{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T19:02:45Z","timestamp":1784314965389,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.pntd.0014520","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000}}],"reference-count":23,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI125147"],"award-info":[{"award-number":["R01AI125147"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>\n                    Leishmaniasis, a neglected tropical disease affecting nearly 10% of the global population, suffers from limited therapeutic options and rising drug resistance. To address this, we developed 343 analogs of AR-12, a compound that has previously illustrated host-directed anti-leishmanial effects. Primary screening using a luminescence-based assay revealed 66 analogs with greater selectivity than the parent compound, AR-12. Sixteen promising candidates, selected for high potency (IC\u2085\u2080\u2009&lt;\u20091 \u00b5M) or high selectivity (&gt;15), underwent secondary screening via Giemsa staining. Four lead compounds (\n                    <jats:bold>53<\/jats:bold>\n                    ,\n                    <jats:bold>134<\/jats:bold>\n                    ,\n                    <jats:bold>197<\/jats:bold>\n                    , and\n                    <jats:bold>354<\/jats:bold>\n                    ) demonstrated therapeutic indices greater than 40. Tertiary assays confirmed their broad\n                    <jats:italic>in vitro<\/jats:italic>\n                    efficacy against both\n                    <jats:italic>Leishmania donovani<\/jats:italic>\n                    and\n                    <jats:italic>Leishmania mexicana<\/jats:italic>\n                    . Notably, 197 exhibited potent host-directed and proteomic analysis identified lysozyme as a mechanistic target, implicating it in the host-mediated clearance of intracellular parasites. These findings highlight the dual host- and pathogen-directed mechanisms of these compounds and support their potential as the basis for new therapeutic strategies. Further optimization and clinical exploration of these leads are warranted to meet the urgent need for effective leishmaniasis treatments.\n                  <\/jats:p>","DOI":"10.1371\/journal.pntd.0014520","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T17:37:46Z","timestamp":1783964266000},"page":"e0014520","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and preliminary evaluation of novel compounds that demonstrate broad host-directed anti-leishmanial activity"],"prefix":"10.1371","volume":"20","author":[{"given":"Elizabeth G.","family":"Gurysh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Shamim Hasan","family":"Zahid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica M.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Landavazo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ojas A.","family":"Namjoshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph W.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devika M.","family":"Varma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan N.","family":"Woodring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron T.","family":"Hendricksen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra M.","family":"Lopez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph F.","family":"Vath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baiyi","family":"Quan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica N.","family":"Pino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Fitzgerald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7173-6352","authenticated-orcid":true,"given":"Kevin J.","family":"Frankowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M.","family":"Bachelder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce E.","family":"Blough","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1820-8382","authenticated-orcid":true,"given":"Kristy M.","family":"Ainslie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"issue":"7","key":"pntd.0014520.ref001","doi-asserted-by":"crossref","first-page":"664","DOI":"10.7326\/0003-4819-124-7-199604010-00007","article-title":"Epidemic visceral leishmaniasis in southern Sudan: treatment of severely debilitated patients under wartime conditions and with limited resources","volume":"124","author":"J Seaman","year":"1996","journal-title":"Ann Intern Med"},{"issue":"3","key":"pntd.0014520.ref002","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.bbrc.2010.07.099","article-title":"Amphotericin B inhibits entry of Leishmania donovani into primary macrophages","volume":"399","author":"YD Paila","year":"2010","journal-title":"Biochem Biophys Res Commun"},{"issue":"2","key":"pntd.0014520.ref003","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1128\/AAC.00030-11","article-title":"Mechanism of amphotericin B resistance in clinical isolates of Leishmania donovani","volume":"56","author":"B Purkait","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"issue":"12","key":"pntd.0014520.ref004","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pntd.0001974","article-title":"Leishmania donovani develops resistance to drug combinations","volume":"6","author":"R Garc\u00eda-Hern\u00e1ndez","year":"2012","journal-title":"PLoS Negl Trop Dis"},{"issue":"11","key":"pntd.0014520.ref005","article-title":"Overcoming reduced antibiotic susceptibility in intracellular Salmonella enterica serovar Typhimurium using AR-12","volume":"368","author":"MSH Zahid","year":"2021","journal-title":"FEMS Microbiol Lett"},{"issue":"32","key":"pntd.0014520.ref006","doi-asserted-by":"crossref","first-page":"13087","DOI":"10.1074\/jbc.M117.780981","article-title":"Autophagy downstream of endosomal Toll-like receptor signaling in macrophages is a key mechanism for resistance to Leishmania major infection","volume":"292","author":"LH