Design, Synthesis, Docking Study, and Antiproliferative Evaluation of Novel Schiff Base–Benzimidazole Hybrids with VEGFR-2 Inhibitory Activity

Abstract

A new series of Schiff–benzimidazole hybrids 3a–o has been designed and synthesized. The structure of the target compounds was proved by different spectroscopic and elemental analysis tools. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI single- and five-dose protocols. Consequently, four compounds were further examined against the most sensitive lung cancer A549 and NCI-H460 cell lines. Compounds 3e and 3g were the most active, achieving 3.58 ± 0.53, 1.71 ± 0.17 and 1.88 ± 0.35, 0.85 ± 0.24 against A549 and NCI-H460 cell lines, respectively. Moreover, they showed remarkable inhibitory activity on the VEGFR-2 TK with 86.23 and 89.89%, respectively, as compared with Sorafenib (88.17%). Moreover, cell cycle analysis of NCI-H460 cells treated with 3e and 3g showed cellular cycle arrest at both G1 and S phases (supported by caspases-9 study) with significant pro-apoptotic activity, as indicated by annexin V-FITC staining. The binding interactions of these compounds were confirmed through molecular docking studies; the most active compounds displayed complete overlay with, and a similar binding mode and pose to, Sorafenib, a reference VEGFR-2 inhibitor.

Benzimidazole-Based Derivatives as Apoptotic Antiproliferative Agents: Design, Synthesis, Docking, and Mechanistic Studies

“…Scheme 1 depicts the synthesis method for compounds 4a – j , 5 , and 6 . Condensation of 3,4-aminobenzoic acid with p-chlorobenzaldehyde in the presence of sodium metabisulphite and DMF resulted in the synthesis of benzimidazole-5-carboxylic acid ( 1 ) in a good yield [ 34 , 35 ]. Compound 1 ’s infrared spectra showed that C=O was present at 1662 cm −1 .…”

“…The key intermediates 1 – 3 were prepared according to previously reported procedures [ 34 , 36 , 38 ].…”

Synthesis, Biological Investigation, and Molecular Docking of Novel Benzimidazole‐Hydrazone Hybrids as Potential Anticancer Agent Candidates

“…[42] The presence of NH group in the structure of our synthesized compounds, unlike the one mentioned above, may have caused an increase in activity.In addition, as stated in the literature, the benzimidazole ring forming the basic structure in the target compounds and imine bond formation were the most important aspects determining the activity. [43,44] Unlike previous studies, the NH group at the C-2 position of the benzimidazole ring increased the activity by interacting with amino acids in the target protein (GLN282, THR276, etc. ).…”

New benzimidazole‐oxadiazole derivatives as potent VEGFR‐2 inhibitors: Synthesis, anticancer evaluation, and docking study

“…There are many studies in the literature regarding the VEGFR‐2 inhibition of benzimidazoles (Abd El‐Lateef et al, 2023a; Abdel‐Mohsen et al, 2020a; Ali et al, 2022; Ding et al, 2020; Mostafa et al, 2019; Tong et al, 2021; Yuan et al, 2019). In 2023, a new series of Schiff base‐benzimidazole hybrids has been developed and synthesized by Abd El‐Lateef et al (2023a, 2023b).…”

“…There are many studies in the literature regarding the VEGFR‐2 inhibition of benzimidazoles (Abd El‐Lateef et al, 2023a; Abdel‐Mohsen et al, 2020a; Ali et al, 2022; Ding et al, 2020; Mostafa et al, 2019; Tong et al, 2021; Yuan et al, 2019). In 2023, a new series of Schiff base‐benzimidazole hybrids has been developed and synthesized by Abd El‐Lateef et al (2023a, 2023b). The anticancer activity of the investigated benzimidazole hybrids is associated with inhibition of the VEGFR‐2 enzyme, wherein two benzimidazoles derivatives demonstrated potent inhibition of the enzyme (86.23% and 89.89%, respectively), in comparison to Sorafenib (88.17% inhibitory activity) (Abdel‐Mohsen et al, 2020b).…”