{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T15:03:04Z","timestamp":1786719784045,"version":"build-2736575974"},"reference-count":41,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100007741","name":"University of Hyderabad","doi-asserted-by":"publisher","award":["RC4-21-012"],"award-info":[{"award-number":["RC4-21-012"]}],"id":[{"id":"10.13039\/501100007741","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Biotechnology , Ministry of Science and Technology","award":["BT\/PR23619\/MED\/29\/1199\/2017"],"award-info":[{"award-number":["BT\/PR23619\/MED\/29\/1199\/2017"]}]},{"name":"Department of Science and Technology, Ministry of Science and Technology","award":["DST\/ICDBRICS\/PilotCall2\/MRP-TB (G)"],"award-info":[{"award-number":["DST\/ICDBRICS\/PilotCall2\/MRP-TB (G)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The obstinatproblem of drug resistance in tuberculosis (TB) requires sustained efforts in the search for new drug molecules. Building on our previously developed synthetic hybrid compound, UH-NIP-16, which demonstrated anti-Mycobacterium tuberculosis (M.tb) activity, we synthesized and evaluated 15 new derivatives to improve its potency. Among these, two lead compounds, UN-7 and UN-14, bearing hydrogen and methyl substitutions at the sixth position, respectively, along with a 2-phenoxy moiety, exhibited a \u223c5-fold reduction in MIC50 values across laboratory, clinical, and multidrug-resistant M.tb strains relative to UH-NIP-16. Both compounds displayed a bacteriostatic mechanism of action and exhibited predominantly additive or indifferent interaction profiles in combinatorial antitubercular studies. Importantly, UN-7 and UN-14 showed minimal cytotoxicity toward mammalian cells and effectively reduced intracellular bacterial burden in an in vitro infection model. A coupled enzymatic assay revealed that UN-7 and UN-14 inhibited mycobacterial shikimate kinase (Mt-SK) activity by approximately 65%, a target not inhibited by the parent compound UH-NIP-16. In silico ADMET analyses indicated several favorable drug-likeness properties despite predicted liabilities, including Ames mutagenicity and low aqueous solubility. Collectively, these findings identify UN-7 and UN-14 as structure\u2013activity relationship (SAR)-guided derivatives of the UH-NIP-16 scaffold with improved antimycobacterial activity and promising potential for further antitubercular lead development.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00376","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T08:39:47Z","timestamp":1783586387000},"page":"2799-2814","source":"Crossref","is-referenced-by-count":0,"title":["Rational Substitution-Driven Enhancement of Anti-\n                    <i>Mycobacterium tuberculosis<\/i>\n                    Activity in a Quinoline\u2013Isonicotinic\nAcid Hydrazide Hybrid"],"prefix":"10.1021","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1378-8362","authenticated-orcid":true,"given":"Govinda Raju","family":"Vadankula","sequence":"first","affiliation":[{"name":"University of Hyderabad (UoH) , , , ,","place":["Hyderabad, Telangana, India, 500046"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anushka","family":"Agarwal","sequence":"additional","affiliation":[{"name":"University of Hyderabad (UoH) , , , ,","place":["Hyderabad, Telangana, India, 500046"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yandrapally","family":"Sriram","sequence":"additional","affiliation":[{"name":"University of Hyderabad (UoH) , , , ,","place":["Hyderabad, Telangana, India, 500046"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalini","family":"Saxena","sequence":"additional","affiliation":[{"name":"University of Hyderabad (UoH) , , , ,","place":["Hyderabad, Telangana, India, 500046"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashmita","family":"Biswas","sequence":"additional","affiliation":[{"name":"National Institute of Pharmaceutical and Educational Research (NIPER) , , , ,","place":["Hyderabad, Telangana, India, 500037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hepsibha","family":"Chirra","sequence":"additional","affiliation":[{"name":"National Institute of Pharmaceutical and Educational Research (NIPER) , , , ,","place":["Hyderabad, Telangana, India, 500037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavitra