{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T10:24:41Z","timestamp":1787653481244,"version":"build-2736575974"},"reference-count":48,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Lercanidipine has previously been investigated in our laboratory as a reference compound in cancer-related combination studies, providing a comparative framework for the present evaluation of thiazole-substituted benzoylpiperazines. In the present study, we evaluated the cytotoxic, anti-inflammatory, and p38\u03b1 MAPK-related activities of thiazole-substituted benzoylpiperazine derivatives. The cytotoxic profiles of the derivatives were evaluated in multiple human cancer cell lines using the MTT assay. Compound 29 showed the highest cytotoxic potency among the tested derivatives and was further evaluated in combination with cisplatin and lercanidipine. In SH-SY5Y cells, the combination treatments produced greater cytotoxic effects than the corresponding monotherapies; however, these findings were evaluated as combination effects rather than as evidence of pharmacological synergy. Mechanistic evaluation further revealed that Compound 29 inhibited p38\u03b1 MAPK enzyme activity and increased caspase-3 and caspase-8 activities. Furthermore, the derivatives exhibited dose-dependent inhibition of TNF-\u03b1 production, with statistically significant effects at increasing concentrations. Docking into the p38\u03b1 ATP-binding pocket produced a Vina score of \u22128.749 kcal\/mol and revealed interactions with Tyr35, Lys53, and Asp168. The co-crystallized inhibitor SB203580 showed a score of \u22129.347 kcal\/mol and additionally formed the canonical hinge hydrogen bond with Met109. These complementary in vitro and in silico findings support p38MAPK as a plausible molecular target of Compound 29. These in vitro and in silico findings suggest that p38\u03b1 MAPK may represent a potential molecular target of Compound 29. Overall, the findings demonstrate the cytotoxic and anti-inflammatory activities of thiazole-substituted benzoylpiperazines and identify Compound 29 as a potent member of this series for further investigation in vitro.<\/jats:p>","DOI":"10.3390\/ijms27177605","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T10:04:55Z","timestamp":1787652295000},"page":"7605","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thiazole-Substituted Benzoylpiperazines with Anti-Cancer and Anti-Inflammatory Activities: Comparative Evaluation with Lercanidipine"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1896-2729","authenticated-orcid":false,"given":"Sevde Nur","family":"Biltekin Kaleli","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Microbiology, School of Pharmacy, Istanbul Medipol University,\u00a034810 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alharbi, A., Zhang, Y., and Parrington, J. 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