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The compounds were obtained through the rational drug design strategy, bioisosterism, by changing the indole scaffold of Aplysinopsin by phenylpyrazole, a subunit extensively explored for designing potent and selective anticancer agents. The synthesis was performed in three simple steps, followed by structural elucidation through nuclear magnetic resonance, infrared spectroscopy, and mass spectrometry, and global yield ranged from 10% to 93%. Regarding the biological assay, the best result was achieved with\n                    <jats:bold>12g<\/jats:bold>\n                    , which showed antiproliferative activity against all cell lines evaluated, with IC\n                    <jats:sub>50<\/jats:sub>\n                    59.22, 58.33, and 55.32\u2009\u03bcM for MCF\u20107, SiHA and HeLa, respectively. The safety profile, in the Zebrafish\u2010based model, showed the mortality rate for\n                    <jats:bold>12g<\/jats:bold>\n                    in concentration\u2010time\u2010dependent, from 87\u2009\u03bcM, over 120\u2009h. All Aplysinopsin analogs demonstrated drug\u2010likeness in agreement to Lipinski and Veber rules. Although the moderate antiproliferative activity displayed by\n                    <jats:bold>12g<\/jats:bold>\n                    , our results include new Aplysinopsin analogs that may be promising lead compounds for further studies, since chemical structures related to this marine compound have provided satisfactory results as anticancer agents against a variety of human tumor cell lines.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70151","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T11:20:51Z","timestamp":1752232851000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure\u2010Based Bioisosterism Design, Synthesis, Antitumor and Toxicity Assessment of Novel Aplysinopsin Analogs"],"prefix":"10.1111","volume":"106","author":[{"given":"B\u00e1rbara Gon\u00e7alves","family":"Rivello","sequence":"first","affiliation":[{"name":"Laboratory of Medicinal Pharmaceutical Chemistry (LQFM), School of Pharmacy Federal University of Goi\u00e1s  Goi\u00e2nia Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia Biz","family":"Willig","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical and Cytological Analysis, Postgraduate Program in Pharmaceutical Sciences, School of Pharmacy Federal University of Rio Grande Do Sul  Porto Alegre Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6291-9528","authenticated-orcid":false,"given":"J\u00e9ssica","family":"Gotardi","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical and Cytological Analysis, Postgraduate Program in Pharmaceutical Sciences, School of Pharmacy Federal University of Rio Grande Do Sul  Porto Alegre Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1547-5354","authenticated-orcid":false,"given":"Michele 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