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In this study, a series of hybrid molecules (<jats:bold>5a\u2013i<\/jats:bold>) was synthesized by linking isoniazid with aromatic sulfonate esters via a hydrazone bridge. Molecular docking studies revealed that these compounds interact effectively with the catalytic triad of the InhA enzyme (Y158, F149, and K165), suggesting their potential as InhA inhibitors. To enhance molecular flexibility and improve binding interactions with both NADH and the catalytic residues, a second generation of derivatives (<jats:bold>8a\u2013k<\/jats:bold>) was designed and synthesized. All synthesized compounds were structurally characterized using spectroscopic techniques, including nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (IR), and high\u2010resolution mass spectrometry. As anticipated, these new compounds exhibited enhanced anti\u2010tubercular activity compared to their precursors. Notably, compound <jats:bold>8b<\/jats:bold> demonstrated significant potency with an MIC of 0.078\u2009\u03bcg\/mL, approximately twofold more active than its precursor <jats:bold>5b<\/jats:bold> (MIC\u2009=\u20090.156\u2009\u03bcg\/mL) against <jats:styled-content style=\"fixed-case\"><jats:italic>Mycobacterium tuberculosis<\/jats:italic><\/jats:styled-content> (Mtb). However, both generations of compounds (e.g., <jats:bold>5a, 5b, 8a, 8b, 8c<\/jats:bold>, and <jats:bold>8\u2009k<\/jats:bold>) lost activity against INH\u2010resistant <jats:italic>Mtb<\/jats:italic> strains harboring <jats:italic>katG<\/jats:italic> mutations. Importantly, no cytotoxicity was observed for these compounds in THP\u20101 human monocytic cells at a concentration of 10\u2009\u03bcg\/mL. The structural integrity of the lead compound 8b was confirmed via <jats:sup>1<\/jats:sup>H NMR stability studies. The ADME\/T parameters (absorption, distribution, metabolism, excretion, and toxicity) were also explored to determine their drug likeness and safety profile. Collectively, these hybrid molecules present valuable scaffolds for further optimization in the pursuit of new anti\u2010tubercular agents.<\/jats:p>","DOI":"10.1111\/cbdd.70171","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T07:57:05Z","timestamp":1757491025000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Rationally Designed <scp>InhA<\/scp> Inhibitors: A Comparative Anti\u2010Tubercular Activity Study of Sulfonate Esters of Isoniazid Hydrazones and Their Structurally Flexible Benzyl Analogues"],"prefix":"10.1111","volume":"106","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0202-2230","authenticated-orcid":false,"given":"Mukanda Gedeon","family":"Kadima","sequence":"first","affiliation":[{"name":"Discipline of Pharmaceutical Sciences, Westville Campus University of KwaZulu\u2010Natal  Durban South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sahil","family":"Mishra","sequence":"additional","affiliation":[{"name":"School of Chemistry and Physics University of KwaZulu\u2010Natal  Durban South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gobind","family":"Kumar","sequence":"additional","affiliation":[{"name":"School of Chemistry and Physics University of KwaZulu\u2010Natal  Durban South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pule","family":"Seboletswe","sequence":"additional","affiliation":[{"name":"School of Chemistry and Physics University of KwaZulu\u2010Natal  Durban South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7oise","family":"Roquet\u2010Ban\u00e8res","sequence":"additional","affiliation":[{"name":"Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM) Universit\u00e9 de Montpellier  Montpellier France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ma\u00eblle","family":"Foubert","sequence":"additional","affiliation":[{"name":"Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM) Universit\u00e9 de Montpellier  Montpellier France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurent","family":"Kremer","sequence":"additional","affiliation":[{"name":"Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM) Universit\u00e9 de Montpellier  Montpellier France"},{"name":"INSERM IRIM  Montpellier France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1247-5754","authenticated-orcid":false,"given":"Rajshekhar","family":"Karpoormath","sequence":"additional","affiliation":[{"name":"Discipline of Pharmaceutical Sciences, Westville Campus University of KwaZulu\u2010Natal  Durban South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6742-6389","authenticated-orcid":false,"given":"Parvesh","family":"Singh","sequence":"additional","affiliation":[{"name":"School of Chemistry and Physics University of KwaZulu\u2010Natal  Durban South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010023\u201040160\u20102"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114531"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20104939\u20106798\u20108_14"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2024.1386113"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.5588\/ijtld.15.0864"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2021.1900162"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/reactions4040043"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/jhet.3161"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a017798"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2021.127982"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph15101301"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202400949"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.2174\/187152607781001817"},{"key":"e_1_2_8_15_1","doi-asserted-by":"crossref","unstructured":"Migliori G. 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