ABSTRACT: A novel series of 3,6-diaryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines were designed, synthesized and biologically evaluated as vinylogous CA-4 analogues, which involved a rigid [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine scaffold to fix the configuration of (Z,E)-butadiene linker of A-ring and B-ring. Among these rigidly vinylogous CA-4 analogues, compounds 4d, 5b, 5i, 6c, 6e, 6g, 6i and 6k showed excellent antiproliferative activities against SGC-7901, A549 and HT-1080 cell lines with IC50 values at the nanomolar level. Compound 6i showed the most highly active antiproliferative activity against the three human cancer cell lines with an IC50 values of 0.011-0.015 µM, which are comparable to those of CA-4 (IC50 = 0.009-0.013 µM). Interestingly, SAR studies
