{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:43:53Z","timestamp":1792806233521,"version":"4.5.0"},"reference-count":113,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Princess Nourah bint Abdulrahman University\n\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/05b0cyh02","award":["PNURSP2026R89"],"award-info":[{"award-number":["PNURSP2026R89"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Cancer patients are highly susceptible to microbial infections due to immune suppression, necessitating therapeutic strategies that integrate anticancer efficacy with effective antimicrobial intervention. Chalcone-derived nitrogen-fused heterocycles represent a promising platform for developing multi-target agents with relevance to antimicrobial drug delivery, particularly for localized infections. Methods: A series of chalcone-based pyrazoline-thiadiazole nitrogen-fused azole hybrids was synthesized via thiosemicarbohydrazide-functionalized intermediates and fully characterized. Antiproliferative activity was evaluated against MCF-7, HepG-2, HeLa, and HCT-116 cell lines, alongside selectivity toward WI-38 normal fibroblasts. Antibacterial, antibiofilm, and in vivo efficacy were assessed against methicillin-resistant Staphylococcus aureus (MRSA USA300) and Acinetobacter baumannii AB5057. Mechanistic investigations included cell-cycle analysis, apoptosis assays, ERK2, RIPK3, p53, BAX\/Bcl-2 quantification, DNA gyrase inhibition, molecular docking, molecular dynamics simulations, and density functional theory calculations. Results: Compound 13 exhibited potent cytotoxicity, particularly against MCF-7 (IC50 = 3.87 \u00b1 0.2 \u00b5M), outperforming doxorubicin (IC50 = 4.17 \u00b1 0.2 \u00b5M), with high selectivity indices (SI = 10.7 for MCF-7). Mechanistically, compound 13 induced G2\/M arrest (40.16% vs. 14.15% control), increased apoptosis to 32.89%, up-regulated ERK2 (3.17-fold), RIPK3 (11.97-fold), and p53 (3.54-fold), and markedly increased the BAX\/Bcl-2 ratio (~42-fold). Compounds 7 and 13 displayed bactericidal activity against MRSA and A. baumannii (MIC\/MBC = 10 mg\/mL), potent antibiofilm effects, and significant in vivo efficacy in an MRSA skin infection model. Compound 13 reduced bacterial load by ~5 log units, outperforming vancomycin. DNA gyrase inhibition (IC50 = 17.10 \u00b1 0.17 \u00b5M) and computational studies supported target engagement. Conclusions: Pyrazoline-thiadiazole-based nitrogen-fused azole hybrids, particularly compound 13, demonstrated quantifiable anticancer and antimicrobial efficacy with strong in vivo validation, supporting their potential as multi-target candidates relevant to antimicrobial drug delivery in infection-prone cancer patients.<\/jats:p>","DOI":"10.3390\/pharmaceutics18040424","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:41:53Z","timestamp":1774878113000},"page":"424","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Multi-Target Nitrogen-Fused Azole Drug Platform Derived from a Pyrazoline-Thiadiazole Moiety: In Vivo Antimicrobial Validation and Comprehensive Anticancer Investigation Supported by Computational Studies"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3841-6122","authenticated-orcid":false,"given":"Hagar S.","family":"El-Hema","sequence":"first","affiliation":[{"name":"Basic Science Department (Chemistry), Thebes Higher Institute for Engineering, Thebes Academy, Maadi 11434, Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa A.","family":"Abed","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Menoufia, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed A.","family":"Hawata","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Menoufia, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6159-5333","authenticated-orcid":false,"given":"Eman S.","family":"Nossier","sequence":"additional","affiliation":[{"name":"Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt"},{"name":"The National Committee of Drugs, Academy of Scientific Research and Technology, Cairo 11516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6372-7141","authenticated-orcid":false,"given":"Najla A.","family":"Altwaijry","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6286-319X","authenticated-orcid":false,"given":"Asmaa","family":"Saleh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7972-9827","authenticated-orcid":false,"given":"Mariam","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo 12613, Egypt"},{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Galala University, New Galala City 43511, Suez, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasha A.","family":"Hashem","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo 12613, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3664-2745","authenticated-orcid":false,"given":"Modather F.","family":"Hussein","sequence":"additional","affiliation":[{"name":"Chemistry Department, College of Science, Jouf University, P.O. Box 2014, Sakaka 72341, Aljouf, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed T.","family":"Elhendawy","sequence":"additional","affiliation":[{"name":"Physics Department, Faculty of Science, Galala University, New Galala City 43511, Suez, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adel A.-H.","family":"Abdel-Rahman","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Kom 32511, Menoufia, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,30]]},"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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