Background:
Natural products have been universally approached in the research of novel trends useful to detail the essential paths of the life sciences and as a strategy for pharmacotherapeutics. Objective: This work focuses on further modification to the 6-hydroxy-flavanone building block aiming to obtain improved BCR-ABL kinase inhibitors.
Methods:
Ether derivatives were obtained from Williamson synthesis and triazole from Microwave-assisted click reaction. Chemical structures were finely characterized through IR, 1H and 13C NMR and HRMS. They were tested for their inhibitory activity against BCR-ABL kinase. Results: Two inhibitors bearing a triazole ring as a pharmacophoric bridge demonstrated the strongest kinase inhibition at IC50 value of 364 nM (compound 3j) and 275 nM (compound 3k).
Conclusion:
6-hydroxy-flavanone skeleton can be considered as a promising core for BCR-ABL kinase inhibitors.
The semisynthesis of 15 new thymol derivatives was achieved through Williamson synthesis and copper-catalyzed azide−alkyne cycloaddition (CuAAC) approaches. The reaction of CuAAC using the "Click Chemistry" strategy, in the presence of an alkynyl thymol derivative and commercial or prepared azides, provided nine thymol derivatives under microwave irradiation. This procedure reduces reaction time and cost. All molecular entities were elucidated by 1 H and 13 C NMR, IR, and HRMS data. These derivatives were evaluated in vitro for their fungicidal activity against Fusarium solani sp. Among the nine triazolic thymol derivatives obtained, seven of them were found to have moderated antifungal activity. In contrast, naphthoquinone/thymol hybrid ether 2b displayed activity comparable with that of the commercial fungicide thiabendazole. The structure−activity relationship for the most active compound 2b was discussed, and the mode of action was predicted by a possible binding to the fungic ergosterol and interference of osmotic balance of K + into the extracellular medium.
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