S.","family":"Thacker","sequence":"additional","affiliation":[{"name":"National Institute of Pharmaceutical and Educational Research (NIPER) , , , ,","place":["Hyderabad, Telangana, India, 500037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0158-5683","authenticated-orcid":true,"given":"Mohammed","family":"Arifuddin","sequence":"additional","affiliation":[{"name":"National Institute of Pharmaceutical and Educational Research (NIPER) , , , ,","place":["Hyderabad, Telangana, India, 500037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Nema","sequence":"additional","affiliation":[{"name":"ICMR-National Institute of Research in Tribal Health , , Nagpur Road, Garha , , ,","place":["Jabalpur, Madhya Pradesh, India, 482003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3770-4725","authenticated-orcid":true,"given":"Alvala","family":"Mallika","sequence":"additional","affiliation":[{"name":"National Institute of Pharmaceutical and Educational Research (NIPER) , , , ,","place":["Hyderabad, Telangana, India, 500037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2263-7320","authenticated-orcid":true,"given":"Sharmistha","family":"Banerjee","sequence":"additional","affiliation":[{"name":"University of Hyderabad (UoH) , , , ,","place":["Hyderabad, Telangana, India, 500046"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"2026081410081588200_cit1","unstructured":"WHO.\n          . Antimicrobial resistance. 2023."},{"key":"2026081410081588200_cit2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.943545","article-title":"Drug Resistant Tuberculosis:\nImplications\nfor Transmission, Diagnosis, and Disease Management","volume":"12","author":"Liebenberg","year":"2022","journal-title":"Front. Cell. Infect. Microbiol."},{"issue":"3","key":"2026081410081588200_cit3","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.molcel.2010.01.003","article-title":"Sublethal\nAntibiotic Treatment Leads\nto Multidrug Resistance via Radical-Induced Mutagenesis","volume":"37","author":"Kohanski","year":"2010","journal-title":"Mol. Cell"},{"key":"2026081410081588200_cit4","article-title":"Consolidated\nGuidelines on Tuberculosis. Module 4: Treatment - Drug-Resistant Tuberculosis\nTreatment, 2022 Update","author":"WHO.","year":"2022"},{"key":"2026081410081588200_cit5","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1093\/cid\/cir889","article-title":"Totally Drug-Resistant\nTuberculosis in India","volume":"54","author":"Udwadia","year":"2012","journal-title":"Clin. Infect. 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Microbiol."},{"issue":"5","key":"2026081410081588200_cit9","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25051239","article-title":"Multitargeting Compounds: A Promising\nStrategy to Overcome Multi-Drug Resistant Tuberculosis","volume":"25","author":"Stelitano","year":"2020","journal-title":"Molecules"},{"issue":"13","key":"2026081410081588200_cit10","doi-asserted-by":"publisher","first-page":"1238","DOI":"10.2174\/0113895575281039231218112953","article-title":"Quinoline Derivatives\nas Promising\nScaffolds for Antitubercular Activity: A Comprehensive Review","volume":"24","author":"Owais","year":"2024","journal-title":"Mini-Rev. Med. 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Dis."},{"issue":"2","key":"2026081410081588200_cit14","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.tube.2013.12.004","article-title":"Identification\nof Shikimate Kinase Inhibitors among Anti-Mycobacterium Tuberculosis\nCompounds by LC-MS","volume":"94","author":"Simithy","year":"2014","journal-title":"Tuberculosis"},{"issue":"4","key":"2026081410081588200_cit15","doi-asserted-by":"publisher","first-page":"2019","DOI":"10.1007\/s00044-013-0803-1","article-title":"Synthesis and Evaluation\nof New Chalcones, Derived\nPyrazoline and Cyclohexenone Derivatives as Potent Antimicrobial,\nAntitubercular and Antileishmanial Agents","volume":"23","author":"Monga","year":"2014","journal-title":"Med.\nChem. Res."