Chalcone-based imidazo[2,1-]thiazole derivatives: synthesis, crystal structure, potent anticancer activity, and computational studies.

In this work, two novel chalcone-based imidazothiazole derivatives and were synthesized and characterized by H NMR, C NMR and high-resolution mass spectrometry with electrospray ionization, and chemical structure of was confirmed by single-crystal X-ray diffraction. Also, the anticancer activity of and was evaluated. First, antiproliferative activity tests were performed against cancer cells namely, human-derived breast adenocarcinoma (MCF-7), lung carcinoma (A-549), and colorectal adenocarcinoma (HT-29) cell lines, and mouse fibroblast healthy cell line (3T3-L1) by XTT assay. Afterward, mitochondrial membrane disruption (MMP), caspase activity, and apoptosis tests were performed on MCF-7 cells to elucidate the anticancer mechanism of action of the test compounds by flow cytometry analysis. XTT results revealed that both compounds exhibited a very high degree of antiproliferative effects on each tested cancer cell line with very low IC values while showing much lower antiproliferation on 3T3-L1 normal cells with much higher IC values. Besides, was determined to have a striking cytotoxic power competing with the chemotherapeutic drug carboplatin. Flow cytometry results demonstrated the mitochondrial-mediated apoptotic effects of both compounds through membrane disruption and multi-caspase activation in MCF-7 cells. Finally, molecular docking studies were performed to determine the structural understanding of the test compounds by their interactions on caspase-3 and DNA dodecamer enzymes, respectively. The interactions between the compound and the crystal structure were determined according to parameters such as free binding energies (ΔG), Glide score values, and determination of the active binding site. The obtained data suggest that and may be considered remarkable anticancer drug candidates. In addition to molecular docking via approaches, the pharmacokinetic properties of compounds and were calculated using the Schrödinger 2021-2 Qikprop wizard.Communicated by Ramaswamy H. Sarma.