{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T14:50:14Z","timestamp":1780066214243,"version":"3.54.0"},"reference-count":92,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Princess Nourah Bint Abdulrahman University","award":["PNURSP2025R158"],"award-info":[{"award-number":["PNURSP2025R158"]}]},{"name":"Princess Nourah Bint Abdulrahman University","award":["143\/2023-24\/3rd call\/10\/2024"],"award-info":[{"award-number":["143\/2023-24\/3rd call\/10\/2024"]}]},{"name":"University of Chittagong, Bangladesh","award":["PNURSP2025R158"],"award-info":[{"award-number":["PNURSP2025R158"]}]},{"name":"University of Chittagong, Bangladesh","award":["143\/2023-24\/3rd call\/10\/2024"],"award-info":[{"award-number":["143\/2023-24\/3rd call\/10\/2024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Nucleoside precursors and derivatives play pivotal roles in the development of antimicrobial and antiviral therapeutics. The 2022 global outbreak of monkeypox (Mpox) across more than 100 nonendemic countries underscores the urgent need for novel antiviral agents. This study aimed to synthesize and evaluate a series of 5\u2032-O-(palmitoyl) derivatives (compounds 2\u20136), incorporating various aliphatic and aromatic acyl groups, for their potential antimicrobial activities. Methods: The structures of the synthesized derivatives were confirmed through physicochemical, elemental, and spectroscopic techniques. In vitro antibacterial efficacy was assessed, including minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) determinations for the most active compounds (4 and 5). The antifungal activity was evaluated based on mycelial growth inhibition. Density functional theory (DFT) calculations were employed to investigate the electronic and structural properties, including the global reactivity, frontier molecular orbital (FMO), natural bond orbital (NBO), and molecular electrostatic potential (MEP). Molecular docking studies were conducted against the monkeypox virus and the Marburg virus. The top-performing compounds (3, 5, and 6) were further evaluated via 200 ns molecular dynamics (MD) simulations. ADMET predictions were performed to assess drug-likeness and pharmacokinetic properties. Results: Compounds 4 and 5 demonstrated remarkable antibacterial activity compared with the precursor molecule, while most derivatives inhibited fungal mycelial growth by up to 79%. Structure-activity relationship (SAR) analysis highlighted the enhanced antibacterial\/antifungal efficacy with CH3(CH2)10CO\u2013 and CH3(CH2)12CO\u2013acyl chains. In silico docking revealed that compounds 3, 5, and 6 had higher binding affinities than the other derivatives. MD simulations confirmed the stability of the protein-ligand complexes. ADMET analyses revealed favorable drug-like profiles for all the lead compounds. Conclusions: The synthesized compounds 3, 5, and 6 exhibit promising antimicrobial and antiviral activities. Supported by both in vitro assays and comprehensive in silico analyses, these derivatives have emerged as potential candidates for the development of novel therapeutics against bacterial, fungal, and viral infections, including monkeypox and Marburg viruses.<\/jats:p>","DOI":"10.3390\/ph18060806","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T04:46:38Z","timestamp":1748493998000},"page":"806","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Unveiling Palmitoyl Thymidine Derivatives as Antimicrobial\/Antiviral Inhibitors: Synthesis, Molecular Docking, Dynamic Simulations, ADMET, and Assessment of Protein\u2013Ligand Interactions"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7964-9117","authenticated-orcid":false,"given":"Sarkar M. A.","family":"Kawsar","sequence":"first","affiliation":[{"name":"Laboratory of Carbohydrate and Nucleoside Chemistry, Department of Chemistry, Faculty of Science, University of Chittagong, Chittagong 4331, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3160-6008","authenticated-orcid":false,"given":"Samiah Hamad","family":"Al-mijalli","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Sciences, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7913-7768","authenticated-orcid":false,"given":"Gassoumi","family":"Bouzid","sequence":"additional","affiliation":[{"name":"Laboratory of Advanced Materials and Interfaces (LIMA), Faculty of Science, University of Monastir, Avenue of Environnment, Monastir 5000, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0549-249X","authenticated-orcid":false,"given":"Emad M.","family":"Abdallah","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0936-6653","authenticated-orcid":false,"given":"Noimul H.","family":"Siddiquee","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Noakhali Science and Technology University, Noakhali 3814, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7445-8183","authenticated-orcid":false,"given":"Mohammed A.","family":"Hosen","sequence":"additional","affiliation":[{"name":"Laboratory of Carbohydrate and Nucleoside Chemistry, Department of Chemistry, Faculty of Science, University of Chittagong, Chittagong 4331, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mabrouk","family":"Horchani","sequence":"additional","affiliation":[{"name":"Laboratory of Heterocyclic Chemistry, Natural Products and Reactivity (LR11Es39), Medicinal Chemistry and Natural Products, Faculty of Science, University of Monastir, Avenue of Environment, Monastir 5000, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houcine","family":"Ghalla","sequence":"additional","affiliation":[{"name":"Quantum and Statistical Physics Laboratory, Faculty of Science, University of Monastir, Monastir 5079, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5858-1803","authenticated-orcid":false,"given":"Hichem","family":"B. Jannet","sequence":"additional","affiliation":[{"name":"Laboratory of Heterocyclic Chemistry, Natural Products and Reactivity (LR11Es39), Medicinal Chemistry and Natural Products, Faculty of Science, University of Monastir, Avenue of Environment, Monastir 5000, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6408-9620","authenticated-orcid":false,"given":"Yuki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Nagasaki International University, 2825-7, Huis Tem Bosch, Sasebo, Nagasaki 859-3298, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2782-6158","authenticated-orcid":false,"given":"Yasuhiro","family":"Ozeki","sequence":"additional","affiliation":[{"name":"Graduate School of NanoBiosciences, Yokohama City University, 22-2, Seto, Kanazawa-ku, Yokohama 236-0027, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.biotechadv.2010.01.006","article-title":"Biocatalytic transformation of nucleoside derivatives","volume":"28","author":"Li","year":"2010","journal-title":"Biotechnol. 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