},{"key":"2026081410081588200_cit16","doi-asserted-by":"publisher","DOI":"10.1038\/srep42717","article-title":"SwissADME: A Free Web\nTool to Evaluate\nPharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness\nof Small Molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"issue":"12","key":"2026081410081588200_cit17","doi-asserted-by":"publisher","first-page":"5415","DOI":"10.1007\/s00253-015-7268-8","article-title":"Screening of Antitubercular Compound Library Identifies\nNovel Shikimate Kinase Inhibitors of Mycobacterium Tuberculosis","volume":"100","author":"Rajput","year":"2016","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"2026081410081588200_cit18","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1104\/pp.64.3.382","article-title":"In Vivo Activity, Purification,\nand Characterization\nof Shikimate Kinase from Sorghum","volume":"64","author":"Bowen","year":"1979","journal-title":"Plant Physiol."},{"issue":"3","key":"2026081410081588200_cit19","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1006\/prep.2001.1457","article-title":"Cloning and Overexpression\nin Soluble Form of Functional Shikimate Kinase and 5-Enolpyruvylshikimate\n3-Phosphate Synthase Enzymes from Mycobacterium Tuberculosis","volume":"22","author":"Oliveira","year":"2001","journal-title":"Protein Expression Purif."},{"key":"2026081410081588200_cit20","doi-asserted-by":"publisher","first-page":"2310","DOI":"10.1107\/S090744490402517X","article-title":"Structure\nof Shikimate Kinase from Mycobacterium Tuberculosis Reveals the Binding\nof Shikimic Acid","volume":"60","author":"Pereira","year":"2004","journal-title":"Acta Crystallogr., Sect. D:Biol.\nCrystallogr."},{"issue":"1","key":"2026081410081588200_cit21","doi-asserted-by":"publisher","DOI":"10.1128\/cmr.00141-20","article-title":"Mechanisms\nof Drug-Induced Tolerance\nin Mycobacterium Tuberculosis","volume":"34","author":"Goossens","year":"2020","journal-title":"Clin. Microbiol.\nRev."},{"issue":"1","key":"2026081410081588200_cit22","doi-asserted-by":"publisher","DOI":"10.3390\/metabo14010063","article-title":"Metabolic Rewiring\nof Mycobacterium Tuberculosis upon Drug Treatment\nand Antibiotics Resistance","volume":"14","author":"Singha","year":"2024","journal-title":"Metabolites"},{"issue":"6","key":"2026081410081588200_cit23","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a021154","article-title":"The Tuberculosis Drug Discovery and\nDevelopment Pipeline and Emerging Drug Targets","volume":"5","author":"Mdluli","year":"2015","journal-title":"Cold Spring Harbor Perspect. Med."},{"issue":"1","key":"2026081410081588200_cit24","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1007\/s44371-025-00361-2","article-title":"A Comprehensive\nReview of Quinoline Scaffolds in Antitubercular\nDrug Discovery","volume":"2","author":"Kumar","year":"2025","journal-title":"Discovery Chem."},{"issue":"9","key":"2026081410081588200_cit25","doi-asserted-by":"publisher","first-page":"10648","DOI":"10.3390\/molecules180910648","article-title":"Antimycobacterial and\nPhotosynthetic Electron Transport Inhibiting Activity of Ring-Substituted\n4-Arylamino-7-Chloroquinolinium Chlorides","volume":"18","author":"Otevrel","year":"2013","journal-title":"Molecules"},{"issue":"14","key":"2026081410081588200_cit26","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241411632","article-title":"Mycobacterium\nTuberculosis Inhibitors Based on Arylated Quinoline Carboxylic Acid\nBackbones with Anti-Mtb Gyrase Activity","volume":"24","author":"Quimque","year":"2023","journal-title":"Int.\nJ. Mol. Sci."},{"issue":"3","key":"2026081410081588200_cit27","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.drup.2012.04.001","article-title":"Resistance Mechanisms and Drug Susceptibility Testing\nof Nontuberculous Mycobacteria","volume":"15","author":"van Ingen","year":"2012","journal-title":"Drug Resistance\nUpdates"},{"issue":"2","key":"2026081410081588200_cit28","doi-asserted-by":"publisher","DOI":"10.3390\/biology10020096","article-title":"Drug Resistance\nin Nontuberculous\nMycobacteria: Mechanisms and Models","volume":"10","author":"Saxena","year":"2021","journal-title":"Biology"},{"key":"2026081410081588200_cit29","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/8168750","article-title":"Nontuberculous Mycobacterial Resistance\nto Antibiotics and Disinfectants: Challenges Still Ahead","volume":"2022","author":"Tarashi","year":"2022","journal-title":"Biomed. Res. Int."},{"issue":"2","key":"2026081410081588200_cit30","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1111\/j.1440-1746.2007.05207.x","article-title":"Antituberculosis Drug-Induced Hepatotoxicity:\nConcise up-to-Date Review","volume":"23","author":"Tostmann","year":"2008","journal-title":"J. Gastroenterol.\nHepatol."