Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors.

ABSTRACT

Deregulation of various protein kinases is considered as one of the important factors resulting in cancer development and metastasis, thus multi-targeting the kinase family is one of the most important strategies in current cancer therapy. This context represents the design and synthesis of two sets of derivatives bearing a pyrazoline-3-one ring conjugated either with a thieno[3,2-d]thiazole or with a dihydrothiazolo[4,5-d]thiazole scaffold via an NH linker, 3a-d and 5a-d respectively, using the pyrazolinone-thiazolinone derivative 1 as a key precursor. All the newly synthesized compounds were assessed in vitro for their anticancer activity against two cancer cell lines (MCF-7 and HepG-2). The safety profile of the most active cytotoxic candidates 1 and 3c was further examined against the normal cell line WI-38. The compounds 1 and 3c were further evaluated as multi-targeting kinase inhibitors against EGFR, VEGFR-2 and BRAFV600E, exhibiting promising suppression impact. Additionally, the latter compounds were investigated for their impact on cell cycle and apoptosis induction potential in the MCF-7 cell line. Moreover, the antimicrobial activity of all the new analogues was evaluated against a panel of Gram-positive and Gram-negative bacteria, yeast and fungi in comparison to streptomycin and amphotericin-B as reference drugs. Interestingly, both 1 and 3c showed the most promising microbial inhibitory effect. Molecular docking studies showed promising binding patterns of the compounds 1 and 3c with the prospective targets, EGFR, VEGFR-2 and BRAFV600E. Finally, additional toxicity studies were performed for the new derivatives which showed their good drug-like properties and low toxicity risks in humans.