{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:53:38Z","timestamp":1785405218025,"version":"3.56.0"},"reference-count":49,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UGC"},{"id":[{"id":"https:\/\/ror.org\/01m800e37","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001332","name":"CSIR","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001332","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/03ad6kn10","id-type":"ROR","asserted-by":"publisher"}]},{"name":"New Delhi"},{"name":"ACT","award":["CSC0301"],"award-info":[{"award-number":["CSC0301"]}]},{"name":"RMIT Micro Nano Research Facility"},{"name":"ANFF Victorian Node, Australia"},{"name":"ANRF PM Professorship Program","award":["ANRF\/PMP\/2025\/000324\/CS"],"award-info":[{"award-number":["ANRF\/PMP\/2025\/000324\/CS"]}]},{"name":"Osmania University, Hyderabad"},{"id":[{"id":"https:\/\/ror.org\/030sjb889","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 \u00b5M 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 \u00b5M, 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.<\/jats:p>","DOI":"10.3390\/molecules31101757","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T14:12:54Z","timestamp":1779286374000},"page":"1757","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["(E)-4-(4-Acrylamidophenoxy)-N-Methylpicolinamides as b-Raf\/VEGFR-2 Inhibitors with Antiangiogenic Activity in HUVEC and Zebrafish Model"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5054-2519","authenticated-orcid":false,"given":"Ganga Reddy","family":"Velma","sequence":"first","affiliation":[{"name":"Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT University, GPO BOX 2476, Melbourne, VIC 3001, Australia"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2-Rafi Marg, New Delhi 110 001, India"},{"name":"Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2806-4300","authenticated-orcid":false,"given":"Srinivasa Reddy","family":"Telukutla","sequence":"additional","affiliation":[{"name":"Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT University, GPO BOX 2476, Melbourne, VIC 3001, Australia"},{"name":"Accelerator for Translational Research in Clinical Trials (ATRACT) Centre, School of Health and Biomedical Sciences, STEM College, RMIT University, Melbourne, VIC 3083, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0419-6525","authenticated-orcid":false,"given":"Jayaram","family":"Vankudoth","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Chemical Synthesis Core Facility, Albert Einstein College of Medicine, Gruss MRRC-314, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2418-9616","authenticated-orcid":false,"given":"Ajmer Singh","family":"Grewal","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Guru Gobind Singh College of Pharmacy, Yamuna Nagar 135 001, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Priv\u00e9r","sequence":"additional","affiliation":[{"name":"Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT University, GPO BOX 2476, Melbourne, VIC 3001, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poornachandra","family":"Yedla","sequence":"additional","affiliation":[{"name":"Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4898-5753","authenticated-orcid":false,"given":"Ravikumar","family":"Akunuri","sequence":"additional","affiliation":[{"name":"Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0780-3362","authenticated-orcid":false,"given":"Donald","family":"Wlodkowic","sequence":"additional","affiliation":[{"name":"Phenomics Laboratory, School of Science, RMIT University, Plenty Road, P.O. Box 71, Bundoora, VIC 3083, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1708-6539","authenticated-orcid":false,"given":"Srihari","family":"Pabbaraja","sequence":"additional","affiliation":[{"name":"Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2-Rafi Marg, New Delhi 110 001, India"},{"name":"Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3127-8166","authenticated-orcid":false,"given":"Suresh K.","family":"Bhargava","sequence":"additional","affiliation":[{"name":"Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT University, GPO BOX 2476, Melbourne, VIC 3001, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6889-3667","authenticated-orcid":false,"given":"Magdalena","family":"Plebanski","sequence":"additional","affiliation":[{"name":"Accelerator for Translational Research in Clinical Trials (ATRACT) Centre, School of Health and Biomedical Sciences, STEM College, RMIT University, Melbourne, VIC 3083, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4107-1775","authenticated-orcid":false,"given":"Ahmed","family":"Kamal","sequence":"additional","affiliation":[{"name":"Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2-Rafi Marg, New Delhi 110 001, India"},{"name":"Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500 007, India"},{"name":"Department of Chemistry, Osmania University, Hyderabad 500 007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/0092-8674(95)90405-0","article-title":"Protein kinases and phosphatases: The yin and yang of protein phosphorylation and signaling","volume":"80","author":"Hunter","year":"1995","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/s41392-021-00572-w","article-title":"Small molecules in targeted cancer therapy: Advances, challenges, and future perspectives","volume":"6","author":"Zhong","year":"2021","journal-title":"Signal Transduct. 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