{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T22:30:49Z","timestamp":1785796249658,"version":"3.56.0"},"reference-count":88,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,3,9]],"date-time":"2020-03-09T00:00:00Z","timestamp":1583712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["Dipartimenti di Eccellenza Program (2018\u20132022)"],"award-info":[{"award-number":["Dipartimenti di Eccellenza Program (2018\u20132022)"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Tuberculosis is still an urgent global health problem, mainly due to the spread of multi-drug resistant M. tuberculosis strains, which lead to the need of new more efficient drugs. A strategy to overcome the problem of the resistance insurgence could be the polypharmacology approach, to develop single molecules that act on different targets. Polypharmacology could have features that make it an approach more effective than the classical polypharmacy, in which different drugs with high affinity for one target are taken together. Firstly, for a compound that has multiple targets, the probability of development of resistance should be considerably reduced. Moreover, such compounds should have higher efficacy, and could show synergic effects. Lastly, the use of a single molecule should be conceivably associated with a lower risk of side effects, and problems of drug\u2013drug interaction. Indeed, the multitargeting approach for the development of novel antitubercular drugs have gained great interest in recent years. This review article aims to provide an overview of the most recent and promising multitargeting antitubercular drug candidates.<\/jats:p>","DOI":"10.3390\/molecules25051239","type":"journal-article","created":{"date-parts":[[2020,3,13]],"date-time":"2020-03-13T08:58:59Z","timestamp":1584089939000},"page":"1239","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Multitargeting Compounds: A Promising Strategy to Overcome Multi-Drug Resistant Tuberculosis"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5219-4770","authenticated-orcid":false,"given":"Giovanni","family":"Stelitano","sequence":"first","affiliation":[{"name":"Department of Biology and Biotechnology \u201cLazzaro Spallanzani\u201d, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3707-3118","authenticated-orcid":false,"given":"Jos\u00e9 Camilla","family":"Sammartino","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u201cLazzaro Spallanzani\u201d, University of Pavia, 27100 Pavia, Italy"},{"name":"IUSS-University School for Advanced Studies, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0348-9764","authenticated-orcid":false,"given":"Laurent Roberto","family":"Chiarelli","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u201cLazzaro Spallanzani\u201d, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,9]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2020, February 13). Global tuberculosis report 2019. Available online: https:\/\/www.who.int\/tb\/publications\/global_report\/en\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/978-3-319-64371-7_3","article-title":"The evolution of strain typing in the Mycobacterium tuberculosis complex","volume":"1019","author":"Merker","year":"2017","journal-title":"Adv Exp Med. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4970","DOI":"10.1038\/s41467-019-12956-2","article-title":"Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development","volume":"10","author":"Beites","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1901719","DOI":"10.1183\/13993003.01719-2019","article-title":"Screening migrants for tuberculosis and latent TB infection: The reward will come later","volume":"54","author":"Zellweger","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.ccm.2019.07.008","article-title":"Treatment of latent tuberculosis infection-an update","volume":"40","author":"Huaman","year":"2019","journal-title":"Clin Chest Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1038\/nrd4001","article-title":"Advances in the development of new tuberculosis drugs and treatment regimens","volume":"12","author":"Zumla","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_7","first-page":"418","article-title":"Multidrug-resistant tuberculosis treatment outcomes in relation to treatment and initial versus acquired second-line drug resistance","volume":"62","author":"Cegielski","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_8","unstructured":"World Health Organization (2020, February 25). Consolidated guidelines on drug-resistant tuberculosis treatment of 2019. Available online: https:\/\/www.who.int\/tb\/publications\/2019\/consolidated-guidelines-drug-resistant-TB-treatment\/en\/."},{"key":"ref_9","unstructured":"World Health Organization (2020, February 25). Treatment guidelines for rifampicin and multidrug-resistant tuberculosis, 2018 update. Available online: https:\/\/www.who.int\/tb\/areas-of-work\/drug-resistant-tb\/treatment\/gdg-meeting-mdr-rr-tb-treatment-2018-update\/en\/."