Novel 7-Chloro-4-aminoquinoline-benzimidazole Hybrids as Inhibitors of Cancer Cells Growth: Synthesis, Antiproliferative Activity, in Silico ADME Predictions, and Docking
Luka Krstulović,
Marijana Leventić,
Vesna Rastija,
Kristina Starčević,
Maja Jirouš,
Ivana Janić,
Maja Karnaš,
Kornelija Lasić,
Miroslav Bajić,
Ljubica Glavaš-Obrovac
Affiliations
Luka Krstulović
Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb, HR-10000 Zagreb, Croatia
Marijana Leventić
Department of Medicinal Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia
Vesna Rastija
Department of Agroecology and Environmental Protection, Faculty of Agrobiotechnical Sciences Osijek, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia
Kristina Starčević
Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb, HR-10000 Zagreb, Croatia
Maja Jirouš
Department of Medicinal Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia
Ivana Janić
Department of Medicinal Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia
Maja Karnaš
Department of Agroecology and Environmental Protection, Faculty of Agrobiotechnical Sciences Osijek, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia
Kornelija Lasić
R&D, Pliva Croatia Ltd., TEVA Group Member, HR-10000 Zagreb, Croatia
Miroslav Bajić
Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb, HR-10000 Zagreb, Croatia
Ljubica Glavaš-Obrovac
Department of Medicinal Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia
In this study, new 7-chloro-4-aminoquinoline-benzimidazole compounds were synthesized and characterized by NMR, MS, and elemental analysis. These novel hybrids differ in the type of linker and in the substituent on the benzimidazole moiety. Their antiproliferative activities were evaluated on one non-tumor (MDCK1) and seven selected tumor (CaCo-2, MCF-7, CCRF-CEM, Hut78, THP-1, and Raji) cell lines by MTT test and flow cytometry analysis. The compounds with different types of linkers and an unsubstituted benzimidazole ring, 5d, 8d, and 12d, showed strong cytotoxic activity (the GI50 ranged from 0.4 to 8 µM) and effectively suppressed the cell cycle progression in the leukemia and lymphoma cells. After 24 h of treatment, compounds 5d and 12d induced the disruption of the mitochondrial membrane potential as well as apoptosis in HuT78 cells. The drug-like properties and bioavailability of the compounds were calculated using the Swiss ADME web tool, and a molecular docking study was performed on tyrosine-protein kinase c-Src (PDB: 3G6H). Compound 12d showed good solubility and permeability and bound to c-Src with an energy of −119.99 kcal/mol, forming hydrogen bonds with Glu310 and Asp404 in the active site and other residues with van der Waals interactions. The results suggest that compound 12d could be a leading compound in the further design of effective antitumor drugs.
