Design, Synthesis, Docking Study, and Antiproliferative Evaluation of Novel Schiff Base–Benzimidazole Hybrids with VEGFR-2 Inhibitory Activity
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Biology
2.2.1. Primary In Vitro One-Dose Anticancer Assay
2.2.2. Full In Vitro Five-Dose Anticancer Assay
2.2.3. MTT Assay against Lung Cancer Cell Lines
2.2.4. In Vitro VEGFR-2 Inhibition Assay
2.2.5. Cell Cycle Analysis of Benzimidazole Hybrids 3e and 3g
2.2.6. Annexin V/ FITC Apoptosis Staining Assay
2.2.7. Caspase Assay
3. Docking Study
4. Conclusions
5. Experimental Section
5.1. Chemistry
5.1.1. General Synthesis of Compounds 3a–o
6-((Z)-((E)-Benzylidenehydrazono)(phenyl)methyl)-2-(4-chlorophenyl)-1H-benzo[d]imidazole (3a)
2-(4-Chlorophenyl)-5-((Z)-phenyl((E)-(1-phenylethylidene)hydrazono)methyl)-1H-benzo[d]imidazole (3b)
4-((E)-((Z)-((2-(4-Chlorophenyl)-1H-benzo[d]imidazol-6-yl)(phenyl) methylene)hydrazono)methyl)phenol (3c)
4-((E)-1-((Z)-((2-(4-Chlorophenyl)-1H-benzo[d]imidazol-5-yl)(phenyl)methylene)hydrazono)ethyl)phenol (3d)
2-(4-Chlorophenyl)-6-((Z)-((E)-(4-methoxybenzylidene)hydrazono)(phenyl)methyl)-1H-benzo[d]imidazole (3e)
2-(4-Chlorophenyl)-5-((Z)-((E)-(1-(4-methoxyphenyl)ethylidene)hydrazono) (phenyl)methyl)-1H-benzo[d]imidazole (3f)
6-((Z)-((E)-(4-Chlorobenzylidene)hydrazono)(phenyl)methyl)-2-(4-chlorophenyl)-1H-benzo[d]imidazole (3g)
4-((E)-1-((Z)-((2-(4-Chlorophenyl)-1H-benzo[d]imidazol-5-yl)(phenyl)methylene)hydrazono)ethyl)aniline (3h)
4-(6-((Z)-((E)-benzylidenehydrazono)(phenyl)methyl)-1H-benzo[d]imidazol-2-yl)phenol (3i)
4-(5-((Z)-Phenyl((E)-(1-phenylethylidene)hydrazono)methyl)-1H-benzo[d]imidazol-2-yl)phenol (3j)
4-(6-((Z)-((E)-(4-hydroxybenzylidene)hydrazono)(phenyl)methyl)-1H-benzo[d]imidazol-2-yl)phenol (3k)
4-((E)-1-((Z)-((2-(4-Hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(phenyl)methylene)hydrazono)ethyl)phenol (3l)
4-(6-((Z)-((E)-(4-Methoxybenzylidene)hydrazono)(phenyl)methyl)-1H-benzo[d]imidazol-2-yl)phenol (3m)
4-(5-((Z)-((E)-(1-(4-Methoxyphenyl)ethylidene)hydrazono)(phenyl)methyl)-1H-benzo[d]imidazol-2-yl)phenol (3n)
4-(6-((Z)-((E)-(4-chlorobenzylidene)hydrazono)(phenyl)methyl)-1H-benzo[d]imidazol-2-yl)phenol (3o)
5.2. Biological Evaluation
5.2.1. NCI Screening Assay
5.2.2. MTT Assay for Cell Viability
5.2.3. VEGFR Inhibitory Assay
5.2.4. Cell Cycle Analysis and Apoptotic Assay
Cell Apoptosis and Apoptotic Detection
5.2.5. Activation of Caspases
5.2.6. Docking Study
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
Appendix A
Appendix A.1. Biological Studies
Appendix A.1.1. Cytotoxic Activity Evaluation against Lung Cancer Cell Lines
Appendix A.1.2. VEGFR-2 Inhibition Assay
Appendix A.1.3. Cell Cycle Analysis of Compounds 3e and 3g
Appendix A.1.4. Apoptosis Assay for Compounds 3e and 3g
Appendix A.1.5. Caspase 9 Assay for Compounds 3e and 3g
Appendix A.1.6. Molecular Modeling Study
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Comp No | IC50 Value (μM) | |
---|---|---|
A549 | NCI-H460 | |
3c | 4.95 ± 0.61 | 3.07 ± 0.42 |
3e | 3.58 ± 0.53 | 1.71 ± 0.17 |
3g | 1.88 ± 0.35 | 0.85 ± 0.24 |
3o | 5.98 ± 0.55 | 5.22 ± 0.42 |
Sorafenib | 4.84 ± 0.23 | 3.49 ± 0.18 |
Comp. No. | VEGFR-2 | ||||
---|---|---|---|---|---|
Affinity kcal/mol | Distance (in Ao) from Main Residue | Amino Acids Residue | Functional Group | Type of Interactions | |
3g | −8.59 | 3.38 | Glu 885 | C24 | H-donor |
3.09 | ASP 1046 | N23 | H-acceptor | ||
3.72 | PHE 1047 | 6-ring | pi-H | ||
Sorafenib | −8.74 | 2.91 | Glu 885 | N12 | H-donor |
3.45 | Glu 885 | N14 | H-donor | ||
2.90 | Asp 1046 | O15 | H-acceptor | ||
3.25 | Cys 919 | N26 | H-acceptor | ||
3.67 | PHE 1047 | 5-ring | pi-H |
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Abd El-Lateef, H.M.; Elbastawesy, M.A.I.; Abdelghani Ibrahim, T.M.; Khalaf, M.M.; Gouda, M.; Wahba, M.G.F.; Zaki, I.; Morcoss, M.M. Design, Synthesis, Docking Study, and Antiproliferative Evaluation of Novel Schiff Base–Benzimidazole Hybrids with VEGFR-2 Inhibitory Activity. Molecules 2023, 28, 481. https://doi.org/10.3390/molecules28020481
Abd El-Lateef HM, Elbastawesy MAI, Abdelghani Ibrahim TM, Khalaf MM, Gouda M, Wahba MGF, Zaki I, Morcoss MM. Design, Synthesis, Docking Study, and Antiproliferative Evaluation of Novel Schiff Base–Benzimidazole Hybrids with VEGFR-2 Inhibitory Activity. Molecules. 2023; 28(2):481. https://doi.org/10.3390/molecules28020481
Chicago/Turabian StyleAbd El-Lateef, Hany M., Mohammed A. I. Elbastawesy, Tamer Mohamed Abdelghani Ibrahim, Mai M. Khalaf, Mohamed Gouda, Mariam G. F. Wahba, Islam Zaki, and Martha M. Morcoss. 2023. "Design, Synthesis, Docking Study, and Antiproliferative Evaluation of Novel Schiff Base–Benzimidazole Hybrids with VEGFR-2 Inhibitory Activity" Molecules 28, no. 2: 481. https://doi.org/10.3390/molecules28020481