Discovery of new fenamate-based derivatives as anticancer agents and potent VEGFR-2 inhibitors
Design, synthesis, and in silico study
Keywords:
tolfenamic acid, synthesis, angiogenesis, VEGFR-2 inhibitors, molecular dockingAbstract
VEGFR-2 is a critical target for the treatment of solid tumors. This work represents synthetic approaches to a new class of fenamate-based derivatives with essential pharmacophoric properties comparable to VEGFR-2 inhibitors. The reaction of tolfenamic acid hydrazide with substituted phenacyl bromide, and phenylisothiocynate derivatives produced novel tolfenamic acid (TA) derivatives (compounds 4 and 5). The target molecules were validated using spectroscopic techniques such as FT-IR and 1HNMR. Docking tests were performed to determine how the synthesized chemicals bind to the putative molecular target, VEGFR-2. The docking results demonstrated that the synthesized compounds could bind VEGFR-2 correctly. Finally, computational physicochemical analysis of the most active candidates revealed that they have favorable assets and reasonable drug-likeness reports.
Downloads
References
Abbas, A. H., Mahmood, A. A. R., Tahtamouni, L. H., Al-Mazaydeh, Z. A., Rammaha, M. S., Alsoubani, F., & Al-bayati, R. I. New picolinic acid derivatives: Synthesis, docking study and anti-EGFR kinase inhibitory effect. Mater Today Proc. Published online. 2021. https://doi.org/10.1016/j.matpr.2021.05.354.
Abdelrehim ESM. Synthesis and Screening of New [1,3,4]Oxadiazole, [1,2,4]Triazole, and [1,2,4]Triazolo[4,3- b][1,2,4]triazole Derivatives as Potential Antitumor Agents on the Colon Carcinoma Cell Line (HCT-116). ACS Omega. 6(2) (2021) 1687-1696. https://doi.org/10.1021/acsomega.0c05718.
Aboul-Fadl, T.; Abdel-Aziz, H.A.; Kadi, A.; Bari, A.; Ahmad, P.; Al-Samani, T.; Ng, S.W. Microwave-assisted one-step synthesis of fenamic acid hydrazides from the corresponding acids. Molecules.16(5) (2011) 3544-3551. https://doi.org/10.3390/molecules16053544.
Ahmed WS, Razzak Mahmood Kubba AA, Al-Bayati RI. Synthesis and evaluation of antimicrobial activity of new imides and schiff bases derived from Ethyl-4-Amino Benzoate. Orient J Chem. 34(5) (2018) 2477-2486. http://dx.doi.org/10.13005/ojc/340533.
Alanazi, M. M., Elwan, A., Alsaif, N. A., Obaidullah, A. J., Alkahtani, H. M., Al-Mehizia, A. A., Alsubaie, S. M., Taghour, M. S., & Eissa, I. H. Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: Design, synthesis, and in silico studies. J Enzyme Inhib Med Chem. 36(1) (2021) 1732-1750. https://doi.org/10.1080/14756366.2021.1945591.
Alanazi, M. M., Mahdy, H. A., Alsaif, N. A., Obaidullah, A. J., Alkahtani, H. M., Al-Mehizia, A. A., Alsubaie, S. M., Dahab, M. A., & Eissa, I. H. New bis ([1, 2, 4] triazolo)[4, 3-a: 3′, 4′-c] quinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, in silico studies, and anticancer evaluation. Bioorg Chem.112 (2021) 104949. https://doi.org/10.1016/j.bioorg.2021.104949.
Al-Bayati, A. I., Razzak Mahmood, A. A., Al-Mazaydeh, Z. A., Rammaha, M. S., Al-bayati, R. I., Alsoubani, F., & Tahtamouni, L. H. Synthesis, Docking Study, and in Vitro Anticancer Evaluation of New Flufenamic Acid Derivatives. Pharmacia. 68(2) (2021) 449-461. https://doi.org/10.3897/pharmacia.68.e66788.
