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Nevertheless, the efficacy of INH has diminished because of the emergence of Mycobacterium tuberculosis (Mtb) strains that are resistant to INH. Our goal in this study was to modify INH to reduce this significant resistance chemically. We synthesized INH-based hydrazones (IP1\u2013IP13) through the reaction of INH with in-house obtained benzaldehydes carrying a piperidine or piperazine ring in refluxing ethanol. Upon confirmation of their proposed structures by various spectral techniques, IP1\u2013IP13 were evaluated for their antimycobacterial capacity against Mtb H37Rv strain and INH-resistant clinical isolates with katG and inhA mutations using the Microplate Alamar Blue Assay (MABA). The compounds were additionally tested for their cytotoxicity. The obtained data indicated that the compounds with moderately increased lipophilicity compared to INH (IP7\u2013IP13) were promising antitubercular drug candidates, exhibiting drug-like properties and negligible cytotoxicity. Out of these, IP11 (N\u2032-(4-(4-cyclohexylpiperazin-1-yl)benzylidene)isonicotinohydrazide) emerged as the most promising derivative, demonstrating the lowest MIC values against all Mtb strains tested. Subsequently, the target molecules were evaluated for their capacity to inhibit enoyl acyl carrier protein reductase (InhA), the main target enzyme of INH. Except for IP11 demonstrating 81% InhA inhibition at a concentration of 50 \u03bcM, direct InhA inhibition was shown not to be the primary mechanism responsible for the antitubercular activity of the compounds. The binding mechanism of IP11 to InhA was analyzed through molecular docking and molecular dynamics simulations. Altogether, our research identified a novel approach to modify INH to address the challenges posed by the rising prevalence of drug-resistant Mtb strains.<\/jats:p>","DOI":"10.3390\/biom15091305","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T07:51:46Z","timestamp":1757577106000},"page":"1305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Isoniazid-Derived Hydrazones Featuring Piperazine\/Piperidine Rings: Design, Synthesis, and Investigation of Antitubercular Activity"],"prefix":"10.3390","volume":"15","author":[{"given":"Esma","family":"\u00d6zcan","sequence":"first","affiliation":[{"name":"Department of Basic Sciences, Faculty of Pharmacy, Erciyes University, 38039 Kayseri, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siva Krishna","family":"Vagolu","sequence":"additional","affiliation":[{"name":"Unit for Genome Dynamics, Department of Microbiology, University of Oslo, 0316 Oslo, Norway"},{"name":"Research Institute of Internal Medicine, Oslo University Hospital, 0424 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9101-7042","authenticated-orcid":false,"given":"Rasoul","family":"Tamhaev","sequence":"additional","affiliation":[{"name":"Laboratoire de Synth\u00e8se et Physico-Chimie de Mol\u00e9cules d\u2019Inter\u00eat Biologique, LSPCMIB, Universit\u00e9 de Toulouse, CNRS, 118 Route de Narbonne, 31062 Toulouse, France"},{"name":"Institut de Pharmacologie et de Biologie Structurale, Universit\u00e9 de Toulouse, CNRS, 205 route de Narbonne, BP 64182, 31077 Toulouse, Cedex 4, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5427-5040","authenticated-orcid":false,"given":"Christian","family":"Lherbet","sequence":"additional","affiliation":[{"name":"Laboratoire de Synth\u00e8se et Physico-Chimie de Mol\u00e9cules d\u2019Inter\u00eat Biologique, LSPCMIB, Universit\u00e9 de Toulouse, CNRS, 118 Route de Narbonne, 31062 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8259-1259","authenticated-orcid":false,"given":"Lionel","family":"Mourey","sequence":"additional","affiliation":[{"name":"Institut de Pharmacologie et de Biologie Structurale, Universit\u00e9 de Toulouse, CNRS, 205 route de Narbonne, BP 64182, 31077 Toulouse, Cedex 4, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1709-6921","authenticated-orcid":false,"given":"Tone","family":"T\u00f8njum","sequence":"additional","affiliation":[{"name":"Unit for Genome Dynamics, Department of Microbiology, University of Oslo, 0316 Oslo, Norway"},{"name":"Unit for Genome Dynamics, Department of Microbiology, Oslo University Hospital, 0424 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2287-9509","authenticated-orcid":false,"given":"Miyase G\u00f6zde","family":"G\u00fcnd\u00fcz","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, S\u0131hhiye, 06100 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u015eeng\u00fcl Dilem","family":"Do\u011fan","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Faculty of Pharmacy, Erciyes University, 38039 Kayseri, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alsayed, S.S.R., and Gunosewoyo, H. 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