Synthesis of novel 6,7-dimethoxy-4-anilinoquinolines as potent c-Met inhibitors

Abstract

HGF/c-Met signalling pathway plays an important role in the development of cancers. A series of 6,7-dimethoxy-4-anilinoquinolines possessing benzimidazole moiety were synthesised and identified as potent inhibitors of the tyrosine kinase c-Met. Their in vitro biological activities against three cancer cell lines (A549, MCF-7, and MKN-45) were also evaluated. Most of these compounds exhibited moderate to remarkable potency. Among them, compound 12n showed the most potent inhibitory activity against c-Met with IC50 value of 0.030 ± 0.008 µM and it also showed excellent anticancer activity against the tested cancer cell lines at low micromolar concentration. Molecular docking verified the results and revealed the possible binding mode of the most promising compound 12n into the ATP-binding site of c-Met kinase.

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

“…The cyclopropane-1,1-dicarboxiamide framework interferes with the Phe 1223 of the DFG motif, determining the disruption of the catalytic conformation (from DFG-in to DFG out) and the reorganization of the activation loop, which almost entirely envelops the ligand ( Figure 4 a). In the cavity the reoriented Phe 1223 forms a π-π stacking with the central fluorophenyl ring, the quinoline nitrogen links with a hydrogen bond the backbone amide of Met 1160 and also the dicarboxamide moiety forms additional hydrogen bonds with Lys 1110 and Asp 1222 ( Figure 4 b) [ 30 , 31 , 32 ].…”

“… ( a ) crystal structure of kinase domain of c-Met in complex with foretinib (PDB ID: 3LQ8). In the box the binding cavity of the receptor occupied by the quinoline small molecule is illustrated (the activation loop is represented with transparent surface) [ 31 ]; ( b ) interactions of foretinib with amino acid residues of the c-Met active site [ 32 ]. …”

Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type

“…Molecular docking, molecular dynamics, and virtual screening approaches can now be efficiently used for the design of new inhibitors of the MET kinase domain [27,56,[76][77][78][79][80]. From all these approaches, new potent compounds were obtained and more highlights revealed about MET kinase domain conformational behavior.…”

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure–activity relationship, and mechanisms of action (2019–2021)

“…[108] The benzimidazole-quinoline hybrids possessed considerable antiproliferative activity, and among them, hybrid 52 (IC 50 : 6.1-13.4 µM, MTT assay) was comparable to cabozantinib (IC 50 : 4.5-11.8 µM) against A549, MCF-7, and MKN-45 cancer cell lines. [109][110][111][112] Molecular docking study demonstrated that hybrid 52 could bind tightly with the active site of c-Met by various interactions, so this hybrid could serve as a promising candidate for the development of novel c-Met inhibitors.…”