Abstract
In an attempt to develop potent antitumor agents, new 1,3,4-thiadiazole derivatives were synthesized and evaluated for their cytotoxic effects on multiple human cancer cell lines, including the K562 chronic myelogenous leukemia cell line that expresses the Bcr-Abl tyrosine kinase. N-(5-Nitrothiazol-2-yl)-2-((5-((4-(trifluoromethyl)phenyl)amino)-1,3,4-thiadiazol-2-yl)thio)acetamide (2) inhibited the Abl protein kinase with an IC50 value of 7.4 µM and showed selective activity against the Bcr-Abl positive K562 cell line. Furthermore, a Bcr-Abl-compound 2 molecular modelling simulation highlighted the anchoring role of the nitrothiazole moiety in bonding and hydrophobic interaction with the key amino acid residues. These results provide promising starting points for further development of novel kinase inhibitors.
Highlights
Cancer is the fastest growing disease throughout the world
As a promising scaffold for antitumor drug discovery and development against different cancer cell the clinical efficacy of tiazofurin, bleomycins (BLMs), and dasatinib has pointed out lines through the inhibition of diverse molecular targets, including histone deacetylase (HDAC), the pivotalc-Src/Abl role oftyrosine the thiazole scaffold in kinase the field ofand current research patents kinase, focal adhesion (FAK), tubulincancer polymerization
Prompted by the aforementioned we explored the possibility of 1,3,4-thiadiazole kinase domain interaction; the Met318,findings, Thr315, Asp381, Glu286, His361, and Ile360 hydrogen as a pivotal scaffold for tyrosine kinase inhibitors
Summary
Cancer is the fastest growing disease throughout the world. In developed countries, cancer has become the leading cause of death, whereas in developing countries, it is the second leading cause of death after cardiovascular disorders. The sulfur atom of the a promising scaffold for antitumor drug discovery and development against different cancer cell lines thiadiazole ring imparts improved liposolubility, and the mesoionic nature of 1,3,4-thiadiazoles through the inhibition of diverse molecular targets, including histone deacetylase (HDAC), c-Src/Abl allows these compounds to cross cellular membranes and interact with biological targets with distinct tyrosine kinase, focal adhesion kinase tubulin polymerization [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29]. As a promising scaffold for antitumor drug discovery and development against different cancer cell the clinical efficacy of tiazofurin, bleomycins (BLMs), and dasatinib has pointed out lines through the inhibition of diverse molecular targets, including histone deacetylase (HDAC), the pivotalc-Src/Abl role oftyrosine the thiazole scaffold in kinase the field ofand current research [30,31,32,33].
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