Franco","year":"2017","journal-title":"J Biol Chem"},{"issue":"2","key":"pntd.0014520.ref007","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.jcmgh.2017.05.002","article-title":"Bacterial autophagy: Offense and defense at the host-pathogen interface","volume":"4","author":"JE Casanova","year":"2017","journal-title":"Cell Mol Gastroenterol Hepatol"},{"issue":"12","key":"pntd.0014520.ref008","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0168339","article-title":"Leishmania infantum induces mild unfolded protein response in infected macrophages","volume":"11","author":"L Galluzzi","year":"2016","journal-title":"PLoS One"},{"key":"pntd.0014520.ref009","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.ijpharm.2016.01.004","article-title":"Host-mediated Leishmania donovani treatment using AR-12 encapsulated in acetalated dextran microparticles","volume":"499","author":"MA Collier","year":"2016","journal-title":"Int J Pharm"},{"key":"pntd.0014520.ref010","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ijpddr.2019.08.004","article-title":"Evaluation of synergy between host and pathogen-directed therapies against intracellular Leishmania donovani","volume":"10","author":"MSH Zahid","year":"2019","journal-title":"Int J Parasitol Drugs Drug Resist"},{"issue":"3","key":"pntd.0014520.ref011","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/0166-6851(86)90001-0","article-title":"Mechanism of action of amphotericin B on Leishmania donovani promastigotes","volume":"19","author":"AK Saha","year":"1986","journal-title":"Mol Biochem Parasitol"},{"issue":"12","key":"pntd.0014520.ref012","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.3390\/antibiotics10121534","article-title":"Applications of lysozyme, an innate immune defense factor, as an alternative antibiotic","volume":"10","author":"P Ferraboschi","year":"2021","journal-title":"Antibiotics (Basel)"},{"issue":"2","key":"pntd.0014520.ref013","doi-asserted-by":"crossref","DOI":"10.3390\/pathogens12020246","article-title":"Unrevealing the mystery of latent leishmaniasis: what cells can host leishmania?","volume":"12","author":"A Valigurov\u00e1","year":"2023","journal-title":"Pathogens"},{"issue":"1","key":"pntd.0014520.ref014","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s12639-011-0066-z","article-title":"Studies on the arginase, 5\u2019-nucleotidase and lysozyme activity by monocytes from visceral leishmaniasis patients","volume":"36","author":"P Kumar","year":"2012","journal-title":"J Parasit Dis"},{"issue":"9","key":"pntd.0014520.ref015","doi-asserted-by":"crossref","first-page":"100630","DOI":"10.1016\/j.mcpro.2023.100630","article-title":"Obtaining functional proteomics insights from thermal proteome profiling through optimized melt shift calculation and statistical analysis with InflectSSP","volume":"22","author":"NA McCracken","year":"2023","journal-title":"Mol Cell Proteomics"},{"issue":"3","key":"pntd.0014520.ref016","doi-asserted-by":"crossref","DOI":"10.15252\/msb.20199232","article-title":"Thermal proteome profiling for interrogating protein interactions","volume":"16","author":"A Mateus","year":"2020","journal-title":"Mol Syst Biol"},{"issue":"10","key":"pntd.0014520.ref017","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1248\/bpb.b12-00419","article-title":"Leishmanicidal activity of two naphthoquinones against Leishmania donovani","volume":"35","author":"CM Lezama-D\u00e1vila","year":"2012","journal-title":"Biol Pharm Bull"},{"key":"pntd.0014520.ref018","article-title":"Bone Marrow-Derived Macrophages (BMM): Isolation and Applications","author":"J Weischenfeldt","year":"2008","journal-title":"CSH Protoc"},{"key":"pntd.0014520.ref019","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ijpddr.2019.08.004","article-title":"Evaluation of synergy between host and pathogen-directed therapies against intracellular Leishmania donovani","volume":"10","author":"MSH Zahid","year":"2019","journal-title":"Int J Parasitol Drugs Drug Resist"},{"issue":"11","key":"pntd.0014520.ref020","doi-asserted-by":"crossref","first-page":"4027","DOI":"10.1021\/acs.jproteome.9b00500","article-title":"Proteome integral solubility alteration: A high-throughput proteomics assay for target deconvolution","volume":"18","author":"M Gaetani","year":"2019","journal-title":"J Proteome Res"},{"issue":"1","key":"pntd.0014520.ref021","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.bbapap.2018.08.002","article-title":"Target deconvolution from phenotype-based drug discovery by using chemical proteomics approaches","volume":"1867","author":"K Kubota","year":"2019","journal-title":"Biochim Biophys Acta Proteins Proteom"},{"issue":"2","key":"pntd.0014520.ref022","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1021\/jasms.9b00041","article-title":"Comparative analysis of mass-spectrometry-based proteomic methods for protein target discovery using a one-pot approach","volume":"31","author":"A Cabrera","year":"2020","journal-title":"J Am Soc Mass Spectrom"},{"issue":"4","key":"pntd.0014520.ref023","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1023\/A:1008942828960","article-title":"Conditional gene targeting in macrophages and granulocytes using LysMcre mice","volume":"8","author":"BE Clausen","year":"1999","journal-title":"Transgenic Res"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0014520","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0014520","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T18:03:27Z","timestamp":1784311407000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0014520"}},"subtitle":[],"editor":[{"given":"Brice","family":"Rotureau","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":23,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7,13]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0014520","relation":{},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,13]]}}}