{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T09:13:11Z","timestamp":1788858791388,"version":"build-2803163510"},"reference-count":28,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Programa de Inserci\u00f3n Acad\u00e9mica 2026 of the Vicerrector\u00eda Acad\u00e9mica and Prorrector\u00eda at Pontificia Universidad Cat\u00f3lica de Chile","award":["1221631"],"award-info":[{"award-number":["1221631"]}]},{"award":["1221631"],"award-info":[{"award-number":["1221631"]}],"id":[{"id":"https:\/\/ror.org\/04teye511","id-type":"ROR","asserted-by":"publisher"}]},{"name":"the Universidad de Concepci\u00f3n through internal research projects","award":["2023000895INT"],"award-info":[{"award-number":["2023000895INT"]}]},{"name":"the Universidad de Concepci\u00f3n through internal research projects","award":["2025001345INI"],"award-info":[{"award-number":["2025001345INI"]}]},{"award":["2023000895INT"],"award-info":[{"award-number":["2023000895INT"]}],"id":[{"id":"https:\/\/ror.org\/0460jpj73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2025001345INI"],"award-info":[{"award-number":["2025001345INI"]}],"id":[{"id":"https:\/\/ror.org\/0460jpj73","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A series of N-phenyl-3-(thiophen-2-yl)acrylamide derivatives were designed and synthesized to investigate the influence of electronic and steric modifications on cytotoxic activity. Although related thiophene-containing acrylamides have been reported, the specific compounds studied in this study have not been previously described. Structural variations were introduced at the para position of the N-phenyl ring (H, CF3, and OCF3) and at the 5-position of the thiophene ring (H and CH3) to enable preliminary structure\u2013activity relationship (SAR) analysis. The target compounds were synthesized via Knoevenagel\u2013Doebner condensation, followed by carbodiimide-mediated amide coupling. The compounds were characterized using nuclear magnetic resonance (NMR) spectroscopy, high-resolution mass spectrometry (HRMS), Fourier-transform infrared (FTIR) spectroscopy, and high-performance liquid chromatography (HPLC). Computational evaluation indicated compliance with Lipinski\u2019s rule of five and the absence of predicted mutagenic, tumorigenic, irritant, and reproductive risks. Cytotoxic activity was determined using the sulforhodamine B (SRB) assay against human breast adenocarcinoma (MCF-7), gastric adenocarcinoma (AGS), colorectal adenocarcinoma (Caco-2), oral squamous cell carcinoma (HSC-3), hepatocellular carcinoma (HepG2) cell lines and non-cancerous human dermal fibroblasts (HDF). Compounds 11 and 16 displayed the most consistent activity, with half-maximal inhibitory concentration (IC50) values of 379, 420, and 265 \u03bcM and 272, 256, and 242 \u03bcM against AGS, Caco-2, and MCF-7 cells, respectively. MCF-7 cells were the most sensitive model. The most active derivative was compound 16, suggesting that the combination of a 5-methylthiophene moiety and a para-CF3 substituent may be beneficial within this limited compound series. These findings provide a preliminary evaluation of this scaffold and will help guide future studies on structural modifications.<\/jats:p>","DOI":"10.3390\/molecules31183147","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T09:02:24Z","timestamp":1788858144000},"page":"3147","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Cytotoxic Evaluation of N-Phenyl-3-(Thiophen-2-Yl)acrylamide Derivatives"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9437-0626","authenticated-orcid":false,"given":"Pablo S.","family":"Cavagnero","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Ciencias Qu\u00edmicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4130000, 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