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"472","DOI":"10.4314\/ahs.v18i3.2","article-title":"Prevalence of rifampicin resistant tuberculosis and associated factors among presumptive tuberculosis patients in a secondary referral hospital in Lagos Nigeria","volume":"18","author":"Adejumo","year":"2018","journal-title":"Afr. Health Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"35","DOI":"10.5365\/wpsar.2016.7.2.002","article-title":"Prevalence of resistance to second-line tuberculosis drug among multidrug-resistant tuberculosis patients in VietNam, 2011","volume":"7","author":"Nguyen","year":"2016","journal-title":"Western Pac. Surveill Resp. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3126","DOI":"10.1021\/jm500131s","article-title":"Multitarget drug discovery for tuberculosis and other infectious diseases","volume":"57","author":"Li","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6356","DOI":"10.1038\/srep06356","article-title":"Characterizing the pocketome of Mycobacterium tuberculosis and application in rationalizing polypharmacological target selection","volume":"4","author":"Anand","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"205","DOI":"10.3389\/fphar.2015.00205","article-title":"Multi-target pharmacology: Possibilities and limitations of the \"skeleton key approach\" from a medicinal chemist perspective","volume":"6","author":"Talevi","year":"2015","journal-title":"Front. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7874","DOI":"10.1021\/jm5006463","article-title":"Polypharmacology: Challenges and opportunities in drug discovery","volume":"57","author":"Anighoro","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1517\/17460441.2013.743991","article-title":"Multitarget ligands in antibacterial research: Progress and opportunities","volume":"8","author":"East","year":"2013","journal-title":"Expert. Opin. Drug Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1021\/acs.chemrev.8b00138","article-title":"Development of multifunctional molecules as potential therapeutic candidates for Alzheimer\u2019s disease, Parkinson\u2019s disease, and amyotrophic lateral sclerosis in the last decade","volume":"119","author":"Savelieff","year":"2019","journal-title":"Chem. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1517\/14656560902781907","article-title":"Multitarget drugs: The present and the future of cancer therapy","volume":"10","author":"Petrelli","year":"2009","journal-title":"Exp. Opin. Pharmaco."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/B978-0-12-397927-8.00001-4","article-title":"Vertical pathway targeting in cancer therapy","volume":"65","author":"Shahbazian","year":"2012","journal-title":"Adv. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Handler, N., Buschmann, H., Mannhold, R., and Holenz, J. (2017). The Linker Approach. Drug Selectivity: An Evolving Concept in Medicinal Chemistry, Wiley-VCH Verlag GmbH.","DOI":"10.1002\/9783527674381"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/nrd4519","article-title":"Principles in the design of ligand-targeted cancer therapeutics and imaging agents","volume":"14","author":"Srinivasarao","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1080\/14787210.2019.1612240","article-title":"Cefiderocol: A promising antibiotic against multidrug-resistant Gram-negative bacteria","volume":"17","author":"Jean","year":"2019","journal-title":"Exp. Rev. Anti-Infect Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5260","DOI":"10.1021\/jm020120c","article-title":"Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer\u2019s disease","volume":"45","author":"Sterling","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1021\/acs.jmedchem.8b00760","article-title":"Polypharmacology by design: A medicinal chemist\u2019s perspective on multitargeting compounds","volume":"62","author":"Proschak","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.ejmech.2014.01.060","article-title":"Multifunctional compounds: Smart molecules for multifactorial diseases","volume":"76","author":"Bansal","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"750","DOI":"10.2174\/1568026618666180528124414","article-title":"Multi-Target Antitubercular Drugs","volume":"18","author":"Ishiki","year":"2018","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1111\/cbdd.13386","article-title":"Design and synthesis of 5-(5-nitrothiophen-2-yl)-3-phenyl-4,5-dihydro-1H-pyrazole derivatives with improved solubility and potential antituberculosis activity","volume":"93","author":"Khambete","year":"2019","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1111\/cbdd.13624","article-title":"Exploration of 5-(5-nitrothiophen-2-yl)-4,5- dihydro-1H-pyrazoles as selective, multitargeted antimycobacterial agents","volume":"95","author":"Agre","year":"2020","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1093\/jac\/dkv010","article-title":"Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase","volume":"70","author":"Guzman","year":"2015","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1016\/j.bmcl.2019.04.034","article-title":"Dual-targeting GroEL\/ES chaperonin and protein tyrosine phosphatase B (PtpB) inhibitors: A polypharmacology strategy