathologies in fetuses of pregnant women and Guillain‐Barre Syndrome in adults, and to date, no therapeutics or vaccines are approved for ZIKV infection. In this study, we conducted rigorous structure activity relationship (SAR) studies on one of the three classes of compounds that we previously reported to display significant anti‐ZIKV activity in vitro. We synthesized and tested 50 derivatives of the parental compound (ASN07115927), a 1,3‐Disubstituted Urea‐based thiadiazole. We were able to identify a few derivatives with improved antiviral activity as well as structural features that will guide further SAR studies. Most notably, we found that the urea moiety at the center of the molecule is essential as all but one of the thiourea substituents were completely or significantly inactive. Presence of chlorine on the aromatic ring demonstrated the highest activity compared to its bromo‐, and iodo‐ counterparts. Furthermore, we tested derivatives with allylthio‐, allylamino‐, and propargylthio‐ moieties on the thiadiazole ring and found that the allylthio‐derivatives had higher activity overall. In addition, the location of the allylthio‐ moiety on the ring as well as the orientation of the thiadiazole ring affected the antiviral activity. These results identify compounds with improved antiviral activity which may be utilized/further optimized for the development of inexpensive and orally available anti‐ZIKV drugs. These compounds may also be beneficial for treatment of other viruses in the same family including Dengue virus.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.