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

Said Dadou; Ahmet Altay; Cemile Baydere; El Hassane Anouar; Burçin Türkmenoğlu; Mohammed Koudad; Necmi Dege; Abdelouahad Oussaid; Noureddine Benchat; Khalid Karrouchi

doi:10.1080/07391102.2023.2280756

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

J Biomol Struct Dyn. 2023 Nov 27:1-16. doi: 10.1080/07391102.2023.2280756. Online ahead of print.

Authors

Affiliations

¹ Laboratory of Applied Chemistry and Environment, Faculty of Sciences, Mohammed First University, Oujda, Morocco.
² Laboratory of Molecular Chemistry, Materials and Environment, Polydisciplinary Faculty of Nador, Mohammed First University, Oujda, Morocco.
³ Department of Chemistry, Faculty of Arts and Science, Erzincan Binali Yıldırım University, Erzincan, Turkey.
⁴ Department of Physics, Faculty of Arts and Sciences, Ondokuz Mayıs University, Samsun, Turkey.
⁵ Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia.
⁶ Department of Analytical Chemistry, Faculty of Pharmacy, Erzincan Binali Yıldırım University, Erzincan, Turkey.
⁷ Laboratory of Analytical Chemistry and Bromatology, Team of Formulation and Quality Control of Health Products, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco.

PMID: 38009853
DOI: 10.1080/07391102.2023.2280756

Abstract

In this work, two novel chalcone-based imidazothiazole derivatives ITC-1 and ITC-2 were synthesized and characterized by ¹H NMR, ¹³C NMR and high-resolution mass spectrometry with electrospray ionization, and chemical structure of ITC-1 was confirmed by single-crystal X-ray diffraction. Also, the anticancer activity of ITC-1 and ITC-2 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 IC₅₀ values while showing much lower antiproliferation on 3T3-L1 normal cells with much higher IC₅₀ values. Besides, ITC-2 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_Bind), Glide score values, and determination of the active binding site. The obtained data suggest that ITC-1 and ITC-2 may be considered remarkable anticancer drug candidates. In addition to molecular docking via in silico approaches, the pharmacokinetic properties of compounds ITC-1 and ITC-2 were calculated using the Schrödinger 2021-2 Qikprop wizard.Communicated by Ramaswamy H. Sarma.

Keywords: Chalcone; anticancer; apoptosis; docking; imidazothiazole;DFT.