{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:46:18Z","timestamp":1785422778815,"version":"3.56.0"},"reference-count":43,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science and Education for Smart Growth Operational Program"},{"name":"European Union through the European Structural and Investment funds (","award":["BG16RFPR002-1.014-0018-C01"],"award-info":[{"award-number":["BG16RFPR002-1.014-0018-C01"]}]},{"award":["BG16RFPR002-1.014-0018-C01"],"award-info":[{"award-number":["BG16RFPR002-1.014-0018-C01"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>With the introduction of Navarixin in clinical trials, the role of squaric acid derivatives as bioisosteres gained popularity. Because of their distinctive electronic properties and hydrogen-bonding capacity, these compounds hold considerable promise for medicinal chemistry applications. In this study, a series of novel furan- and thiophene-containing squaric acid derivatives was synthesized via base-catalyzed nucleophilic substitution and characterized by spectroscopic techniques. The structures of three compounds were additionally confirmed by X-ray crystallography. Density functional theory calculations showed good agreement with the experimental vibrational spectra. In silico evaluation predicted favorable drug-like characteristics, including compliance with Lipinski\u2019s rule of five and high gastrointestinal absorption. The cytotoxic activity of the synthesized compounds was assessed against HeLa, HT-29, HL-60, A-549, and MCF-7 cancer cell lines, as well as the non-cancerous CCL-1 cell line. Several derivatives displayed moderate to strong antiproliferative activity with selectivity toward malignant cells. Compound 3d exhibited the most pronounced improvement (five-fold) over Navarixin in HL-60 cells 5.81 \u00b5M, while compounds 3a and 3c demonstrated superior potency and selectivity in A-549 cells (10.33 \u00b5M and 9.65 \u00b5M). These findings identify squaric acid derivatives as promising candidates for further anticancer drug development and structure\u2013activity relationship studies.<\/jats:p>","DOI":"10.3390\/ijms27136047","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T13:43:14Z","timestamp":1783345394000},"page":"6047","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Squaramides and Squaramates Containing a Five-Membered Heterocyclic Ring: Synthesis, Structure, and Cytotoxicity"],"prefix":"10.3390","volume":"27","author":[{"given":"Georgi","family":"Tirolski","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Dunav 2 Street, 1000 Sofia, Bulgaria"},{"name":"Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Build. 9, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Vasilev","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Dunav 2 Street, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9761-0355","authenticated-orcid":false,"given":"Mariyana","family":"Atanasova","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, Dunav 2 Street, 1000 Sofia, Bulgaria"},{"name":"Centre of Excellence in Informatics and Information and Communication Technologies, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2841-7089","authenticated-orcid":false,"given":"Georgi","family":"Momekov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Dunav 2 Street, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0296-7229","authenticated-orcid":false,"given":"Hristina","family":"Sbirkova-Dimitrova","sequence":"additional","affiliation":[{"name":"Institute of Mineralogy and Crystallography \u201cAcad. Ivan Kostov\u201d, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Build. 107, 1113 Sofia, Bulgaria"},{"name":"Center of Competence PERIMED-2, Vasil Aprilov Blvd. 15A, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3017-3258","authenticated-orcid":false,"given":"Adriana","family":"Bakalova","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, Dunav 2 Street, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1097-1850","authenticated-orcid":false,"given":"Emiliya","family":"Cherneva","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, Dunav 2 Street, 1000 Sofia, Bulgaria"},{"name":"Centre of Excellence in Informatics and Information and Communication Technologies, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2578","DOI":"10.1021\/cg500264k","article-title":"Experimental and theoretical study of aromaticity effects in the solid state architecture on squaric acid derivatives","volume":"14","author":"Prohens","year":"2014","journal-title":"Cryst. 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