{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T03:52:58Z","timestamp":1789617178834,"version":"build-2803163510"},"reference-count":20,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Breast cancer remains the most frequently diagnosed malignant tumor among women worldwide, and the limited selectivity as well as the emerging resistance to currently used therapies highlight the need to search for new therapeutic compounds. Aromatase, a key enzyme in the estrogen biosynthesis pathway, represents a recognized molecular target in the treatment of hormone-dependent cancers. In this study, six new 1,3,4-thiadiazole derivatives containing two halogen-substituted aromatic rings were designed and synthesized as potential nonsteroidal aromatase inhibitors. The cytotoxic activity of the obtained compounds was evaluated against two breast cancer cell lines: MCF-7 (estrogen-dependent) and MDA-MB-231 (estrogen-independent). All tested compounds exhibited concentration-dependent cytotoxic activity against MCF-7 cells, with the strongest effects observed for compounds A2, A3, B1, and B3 (IC50 \u2248 52\u201355 \u00b5M). In contrast, none of the tested compounds showed significant activity against MDA-MB-231 cells (IC50 &gt; 100 \u00b5M), suggesting their selectivity toward estrogen-dependent cancer cells. Compound B3, identified as the most promising, was further subjected to in silico analyses. Molecular docking and molecular dynamics simulations revealed that B3 occupies a binding site similar to that of the co-crystallized native inhibitor and forms interactions characteristic of strong aromatase inhibitors. The obtained results confirm a mechanism of action related to aromatase inhibition and indicate that fluorophenyl-substituted 1,3,4-thiadiazole derivatives represent a promising scaffold for the design of new, selective, and less toxic aromatase inhibitors.<\/jats:p>","DOI":"10.3390\/molecules30244744","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T09:37:48Z","timestamp":1765532268000},"page":"4744","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis and In Vitro Evaluation of Anticancer Activity of Fluorophenyl Derivatives of 1,3,4-Thiadiazole Against Estrogen-Dependent Breast Cancer"],"prefix":"10.3390","volume":"30","author":[{"given":"Sara","family":"Janowska","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, Medical University of Lublin, 8b Jaczewskiego Street, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Makuch-Kocka","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical University of Lublin, Radziwi\u0142\u0142owska 11 Street, 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9555-3905","authenticated-orcid":false,"given":"Rafa\u0142","family":"Kurczab","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5571-1593","authenticated-orcid":false,"given":"Oleg M.","family":"Demchuk","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The John Paul II Catholic University of Lublin, 1J Konstantyn\u00f3w Street, 20-708 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9816-1934","authenticated-orcid":false,"given":"Monika","family":"Wujec","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Medical University of Lublin, 4A Chod\u017aki Street, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1038\/s41591-025-03502-3","article-title":"Global Patterns and Trends in Breast Cancer Incidence and Mortality across 185 Countries","volume":"31","author":"Kim","year":"2025","journal-title":"Nat. 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