Alsaad H, Kubba A, Tahtamouni LH, Hamzah AH. Synthesis , docking study , and structure activity relationship of novel anti-tumor 2- ( 2 , 3- dimethyl aminobenzoic acid ) moiety. Pharmacia. 69(2) (2022) 415-428.. https://doi:10.3897/pharmacia.69.e83158.
Amir M, Shikha K. Synthesis and anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation activities of some new 2-[(2,6-dichloroanilino) phenyl]acetic acid derivatives. Eur J Med Chem. 39(6) (2004) 535-545. https://doi.org/10.1016/j.ejmech.2004.02.008.
Aziz, M. A., Serya, R. A. T., Lasheen, D. S., Abdel-Aziz, A. K., Esmat, A., Mansour, A. M., Singab, A. N. B., & Abouzid, K. A. M. Discovery of potent VEGFR-2 inhibitors based on furopyrimidine and thienopyrimidne scaffolds as cancer targeting agents. Sci Rep. 6(1) (2016) 1-20. https://doi.org/10.1038/srep24460.
Coutsias EA, Seok C, Dill KA. Using quaternions to calculate RMSD. J Comput Chem. 25(15) 2(004) 1849-1857. https://doi.org/10.1002/jcc.20110.
Davoud Ahmadvand, PhD, Fatemeh Rahbarizadeh, PhD, Farnoush Jafari Iri-Sofla, PhD student, Gholamreza Namazi, PhD student, Sepideh Khaleghi, MSc, Bita Geramizadeh, PhD, Parvin Pasalar, PhD, Hosein Karimi, PhD, Seyed Hamid Aghaee Bakhtiari, PhD student. Inhibition of angiogenesis by recombinant VEGF receptor fragments. Lab Med. 41(7) (2010) 417-422. https://doi.org/10.1309/LMMH2WYRLP7B3HJN.
El-Adl, K., Sakr, H. M., Yousef, R. G., Mehany, A. B. M., Metwaly, A. M., Elhendawy, M. A., Radwan, M. M., ElSohly, M. A., Abulkhair, H. S., & Eissa, I. H. Discovery of new quinoxaline-2 (1H)-one-based anticancer agents targeting VEGFR-2 as inhibitors: Design, synthesis, and anti-proliferative evaluation. Bioorg Chem. 114 (2021) 105105. https://doi.org/10.1016/j.bioorg.2021.105105.
El‐Helby AA, Sakr H, Eissa IH, Abulkhair H, Al‐Karmalawy AA, El‐Adl K. Design, synthesis, molecular docking, and anticancer activity of benzoxazole derivatives as VEGFR‐2 inhibitors. Arch Pharm (Weinheim). 352(10) (2019)1900113. https://doi.org/10.1002/ardp.201900113.
Hmood, K. S., & Razzak Mahmood Kubba, A. A. Synthesis, docking study and in Vitro anticancer evaluation of new derivatives of 2-(1-(2-flouro-[1,1-biphenyl]-4-Yl)Ethyl)-6-(Substituted Phenyl) imidazole[2,1-B][1,3,4]thiadiazole derived from flurbiprofen. Systematic Reviews in Pharmacy, 12(2) (2020) 184–201. https://doi.org/10.31838/srp.2021.2.24.
Kardina, I., Ramadany, S., Sanusi B, Y., Made, S., Stang, S., & Syarif, S. (2020). Children’s midwifery learning media application about android-based rough motor development in improving midwifery student skills. International Journal of Health & Medical Sciences, 3(1), 146-152. https://doi.org/10.31295/ijhms.v3n1.300
Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 141(7) (2010) 1117-1134. https://doi.org/10.1016/j.cell.2010.06.011.
Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci. 77(9) (2020) 1745-1770. https://doi:10.1007/s00018-019-03351-7.