for treating Mycobacterium tuberculosis infections","volume":"29","author":"Washburn","year":"2019","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.ejmech.2015.06.007","article-title":"Design, synthesis and characterization of dual inhibitors against new targets FabG4 and HtdX of Mycobacterium tuberculosis","volume":"100","author":"Banerjee","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Degiacomi, G., Belardinelli, J.M., Pasca, M.R., De Rossi, E., Riccardi, G., and Chiarelli, L.R. (2020). Promiscuous targets for antitubercular drug discovery: The paradigm of DprE1 and MmpL3. Appl. Sci., 10.","DOI":"10.3390\/app10020623"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1093\/jac\/dki319","article-title":"Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines","volume":"56","author":"Protopopova","year":"2005","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_34","unstructured":"(2020, February 13). Working Group on New TB Drugs. Available online: www.newtbdrugs.org\/pipeline\/compound\/sq109."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"823","DOI":"10.2217\/fmb.12.56","article-title":"Discovery and development of SQ109: A new antitubercular drug with a novel mechanism of action","volume":"7","author":"Sacksteder","year":"2012","journal-title":"Fut. Microbio."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6413","DOI":"10.1128\/AAC.03229-14","article-title":"Novel insights into the mechanism of inhibition of MmpL3, a target of multiple pharmacophores in Mycobacterium tuberculosis","volume":"58","author":"Li","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1021\/acsinfecdis.9b00048","article-title":"Direct inhibition of MmpL3 by novel antitubercular compounds","volume":"5","author":"Li","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.cell.2019.01.003","article-title":"Crystal structures of membrane transporter MmpL3, an anti-TB drug target","volume":"176","author":"Zhang","year":"2019","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1128\/AAC.05270-11","article-title":"MmpL3 is the cellular target of the antitubercular pyrrole derivative BM212","volume":"56","author":"Poce","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1128\/AAC.05708-11","article-title":"SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis","volume":"56","author":"Tahlan","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1128\/CMR.18.1.81-101.2005","article-title":"Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis","volume":"18","author":"Takayama","year":"2005","journal-title":"Clin. Microbio. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"40174","DOI":"10.1074\/jbc.M406796200","article-title":"The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: Novel insights into drug mechanisms of action","volume":"279","author":"Boshoff","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1093\/oxfordjournals.jbchem.a133997","article-title":"New malonyl-CoA-dependent fatty acid elongation system in Mycobacterium smegmatis","volume":"92","author":"Kikuchi","year":"1982","journal-title":"J. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4693","DOI":"10.1016\/j.bmc.2009.04.055","article-title":"Antimycobacterial activity of new 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-one derivatives. Molecular modeling investigations","volume":"17","author":"Zampieri","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3797","DOI":"10.1016\/j.bmc.2005.03.013","article-title":"Antimycobacterial activity of new 3-substituted 5-(pyridin-4-yl)-3H-1,3,4-oxadiazol-2-one and 2-thione derivatives. Preliminary molecular modeling investigations","volume":"13","author":"Mamolo","year":"2005","journal-title":"Bioorg. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.biochi.2014.01.019","article-title":"Using the reversible inhibition of gastric lipase by Orlistat for investigating simultaneously lipase adsorption and substrate hydrolysis at the lipid-water interface","volume":"101","author":"Point","year":"2014","journal-title":"Biochimie"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.biochi.2012.07.008","article-title":"Mycobacterial lipolytic enzymes: A gold mine for tuberculosis research","volume":"95","author":"Dedieu","year":"2013","journal-title":"Biochimie"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.bioorg.2018.08.025","article-title":"Oxadiazolone derivatives, new promising multi-target inhibitors against M. tuberculosis","volume":"81","author":"Nguyen","year":"2018","journal-title":"Bioorg. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/j.chembiol.2015.05.016","article-title":"Thiophenecarboxamidederivatives activated by EthA kill Mycobacterium tuberculosis by inhibiting the CTP synthetase PyrG","volume":"22","author":"Mori","year":"2015","journal-title":"Chem. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3187","DOI":"10.1038\/s41598-018-21614-4","article-title":"A multitarget approach to drug discovery inhibiting Mycobacterium tuberculosis PyrG and PanK","volume":"8","author":"Chiarelli","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1021\/acsinfecdis.7b00006","article-title":"A phenotypic based target screening approach delivers new antitubercular CTP synthetase inhibitors","volume":"3","author":"Esposito","year":"2017","journal-title":"ACS Infect. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3312","DOI":"10.1128\/AAC.00140-14","article-title":"Assessment of Mycobacterium tuberculosis pantothenate kinase vulnerability through target knockdown and mechanistically diverse inhibitors","volume":"58","author":"Reddy","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.bmc.2008.02.046","article-title":"ATP competitive inhibitors of D-alanine-D-alanine ligase based on protein kinase inhibitor scaffolds","volume":"17","author":"Triola","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"8512","DOI":"10.1016\/j.bmc.2010.10.036","article-title":"High-throughput identification of antibacterials against methicillin-resistant Staphylococcus aureus (MRSA) and the transglycosylase","volume":"18","author":"Cheng","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2752","DOI":"10.1021\/jacs.7b13205","article-title":"Affinity-Based Screen for Inhibitors of Bacterial Transglycosylase","volume":"140","author":"Wu","year":"2018","journal-title":"J. Am. Chem. Soc."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.tube.2012.06.001","article-title":"Salicylanilide derivatives block Mycobacterium tuberculosis through inhibition of isocitrate lyase and methionine aminopeptidase","volume":"92","author":"Trejtnar","year":"2012","journal-title":"Tuberculosis (Edinb)"},{"key":"ref_57","first-page":"703053","article-title":"Salicylanilide diethyl phosphates as potential inhibitors of some mycobacterial enzymes","volume":"2014","author":"Saxena","year":"2014","journal-title":"Sci. World J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.bmc.2012.10.056","article-title":"Structure-activity relationships of antitubercular salicylanilides consistent with disruption of the proton gradient via proton shuttling","volume":"21","author":"Lee","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"111578","DOI":"10.1016\/j.ejmech.2019.111578","article-title":"Phenolic N-monosubstituted carbamates: Antitubercular and toxicity evaluation of multi-targeting compounds","volume":"181","author":"Baranyai","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1021\/jm00394a014","article-title":"Carbamate ester derivatives as potential prodrugs of the presynaptic dopamine autoreceptor agonist (-)-3-(3-hydroxyphenyl)-N-propylpiperidine","volume":"30","author":"Thorberg","year":"1987","journal-title":"J. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/j.bmc.2009.12.055","article-title":"Salicylanilide carbamates: Antitubercular agents active against multidrug-resistant Mycobacterium tuberculosis strains","volume":"18","author":"Kunc","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1016\/j.bmc.2016.02.004","article-title":"Salicylanilide N-monosubstituted carbamates: Synthesis and in vitro antimicrobial activity","volume":"24","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.ejmech.2015.07.001","article-title":"Combating highly resistant emerging pathogen Mycobacterium abscessus and Mycobacterium tuberculosis with novel salicylanilide esters and carbamates","volume":"101","author":"Baranyai","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4073","DOI":"10.1016\/j.bmc.2014.05.064","article-title":"Synthesis and biological activity of new salicylanilide N,N-disubstituted carbamates and thiocarbamates","volume":"22","author":"Trejtnar","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6126","DOI":"10.2174\/0929867311209066126","article-title":"Advances in mycobacterial isocitrate lyase targeting and inhibitors","volume":"19","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1021\/acsinfecdis.7b00231","article-title":"Targeting the proteostasis network for mycobacterial drug discovery","volume":"4","author":"Lupoli","year":"2018","journal-title":"ACS Infect. Dis."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1128\/IAI.01078-07","article-title":"A Mycobacterium tuberculosis mutant lacking the groEL homologue cpn60.1 is viable but fails to induce an inflammatory response in animal models of infection","volume":"76","author":"Hu","year":"2008","journal-title":"Infect. Immun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.bmcl.2013.12.100","article-title":"A biochemical screen for GroEL\/GroES inhibitors","volume":"24","author":"Johnson","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.1016\/j.bmcl.2016.04.089","article-title":"GroEL\/ES inhibitors as potential antibiotics","volume":"26","author":"Abdeen","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5247","DOI":"10.1016\/j.bmcl.2016.09.051","article-title":"Targeting the HSP60\/10 chaperonin systems of Trypanosoma brucei as a strategy for treating African sleeping sickness","volume":"26","author":"Abdeen","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"7345","DOI":"10.1021\/acs.jmedchem.8b00989","article-title":"Sulfonamido-2-arylbenzoxazole GroEL\/ES inhibitors as potent antibacterials against Methicillin-Resistant Staphylococcus aureus (MRSA)","volume":"61","author":"Abdeen","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3110","DOI":"10.2174\/0929867322666150812150036","article-title":"Mycobacterium tuberculosis low molecular weight phosphatases (MPtpA and MPtpB): From biological insight to inhibitors","volume":"22","author":"Fanzani","year":"2015","journal-title":"Curr. Med. