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Methods: The compounds were designed as structural analogues of halicin with two points of variation and were synthesized through a process with multiple condensation steps. The compounds were evaluated in vitro through MIC determinations for the antimicrobial activity and percentage of biofilm inhibition, and in silico, respectively, through molecular docking, druggability, and ADMETox prediction. A 2D-QSAR study was conducted for antimicrobial activity using the Free-Wilson model. Results: In terms of antibacterial activity, all compounds displayed important activity on the tested strains (MICs = 15.62\u2013250 \u03bcg\/mL), except against Staphylococcus aureus. Regarding the antifungal activity, the effect against Candida albicans was similar to fluconazole in most cases (MIC = 15.62 \u03bcg\/mL). With respect to the antibiofilm activity, the most effective activity was registered against the Pseudomonas aeruginosa biofilm. The in vitro results for the antibacterial activity against Escherichia coli were correlated with the observations drawn in the molecular docking study on the ATPase domain of the GyrB subunit of E. coli. The in silico predictions of the molecular properties concluded that all compounds have good druggability properties, while the ADMETox predictions concluded that the compounds could have low gastrointestinal absorption and blood\u2013brain barrier permeation capacity, but raised safety flags (e.g., hepatotoxicity and high acute oral toxicity). The 2D-QSAR study concluded that the thiazolyl-methylthio-thiadiazole scaffold had the highest contribution to antimicrobial activity in almost all cases. Conclusions: The two series of compounds highlight the impact of structural modulations of the scaffold and its substituents on the investigated biological activities.<\/jats:p>","DOI":"10.3390\/antibiotics15050448","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T13:32:22Z","timestamp":1777469542000},"page":"448","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Thiazolyl-Methylthio-1,3,4-Thiadiazole Hybrids as Halicin Analogues with Antimicrobial and Antibiofilm Activities: Chemical Development, Biological Assessment, and 2D-QSAR Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5980-6963","authenticated-orcid":false,"given":"Daniel","family":"Ungureanu","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 41 Victor Babe\u0219 Street, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9397-0388","authenticated-orcid":false,"given":"Gabriel","family":"Marc","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 41 Victor Babe\u0219 Street, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4438-7425","authenticated-orcid":false,"given":"Mihaela Niculina","family":"Duma","sequence":"additional","affiliation":[{"name":"State Veterinary Laboratory for Animal Health and Safety, 1 Pia\u021ba M\u0103r\u0103\u0219ti Street, 400609 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5407-8071","authenticated-orcid":false,"given":"Dan Cristian","family":"Vodnar","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences, University of Agricultural Sciences and Veterinary Medicine, 3-5 Calea M\u0103n\u0103\u0219tur, 400372 Cluj-Napoca, Romania"},{"name":"Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, 3-5 Calea M\u0103n\u0103\u0219tur, 400372 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8220-1030","authenticated-orcid":false,"given":"Gheorghe-Adrian","family":"Mart\u0103u","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences, University of Agricultural Sciences and Veterinary Medicine, 3-5 Calea M\u0103n\u0103\u0219tur, 400372 Cluj-Napoca, Romania"},{"name":"Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, 3-5 Calea M\u0103n\u0103\u0219tur, 400372 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0664-3387","authenticated-orcid":false,"given":"Laurian","family":"Vlase","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Biopharmacy, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 41 Victor Babe\u0219 Street, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2313-9350","authenticated-orcid":false,"given":"Adrian","family":"P\u00eern\u0103u","sequence":"additional","affiliation":[{"name":"National Institute for Research and Development of Isotopic and Molecular Technologies, 67-103 Donath Street, 400293 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1333-5649","authenticated-orcid":false,"given":"Br\u00eendu\u0219a","family":"Tiperciuc","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 41 Victor Babe\u0219 Street, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5803-6108","authenticated-orcid":false,"given":"Cristina","family":"Moldovan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 41 Victor Babe\u0219 Street, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana","family":"Ionu\u021b","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 41 Victor Babe\u0219 Street, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8453-3642","authenticated-orcid":false,"given":"Anca","family":"Stana","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 41 Victor Babe\u0219 Street, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7660-9993","authenticated-orcid":false,"given":"Ilioara","family":"Oniga","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 12 Ion Creang\u0103 Street, 400010 Cluj-Napoca, 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