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Volume 31
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10.3390/molecules31101757
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

(E)-4-(4-Acrylamidophenoxy)-N-Methylpicolinamides as b-Raf/VEGFR-2 Inhibitors with Antiangiogenic Activity in HUVEC and Zebrafish Model

by
Ganga Reddy Velma
1,2,3,
Srinivasa Reddy Telukutla
1,4,*,
Jayaram Vankudoth
5,
Ajmer Singh Grewal
6,
Steven Privér
1,
Poornachandra Yedla
3,
Ravikumar Akunuri
3,
Donald Wlodkowic
7,
Srihari Pabbaraja
2,3,
Suresh K. Bhargava
1,
Magdalena Plebanski
4,* and
Ahmed Kamal
2,3,8,*
1
Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT University, GPO BOX 2476, Melbourne, VIC 3001, Australia
2
Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2-Rafi Marg, New Delhi 110 001, India
3
Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, Telangana, India
4
Accelerator for Translational Research in Clinical Trials (ATRACT) Centre, School of Health and Biomedical Sciences, STEM College, RMIT University, Melbourne, VIC 3083, Australia
5
Department of Biochemistry, Chemical Synthesis Core Facility, Albert Einstein College of Medicine, Gruss MRRC-314, Bronx, NY 10461, USA
6
Department of Pharmaceutical Sciences, Guru Gobind Singh College of Pharmacy, Yamuna Nagar 135 001, Haryana, India
7
Phenomics Laboratory, School of Science, RMIT University, Plenty Road, P.O. Box 71, Bundoora, VIC 3083, Australia
8
Department of Chemistry, Osmania University, Hyderabad 500 007, Telangana, India
*
Authors to whom correspondence should be addressed.
Molecules 2026, 31(10), 1757; https://doi.org/10.3390/molecules31101757 (registering DOI)
Submission received: 12 February 2026 / Revised: 11 May 2026 / Accepted: 15 May 2026 / Published: 20 May 2026
(This article belongs to the Special Issue Novel Heterocyclic Compounds: Synthesis and Applications)
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Abstract

Pharmacophore hybridization is a well-established strategy for developing novel anticancer agents with improved biological profiles. In this study, a new series of (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide derivatives has been rationally designed by hybridizing key structural features of sorafenib with cinnamide pharmacophores and subsequently synthesized. The antiproliferative activities of the synthesized compounds were evaluated against a panel of human cancer cell lines, including A549 (lung), DU-145 (prostate), SKOV3 (ovarian), and HepG2 (liver), along with non-cancerous Hek293T cells. In comparison with the standard drug sorafenib, most of the (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamides demonstrated significant antiproliferative activity, with specificity toward the HepG2 (liver cancer) cell line, and no effect on the noncancerous cells (Hek293T). Among them, compound 5f, the derivative containing a trifluoromethyl-substituted cinnamoyl moiety was identified as the lead candidate, exhibiting an IC50 of 5.3 µM towards HepG2 (liver) cancer cells, comparable to the reference drug sorafenib. Enzyme inhibition studies showed that compound 5f inhibited both b-Raf and VEGFR-2 with IC50 values of 1.45 and 0.37 µM, respectively. Furthermore, compound 5f suppressed angiogenesis in vitro and in vivo, as evidenced by the tube formation assay using HUVECs and in transgenic zebrafish Tg(fli1a:EGFP) models, respectively. Mechanistic studies indicated that compound 5f induced apoptosis in HepG2 cells through mitochondrial membrane depolarization and increased ROS generation. Molecular docking studies supported experimental findings and showed that 5f can interact with catalytically active residues via hydrogen-bonding interactions. Overall, these results highlight the potential of compound 5f as a promising dual target therapeutic lead with dual direct anticancer and antiangiogenic properties.
Keywords: anticancer; b-Raf inhibitors; VEGFR-2 inhibitors; angiogenesis; apoptosis; zebrafish anticancer; b-Raf inhibitors; VEGFR-2 inhibitors; angiogenesis; apoptosis; zebrafish
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MDPI and ACS Style

Velma, G.R.; Telukutla, S.R.; Vankudoth, J.; Grewal, A.S.; Privér, S.; Yedla, P.; Akunuri, R.; Wlodkowic, D.; Pabbaraja, S.; Bhargava, S.K.; et al. (E)-4-(4-Acrylamidophenoxy)-N-Methylpicolinamides as b-Raf/VEGFR-2 Inhibitors with Antiangiogenic Activity in HUVEC and Zebrafish Model. Molecules 2026, 31, 1757. https://doi.org/10.3390/molecules31101757

AMA Style

Velma GR, Telukutla SR, Vankudoth J, Grewal AS, Privér S, Yedla P, Akunuri R, Wlodkowic D, Pabbaraja S, Bhargava SK, et al. (E)-4-(4-Acrylamidophenoxy)-N-Methylpicolinamides as b-Raf/VEGFR-2 Inhibitors with Antiangiogenic Activity in HUVEC and Zebrafish Model. Molecules. 2026; 31(10):1757. https://doi.org/10.3390/molecules31101757

Chicago/Turabian Style

Velma, Ganga Reddy, Srinivasa Reddy Telukutla, Jayaram Vankudoth, Ajmer Singh Grewal, Steven Privér, Poornachandra Yedla, Ravikumar Akunuri, Donald Wlodkowic, Srihari Pabbaraja, Suresh K. Bhargava, and et al. 2026. "(E)-4-(4-Acrylamidophenoxy)-N-Methylpicolinamides as b-Raf/VEGFR-2 Inhibitors with Antiangiogenic Activity in HUVEC and Zebrafish Model" Molecules 31, no. 10: 1757. https://doi.org/10.3390/molecules31101757

APA Style

Velma, G. R., Telukutla, S. R., Vankudoth, J., Grewal, A. S., Privér, S., Yedla, P., Akunuri, R., Wlodkowic, D., Pabbaraja, S., Bhargava, S. K., Plebanski, M., & Kamal, A. (2026). (E)-4-(4-Acrylamidophenoxy)-N-Methylpicolinamides as b-Raf/VEGFR-2 Inhibitors with Antiangiogenic Activity in HUVEC and Zebrafish Model. Molecules, 31(10), 1757. https://doi.org/10.3390/molecules31101757

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