Background:
Dimedone and thiazole moieties are privileged scaffolds (acting as primary pharmacophores)
in many compounds that are useful to treat several diseases, mainly tropical infectious diseases. Thiazole
derivatives are a very important class of compounds due to their wide range of pharmaceutical and therapeutic
activities. On the other hand, dimedone is used to synthesize many therapeutically active compounds. Therefore,
the combination of both moieties through a single molecule to produce heterocyclic compounds will produce
excellent anticancer agents.
Objective:
The present work reports the synthesis of 47 new substances belonging to two classes of compounds:
Dimedone and thiazoles, with the purpose of developing new drugs that present high specificity for tumor
cells and low toxicity to the organism. To achieve this goal, our strategy was to synthesize a series of
4,5,6,7-tetrahydrobenzo[d]-thiazol-2-yl derivatives using the reaction of the 2-bromodimedone with cyanothioacetamide.
Methods:
The reaction of 2-bromodimedone with cyanothioacetamide gave the 4,5,6,7-tetrahydrobenzo[d]-
thiazol-2-yl derivative 4. The reactivity of compound 4 towards some chemical reagents was observed to produce
different heterocyclic derivatives.
Results:
A cytotoxic screening was performed to evaluate the performance of the new derivatives in six tumor
cell lines. Thirteen compounds were shown to be promising toward the tumor cell lines which were further
evaluated toward five tyrosine kinases.
Conclusion:
The results of antitumor screening showed that many of the tested compounds were of high inhibition
towards the tested cell lines. Compounds 6c, 8c, 11b, 11d, 13b, 14b, 15c, 15g, 21b, 21c, 20d and 21d were
the most potent compounds toward c-Met kinase and PC-3 cell line. The most promising compounds 6c, 8c, 11b,
11d, 13b, 14b, 15c, 15g, 20c, 20d, 21b, 21c and 21d were further investigated against tyrosine kinase (c-Kit, Flt-3,
VEGFR-2, EGFR, and PDGFR). Compounds 6c, 11b, 11d, 14b, 15c, and 20d were selected to examine their
Pim-1 kinase inhibition activity the results revealed that compounds 11b, 11d and 15c had high activities.
Crystal structure and biological evaluation of 4-methylmorpholin-4-ium 1,3-dimethyl-2,6-dioxo-5-(2,4,6-trinitrophenyl)-1,2,3,6-tetrahydropyrimidin-4-olate