},{"issue":"8","key":"2026081410081588200_cit31","doi-asserted-by":"publisher","first-page":"1910","DOI":"10.3390\/12081910","article-title":"Biological\nActivities of Hydrazone\nDerivatives","volume":"12","author":"Rollas","year":"2007","journal-title":"Molecules"},{"issue":"3","key":"2026081410081588200_cit32","doi-asserted-by":"publisher","first-page":"127","DOI":"10.3897\/PHARMACIA.66.E47035","article-title":"Devel opment and Validation of RP-HPLC Method\nfor Stability Evaluation\nof Model Hydrazone, Containing a Pyrrole Ring","volume":"66","author":"Tzankova","year":"2019","journal-title":"Pharmacia"},{"issue":"15","key":"2026081410081588200_cit33","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00707-18","article-title":"Metabolomics\nStudies to Decipher\nStress Responses in Mycobacterium Smegmatis Point to a Putative Pathway\nof Methylated Amine Biosynthesis","volume":"201","author":"Rizvi","year":"2019","journal-title":"J. Bacteriol."},{"key":"2026081410081588200_cit34","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.02417","article-title":"Rewiring\nof Metabolic Network in Mycobacterium Tuberculosis During Adaptation\nto Different Stresses","volume":"10","author":"Rizvi","year":"2019","journal-title":"Front. Microbiol."},{"key":"2026081410081588200_cit35","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2016.01347","article-title":"Mycobacterium Tuberculosis\nZinc Metalloprotease-1\nAssists Mycobacterial Dissemination in Zebrafish","volume":"7","author":"Vemula","year":"2016","journal-title":"Front. Microbiol."},{"key":"2026081410081588200_cit36","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1276817","article-title":"Mycobacterium Tuberculosis\nEspR Modulates Th1-Th2 Shift\nby Transcriptionally Regulating IL-4, Steering Increased Mycobacterial\nPersistence and HIV Propagation during Co-Infection","volume":"14","author":"Yandrapally","year":"2023","journal-title":"Front. Immunol."},{"issue":"1","key":"2026081410081588200_cit37","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-11-18","article-title":"Human Protein\nStaufen-2 Promotes HIV-1 Proliferation by Positively Regulating RNA\nExport Activity of Viral Protein Rev","volume":"11","author":"Banerjee","year":"2014","journal-title":"Retrovirology"},{"key":"2026081410081588200_cit38","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00439","article-title":"Small Molecule\nMediated Restoration\nof Mitochondrial Function Augments Anti-Mycobacterial Activity of\nHuman Macrophages Subjected to Cholesterol Induced Asymptomatic Dyslipidemia","volume":"7","author":"Asalla","year":"2017","journal-title":"Front. Cell. Infect. Microbiol."},{"issue":"33","key":"2026081410081588200_cit39","doi-asserted-by":"publisher","first-page":"12366","DOI":"10.1021\/ja405853p","article-title":"Mycobacterium Tuberculosis Shikimate\nKinase Inhibitors: Design and Simulation Studies of the Catalytic\nTurnover","volume":"135","author":"Blanco","year":"2013","journal-title":"J. Am. Chem. Soc."},{"issue":"10","key":"2026081410081588200_cit40","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1701881","article-title":"Efficient Measurement and Factorization\nof High-Order\nDrug Interactions in Mycobacterium Tuberculosis","volume":"3","author":"Cokol","year":"2017","journal-title":"Sci. Adv."},{"issue":"5","key":"2026081410081588200_cit41","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02554-20","article-title":"Developing Synergistic\nDrug Combinations to Restore\nAntibiotic Sensitivity in Drug-Resistant Mycobacterium Tuberculosis","volume":"65","author":"Omollo","year":"2023","journal-title":"Antimicrob. Agents Chemother."}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.6c00376","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/8\/2799\/65832396\/acsinfecdis.6c00376.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/8\/2799\/65832396\/acsinfecdis.6c00376.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T14:21:16Z","timestamp":1786717276000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/12\/8\/2799\/5203786\/Rational-Substitution-Driven-Enhancement-of-Anti"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":41,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,7,9]]},"published-print":{"date-parts":[[2026,8,14]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.6c00376","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]}}}