{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T20:12:48Z","timestamp":1785269568889,"version":"3.55.0"},"reference-count":72,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007771","name":"Medical University of Silesia in Katowice","doi-asserted-by":"publisher","award":["BNW-1-048\/5\/F"],"award-info":[{"award-number":["BNW-1-048\/5\/F"]}],"id":[{"id":"10.13039\/100007771","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Phenothiazine derivatives bearing trifluoromethyl substituents have attracted increasing interest as multifunctional scaffolds in drug repositioning strategies, particularly in cancer and infectious diseases. Structural modification of classical phenothiazines by incorporation of a quinoline moiety has previously been shown to enhance biological activity. Objectives: The present study aimed to develop an efficient synthesis of 8-trifluoromethylquinobenzothiazines and to evaluate the anticancer and antibacterial potential of their N-substituted analogues inspired by triflupromazine, trifluoperazine, and fluphenazine. Methods: 6H-8-Trifluoromethylquinobenzothiazine was synthesized by cyclization of 2-amino-4-trifluoromethylbenzenethiol and 3-bromo-2-chloroquinoline. The resulting quinobenzothiazine, unsubstituted at the nitrogen atom, was subjected to N-alkylation reactions to afford eleven new 6-dialkylaminoalkyl derivatives. Structural elucidation was performed using NMR and HRMS techniques. Anticancer activity was evaluated by MTT assay against human breast (MDA-MB-231), pancreatic (Mia-PaCa-2), and lung (A-549) carcinoma cell lines, as well as normal HaCaT keratinocytes. Antibacterial activity was assessed by MIC\/MBC determination against selected Gram-positive and Gram-negative reference strains and clinical isolates. Results: Among the synthesized compounds, derivatives 8 and 12 exhibited the most favorable anticancer profiles, showing micromolar cytotoxicity (IC50 \u2248 4\u201310 \u00b5M) against lung and pancreatic cancer cells combined with moderate selectivity toward cancer cells over normal keratinocytes. Compound 6 displayed lower cytotoxic potency but a notably high selectivity index due to minimal toxicity toward normal cells. In antibacterial assays, compound 3 exhibited activity against Gram-positive bacteria, including a methicillin-resistant Staphylococcus aureus isolate, with MIC values ranging from 7.8 to 15.6 \u00b5g\/mL. The corresponding MBC values were equal to or twofold higher than the MICs (MBC\/MIC = 1\u20132), fulfilling commonly accepted criteria for bactericidal activity (MBC\/MIC \u2264 4). OD-based growth kinetics confirmed concentration-dependent inhibition of S. aureus growth. Conclusions: The obtained results identify 8-trifluoromethylquinobenzothiazines as a promising class of multifunctional compounds. Selected derivatives combine anticancer activity with acceptable selectivity or display potent antibacterial effects against clinically relevant Gram-positive pathogens.<\/jats:p>","DOI":"10.3390\/ph19030422","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T16:17:31Z","timestamp":1772641051000},"page":"422","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel 8-trifluoromethylquinobenzothiazines\u2014Synthesis and Evaluation for Antiproliferative and Antibacterial Activity"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0561-5082","authenticated-orcid":false,"given":"Daria","family":"Klimoszek","sequence":"first","affiliation":[{"name":"Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jagiello\u0144ska Street 4, 41-200 Sosnowiec, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9036-7452","authenticated-orcid":false,"given":"Anna","family":"Majewska","sequence":"additional","affiliation":[{"name":"Chair and Department of Medical Microbiology, Medical University of Warsaw, Chalubinski 5 Street, 02-004 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4144-990X","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Jele\u0144","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmaceutical Sciences, The Medical University of Silesia, Jagiello\u0144ska 4, 41-200 Sosnowiec, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0181-3607","authenticated-orcid":false,"given":"Marta","family":"Struga","sequence":"additional","affiliation":[{"name":"Chair and Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5389-1079","authenticated-orcid":false,"given":"Beata","family":"Morak-M\u0142odawska","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmaceutical Sciences, The Medical University of Silesia, Jagiello\u0144ska 4, 41-200 Sosnowiec, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0425-5468","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Do\u0142owy","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jagiello\u0144ska Street 4, 41-200 Sosnowiec, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA. 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