Synthesis, antioxidant and antiproliferative activities of 1,3,4-thiadiazoles derived from phenolic acids

Two 2-amino-1,3,4-thiadiazoles containing phenolic hydroxyl groups were combined with different carboxylic acid chlorides giving sixteen amide derivatives with good antioxidant and antiproliferative
potential. The compound 30c with an adamantane ring displayed excellent DPPH radical scavenging activity and good cytotoxic activity against human acute promyelocytic leukemia HL-60 cells, while 1,3,4-
thiadiazole 30h with 4-chlorophenyl moiety was found to be the most effective in inhibition of survival
of lung carcinoma A549 cells. All examined thiadiazoles except 3a and 30a exerted higher cytotoxic activities on A549 and HL-60 cancer cells when compared with normal fibroblasts MRC-5, pointing to selectivity in their antiproliferative action. Some of the most active novel compounds 3c, 30c, 30g and 30h
induced significant increase in the percentage of HL-60 cells in the subG1 cell cycle phase in comparison
with the control cells. The induction of cell death in HL-60 cells by these compounds was at least partially
dependent on activation of caspase-3 and caspase-8. The compounds 3c and 30c exerted strong antiangiogenic activity. Furthermore, compounds 3c, 30c, 30g and 30h showed the ability to down-regulate the MMP2 and VEGFA expression levels in the treated HL-60 cells when compared with the control cell
samples.