Design, synthesis, and structure–activity relationships of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety as potent antitumor agents

• 36 novel benzothiazole derivatives were designed and synthesized.
• Target compounds showed excellent antitumor potency in vitro against 5 cancer cell lines.
• The cytotoxic activities of 15g and 16b were 1.8–8.7 times more active than PAC-1.
• Enzymatic activities of 15g and 16b were 2.9 times and 16 times better than PAC-1.

A series of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety were designed and synthesized and their cytotoxic activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN45, and MDA-MB-231) were screened in vitro. Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 15g (procaspase-3 EC50 = 1.42 μM) and 16b (procaspase-3 EC50 = 0.25 μM) exhibited excellent antitumor activity with IC50 values ranging from 0.14 μM to 0.98 μM against all cancer cell lines, which were 1.8–8.7 times more active than the first procaspase activating compound (PAC-1) (procaspase-3 EC50 = 4.08 μM). The structure–activity relationship (SAR) analyses indicated that the introduction of a lipophilic group (a benzyloxy or heteroaryloxy group) at the 4-position of the 2-hydroxy phenyl ring was beneficial to antitumor activity, and the presence of substituents containing nitrogen that are positively charged at physiological pH could also improve antitumor activity. It was also confirmed that the steric effect of the 4-position substituent of the benzyloxy group had a significant influence on cytotoxic activity.

A series of novel benzothiazole derivatives bearing ortho-hydroxy N-carbamoylhydrazone moiety were synthesized and evaluated for their cytotoxic activities. Six potent compounds were further examined for their procaspase-3 kinase activity.Figure optionsDownload as PowerPoint slide