Background:
Recently tetrahydrobenzo[b]thiazole derivatives acquired a special attention due to their
wide range of pharmacological activities especially the therapeutic activities. Through the market it was found
that many pharmacological drugs containing the thiazole nucleus were known.
Objective:
This work aimed to synthesize target molecules not only possess anti-tumor activities but also kinase
inhibitors. The target molecules were obtained starting from the arylhydrazonocyclohexan-1,3-dione followed
by their heterocyclization reactions to produce anticancer target molecules.
Methods:
The arylhydrazone derivatives 3a-c underwent different heterocyclization reactions to produce thiophene,
thiazole, pyrazole and 1,2,4-triazine derivatives. The anti-proliferative activity of twenty six compounds
among the synthesized compounds toward the six cancer cell lines namely A549, H460, HT-29, MKN-45,
U87MG, and SMMC-7721 was studied.
Results:
Anti-proliferative evaluations, tyrosine and Pim-1 kinase inhibitions were perform for most of the
synthesized compounds where the varieties of substituent through the aryl ring and the thiophene moiety afforded
compounds with high activities.
Conclusion:
The compounds with high anti-proliferative activity towards the cancer cell lines showed that compounds
3b, 3c, 5e, 5f, 8c, 9c, 11c, 12c, 14e, 14f and 16c were the most cytotoxic compounds. Further tests of the
latter compounds toward the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR and Pim-1 kinase
showed that compounds 3c, 5e, 5f, 8c, 9c, 12c, 14e, 14f and 16c were the most potent of the tested compounds
toward the five tyrosine kinases and compounds 6d, 11a, 20b and 21e were of the highest inhibitions towards
Pim-1 kinase. Pan Assay Interference Compounds (PAINS) for the most cytotoxic compounds showed zero
PAINS alert and can be used as lead compounds.
