ABSTRACT. A quantitative high throughput screen (qHTS) of 7,988 compounds with annotated libraries using biliary tract cancer cell lines with or without isocitrate dehydrogenase I (IDH1) mutations had identified YC-1 as being selectively cytotoxic against the IDH1 mutant cell lines. We present the structure-activity relationship study of YC-1 analogs and identify the key structural motifs that are essential for activity. We highlight the narrow SAR around the furfuryl alcohol that has been reported as a critical motif that is activated by the sulfotransferase enzyme SULT1A1. Drug-like properties of key analogs are evaluated. We also show the SAR of a smaller subset of 2-choloro-4-amino benzyl alcohols from the NCI compound collection with a similar benzyl alcohol motif. We also demonstrate the ability of key analogs to act as substrates of SULT1A1 in a colorimetric biochemical assay.