Maiti P., Sharma, P., Nand, M., Bhatt, I. D., Ramakrishnan, M. A., Mathpal, S., Joshi, T., Pant, R., Mahmud, S., & Simal-Gandara, J. Integrated Machine Learning and Chemoinformatics-Based Screening of Mycotic Compounds against Kinesin Spindle ProteinEg5 for Lung Cancer Therapy. Molecules. 27(5) (2022) 1639. https://doi.org/10.3390/molecules27051639.
Modi SJ, Kulkarni VM. Vascular Endothelial Growth Factor Receptor (VEGFR-2)/KDR Inhibitors: Medicinal Chemistry Perspective. Med Drug Discov. 2 (2019) 100009. https://doi.org/10.1016/j.medidd.2019.100009.
Nara, Sukanya Garlapati A. Design, Synthesis and molecular docking study of hybrids of quinazolin-4(3H)-one as anticancer agents TT - Diseño, síntesis y estudio de acoplamiento molecular de híbridos de quinazolinona-tiazolidin-4-onas como agentes anticancerígenos. Ars Pharm. 59(3) (2018) 121-131. http://dx.doi.org/10.1016/j.bmcl.2016.08.013.
Nawaf A. Alsaif, Mohammed S. Taghour, Mohammed M. Alanazi, Ahmad J. Obaidullah, Abdulrahman A. Al-Mehizia, Manal M. Alanazi, Saleh Aldawas, Alaa Elwan & Hazem Elkady. Discovery of new VEGFR-2 inhibitors based on bis ([1, 2, 4] triazolo)[4, 3-a: 3’, 4’-c] quinoxaline derivatives as anticancer agents and apoptosis inducers. J Enzyme Inhib Med Chem. 36(1) (2021) 1093-1114. https://doi.org/10.1080/14756366.2021.1915303.
Rizkiyati, I., Ahmad, M., Syarif, S., & Ahmar, H. (2021). Analysis of motivation and behavior of midwives in using digital partographs. International Journal of Life Sciences, 5(2), 48–58. https://doi.org/10.29332/ijls.v5n2.1234
Sana, S., Reddy, V. G., Bhandari, S., Reddy, T. S., Tokala, R., Sakla, A. P., Bhargava, S. K., & Shankaraiah, N. Exploration of carbamide derived pyrimidine-thioindole conjugates as potential VEGFR-2 inhibitors with anti-angiogenesis effect. Eur J Med Chem. 200 (2020) 112457. https://doi.org/10.1016/j.ejmech.2020.112457.
Suryasa, I. W., Rodríguez-Gámez, M., & Koldoris, T. (2021). The COVID-19 pandemic. International Journal of Health Sciences, 5(2), vi-ix. https://doi.org/10.53730/ijhs.v5n2.2937
Zhang Y, Zou JY, Wang Z, Wang Y. Fruquintinib: a novel antivascular endothelial growth factor receptor tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer. Cancer Manag Res. 11 (2019) 7787-7803. https://doi:10.2147/CMAR.S215533.
Zirlik, K., & Duyster, J.. Anti-angiogenics: current situation and future perspectives. Oncology Research and Treatment. 41(4) (2018)166–171. https://doi.org/10.1159/000488087.
Published
How to Cite
Issue
Section
Copyright (c) 2022 International journal of health sciences
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Articles published in the International Journal of Health Sciences (IJHS) are available under Creative Commons Attribution Non-Commercial No Derivatives Licence (CC BY-NC-ND 4.0). Authors retain copyright in their work and grant IJHS right of first publication under CC BY-NC-ND 4.0. Users have the right to read, download, copy, distribute, print, search, or link to the full texts of articles in this journal, and to use them for any other lawful purpose.
Articles published in IJHS can be copied, communicated and shared in their published form for non-commercial purposes provided full attribution is given to the author and the journal. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
This copyright notice applies to articles published in IJHS volumes 4 onwards. Please read about the copyright notices for previous volumes under Journal History.
