{
  "abstract": "Isoniazid is an established antitubercular pharmacophore widely used as a structural platform for developing compounds with potential activity against Mycobacterium tuberculosis. This study investigated isoniazid-derived thiosemicarbazides as precursors for the synthesis of thiazolidin-4-one derivatives, focusing on the influence of pyridine regioisomerism and aryl substitution on cyclization outcomes. Thiosemicarbazides containing 2-, 3-, or 4-pyridyl moieties and fluoro- or chloro-substituted phenyl groups were synthesized and subjected to cyclization with ethyl bromoacetate. Density functional theory (DFT) calculations were performed to compare the competing pathways leading to thiazolidin-4-one and 1,3,4-oxadiazole formation, and the resulting heterocyclic compounds were evaluated against four M. tuberculosis strains. An initial control experiment using a 2-pyridyl/2-fluorophenyl thiosemicarbazide yielded the target thiazolidin-4-one as the sole product. However, investigation of the broader substrate series revealed pronounced substrate-dependent differences in cyclization selectivity. Most substrates afforded 1,3,4-oxadiazoles, whereas 2-pyridyl thiosemicarbazides bearing ortho-fluoro or ortho-chloro substituents selectively formed thiazolidin-4-ones. DFT calculations provided an energetic rationale for the observed divergence in cyclization pathways. Despite systematic structural diversification, none of the investigated 1,3,4-oxadiazole or thiazolidin-4-one derivatives, including ester-functionalized analogues, exhibited appreciable antimycobacterial activity (MIC ≥ 512 µg/mL). These findings demonstrate that pyridine regioisomerism combined with aryl substitution strongly influences the cyclization pathways of isoniazid-derived thiosemicarbazides. However, the pronounced structure–reactivity relationship governing cyclization was not accompanied by a meaningful structure–activity relationship against Mycobacterium tuberculosis. The combined experimental and computational results provide insight into the factors governing cyclization selectivity and inform the design of future INH-derived analogues.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Organic Chemistry, Medical University of Lublin, Chodzki 4A, 20-093 Lublin, Poland",
    "Department of Microbiology, National Tuberculosis and Lung Diseases Research Institute, Plocka 26, 01-138 Warsaw, Poland",
    "Institute of Applied Radiation Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Agata Paneth",
      "orcid": "0000-0002-8198-7702"
    },
    {
      "affs": [
        0
      ],
      "name": "Nazar Trotsko",
      "orcid": "0000-0002-8817-7470"
    },
    {
      "affs": [
        1
      ],
      "name": "Agnieszka Głogowska",
      "orcid": "0000-0003-1296-4934"
    },
    {
      "affs": [
        1
      ],
      "name": "Ewa Augustynowicz-Kopeć",
      "orcid": "0000-0001-6162-8748"
    },
    {
      "affs": [
        2
      ],
      "name": "Piotr Paneth",
      "orcid": "0000-0002-3091-8387"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6mvhhte73vf26.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27219477",
  "fulltext_url": null,
  "id": "6mvhhte73vf26",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/21/9477",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1605|Structural and Chemical Analysis of Organic and Inorganic Compounds"
    ]
  ],
  "openalex": "W7223826518",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-23",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/6mvhhte73vf26.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:57Z",
      "native_id": "10.3390/ijms27219477",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/21/9477"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1605|Structural and Chemical Analysis of Organic and Inorganic Compounds",
      "subfield": "organic"
    }
  ],
  "title": "Pyridine Regioisomerism and Aryl Substitution Govern the Divergent Cyclization of Isoniazid-Derived Thiosemicarbazides: Mechanistic DFT Analysis and Antimycobacterial Evaluation",
  "title_text": "Pyridine Regioisomerism and Aryl Substitution Govern the Divergent Cyclization of Isoniazid-Derived Thiosemicarbazides: Mechanistic DFT Analysis and Antimycobacterial Evaluation",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:57Z",
  "url": "https://research.draconitic.com/paper/6mvhhte73vf26",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}