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.hoc.2012.02.002","article-title":"The antifolates","volume":"26","author":"Visentin","year":"2012","journal-title":"Hematol. Oncol. Clin. North. Am."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.chembiol.2014.04.009","article-title":"Folate pathway disruption leads to critical disruption of methionine derivatives in Mycobacterium tuberculosis","volume":"21","author":"Nixon","year":"2014","journal-title":"Chem. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"8983","DOI":"10.1021\/jacs.5b01442","article-title":"Nonracemic antifolates stereoselectively recruit alternate cofactors and overcome resistance in S. aureus","volume":"137","author":"Keshipeddy","year":"2015","journal-title":"J. Am. Chem. Soc."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Hajian, B., Scocchera, E., Keshipeddy, S., G-Dayanandan, N., Shoen, C., Krucinska, J., Reeve, S., Cynamon, M., Anderson, A.C., and Wright, D.L. (2016). Propargyl-linked antifolates are potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0161740"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.chembiol.2019.02.013","article-title":"Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents","volume":"26","author":"Hajian","year":"2019","journal-title":"Cell Chem. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1021\/acs.biochem.5b00993","article-title":"Structural insights into Mycobacterium tuberculosis Rv2671 Protein as a Dihydrofolate Reductase Functional Analogue Contributing to para-Aminosalicylic Acid Resistance","volume":"55","author":"Cheng","year":"2016","journal-title":"Biochemistry"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1126\/science.aad0300","article-title":"An unprecedented mechanism of nucleotide methylation in organisms containing thyX","volume":"351","author":"Mishanina","year":"2016","journal-title":"Science"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.drudis.2016.09.006","article-title":"New prodrugs against tuberculosis","volume":"22","author":"Mori","year":"2017","journal-title":"Drug Discov. Today"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"9677","DOI":"10.1073\/pnas.97.17.9677","article-title":"3rd. Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis","volume":"97","author":"DeBarber","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nm.1950","article-title":"Synthetic EthR inhibitors boost antituberculous activity of ethionamide","volume":"15","author":"Willand","year":"2009","journal-title":"Nat. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1021\/jm200076a","article-title":"Ethionamide boosters: Synthesis, biological activity, and structure-activity relationships of a series of 1,2,4-oxadiazole EthR inhibitors","volume":"54","author":"Flipo","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"4876","DOI":"10.1021\/jm500422b","article-title":"Ligand efficiency driven design of new inhibitors of Mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging, and linking approaches","volume":"57","author":"Villemagne","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"5390","DOI":"10.1038\/s41598-017-05453-3","article-title":"Combination therapy for tuberculosis treatment: Pulmonary administration of ethionamide and booster co-loaded nanoparticles","volume":"7","author":"Pancani","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"5129","DOI":"10.1039\/C9OB00680J","article-title":"A novel codrug made of the combination of ethionamide and its potentiating booster: Synthesis, self-assembly into nanoparticles and antimycobacterial evaluation","volume":"17","author":"Pastor","year":"2019","journal-title":"Org. Biomol. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1080\/1062936X.2017.1398782","article-title":"A QSAR and molecular modelling study towards new lead finding: Polypharmacological approach to Mycobacterium tuberculosis","volume":"28","author":"Janardhan","year":"2017","journal-title":"SAR QSAR Environ. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1007\/s10822-019-00245-5","article-title":"Dual-targeted hit identifcation using pharmacophore screening","volume":"33","author":"Volynets","year":"2019","journal-title":"J. Computer-Aided Mol. Des."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/5\/1239\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:05:37Z","timestamp":1760173537000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/5\/1239"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,9]]},"references-count":88,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["molecules25051239"],"URL":"https:\/\/doi.org\/10.3390\/molecules25051239","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,9]]}}}