Novel 7-Chloro-4-aminoquinoline-benzimidazole Hybrids as Inhibitors of Cancer Cells Growth: Synthesis, Antiproliferative Activity, in Silico ADME Predictions, and Docking

Abstract

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.

Recent Advances in the Anticancer Applications of Benzimidazole Derivatives

“…As one of the latest works about designing benzimidazolebased anticancer agents, novel aminoquinoline-benzimidazole hybrid compounds were manufactured with differences in the linker and the substituent on the benzimidazole motif. [75] The antiproliferative behaviors of the obtained compounds were checked out against MDCK1 (Madine-Darby canine kidney) nontumor cells, as well as several tumor cell lines comprising CaCo-2 (human colorectal adenocarcinoma), MCF-7, CCRF-CEM (human acute lymphoblastic leukemia), HuT78 (T-cell lymphoma), THP-1 (acute monocytic leukemia), and Raji (Burkitt lymphoma). Some of these compounds (25, 26, and 27, Figure 7) unveiled more potent cytotoxic ability (GI 50 limit: 0.4-8 μM) and effectual cell cycle arrest in leukemia and lymphoma cell lines.…”

Design, Synthesis, Antitumor, and Antiplasmodial Evaluation of New 7-Chloroquinoline–Benzimidazole Hybrids

“…As part of our ongoing efforts to synthesize and biologically evaluate hybrid compounds [18][19][20], we report here on newly prepared hybrids containing two pharmacophores found in natural and synthetic therapeutics: quinoline and benzimidazole. Molecular hybridization is a strategy based on the fusion of two or more known pharmacophores into a single molecule [21][22][23].…”

Anti-proliferative activity of nitroquinolone fused acylhydrazones as non-small cell human lung cancer agents

“…27 The presence of hydrazide-hydrazone linkers have also shown anti-cancer activity against non-small cell lung cancer cell lines (NSCLC's). [28][29][30] Quinolines are well known for their antimalarial nature and recently their uses have extended further into the disciplines of anti-diabetic agents, 31 anti-cancer therapeutics, 32,33 neurodegenerative diseases 34 etc. The quinoline base exhibits strong binding with various apoptotic proteins, thereby making the heterocycle a good starting point for anti-cancer drug design strategies.…”