{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:47:01Z","timestamp":1792784821219,"version":"4.5.0"},"reference-count":37,"publisher":"American Chemical Society (ACS)","issue":"39","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["2R15AI 103889-02"],"award-info":[{"award-number":["2R15AI 103889-02"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Center for Gene Regulation in Health and Disease"},{"name":"Faculty Research Development program"},{"name":"summer undergraduate research program of Cleveland State University","id":[{"id":"https:\/\/ror.org\/002tx1f22","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Current therapeutic interventions for Human African Trypanosomiasis (HAT) are severely limited by emerging drug resistance and profound systemic toxicity, necessitating the urgent development of novel chemotypes. Building upon our previous identification of the alpha-adrenoceptor antagonist Prazosin as a scaffold with off-target activity against Trypanosoma bruceibrucei (T. b. brucei), we have targeted the Flagellum Attachment Zone 1 (FAZ1) filament. As a parasite-specific protein, FAZ1 presents an ideal target for achieving high selectivity and minimizing host toxicity. In this study, we designed and synthesized a series of Prazosin derivatives and characterized their Structure\u2013Activity Relationship (SAR) through biological evaluation against T. b. brucei and mammalian cell lines (HEK293 and RAW264.7). Several derivatives exhibited potent antitrypanosomal activity with IC50 values below 50 nM and a selectivity index exceeding 500-fold relative to mammalian cells. Crucially, these candidates demonstrated negligible affinity for alpha-adrenoceptors at their effective antiparasitic concentrations. Molecular docking simulations, utilizing AlphaFold-generated FAZ1 structures, suggest that these candidates interact specifically with the FAZ1 N-terminal domain. Furthermore, in vivo studies indicated that the lead derivatives extended the lifespan of T. b. brucei-infected mice without the marked toxicity observed with the parent compound, Prazosin. These findings identify prazosin-derived compounds as promising antitrypanosomal agents and suggest FAZ1 as a potential target for future mechanistic validation, warranting further optimization as safer, more effective alternatives for the treatment of HAT.<\/jats:p>","DOI":"10.1021\/acsomega.6c03993","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T14:02:16Z","timestamp":1790344936000},"page":"58918-58940","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and Biological\nEvaluation of Prazosin-Derived\nAntitrypanosomal Agents Putatively Targeting FAZ1"],"prefix":"10.1021","volume":"11","author":[{"given":"Fatma M.","family":"Salem","sequence":"first","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0616-0462","authenticated-orcid":true,"given":"William R.","family":"Martin","sequence":"additional","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]},{"name":"Lerner Research Institute, Cleveland Clinic , , , ,","place":["Cleveland, Ohio, United States, 44195"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9557-8290","authenticated-orcid":true,"given":"Tyler E.","family":"Roeper","sequence":"additional","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie A.","family":"Schuster","sequence":"additional","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre C.","family":"Martin","sequence":"additional","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchitha","family":"Korem","sequence":"additional","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soha M.","family":"Bolbol","sequence":"additional","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace M","family":"Weske","sequence":"additional","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"SK Abdus","family":"Sayeed","sequence":"additional","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7188-833X","authenticated-orcid":true,"given":"Afonso Santine MM","family":"Velez","sequence":"additional","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]},{"name":"Universidade Federal Rural do Rio de Janeiro , , , ,","place":["Seropedica, Rio de Janeiro, Brazil, 23890-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyubomyr","family":"Turchyn","sequence":"additional","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibo","family":"Li","sequence":"additional","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0711-441X","authenticated-orcid":true,"given":"Bin","family":"Su","sequence":"additional","affiliation":[{"name":"Cleveland State University , , 2121 Euclid Avenue , , ,","place":["Cleveland, Ohio, United States, 44115"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"2026100610465498600_cit1","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1016\/B978-0-323-55512-8.00102-2","article-title":"African Trypanosomiasis","volume-title":"Hunter\u2019s Tropical Medicine and Emerging Infectious\nDiseases","author":"Krishna","year":"2020"},{"key":"2026100610465498600_cit2","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3389\/fvets.2022.828111","article-title":"An Update\non African\nTrypanocide Pharmaceutics and Resistance","volume":"9","author":"Kasozi","year":"2022","journal-title":"Front.\nVet. Sci"},{"issue":"2","key":"2026100610465498600_cit3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003397","article-title":"A Literature Review\nof Economic Evaluations for a Neglected Tropical Disease: Human African\nTrypanosomiasis (\u201cSleeping Sickness\u201d)","volume":"9","author":"Sutherland","year":"2015","journal-title":"PLoS Negl. Trop. Dis"},{"issue":"9709","key":"2026100610465498600_cit4","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/S0140-6736(09)60829-1","article-title":"Human African\nTrypanosomiasis","volume":"375","author":"Brun","year":"2010","journal-title":"Lancet"},{"issue":"1","key":"2026100610465498600_cit5","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1051\/parasite\/2010171061","article-title":"Domestic Animals\nas\nPotential Reservoir Hosts of Trypanosoma Brucei Gambiense in Sleeping\nSickness Foci in Cameroon","volume":"17","author":"Njiokou","year":"2010","journal-title":"Parasite"},{"issue":"1","key":"2026100610465498600_cit6","first-page":"90","article-title":"Trypanosome\nInfection in Cattle and African Sleeping Sickness","volume":"5","author":"Smith","year":"2007","journal-title":"Int. J. Glob. Health Health Disparities"},{"issue":"8","key":"2026100610465498600_cit7","doi-asserted-by":"publisher","first-page":"967","DOI":"10.3390\/pathogens10080967","article-title":"Regulation of Antigenic Variation by Trypanosoma Brucei Telomere\nProteins Depends on Their Unique DNA Binding Activities","volume":"10","author":"Li","year":"2021","journal-title":"Pathogens"},{"issue":"4","key":"2026100610465498600_cit8","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01725-21","article-title":"Turnover\nof Variant Surface Glycoprotein in Trypanosoma Brucei Is a Bimodal\nProcess","volume":"12","author":"Garrison","year":"2021","journal-title":"mBio"},{"issue":"1","key":"2026100610465498600_cit9","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0166-6851(97)00183-7","article-title":"Expression and Function\nof Surface Proteins in Trypanosoma\nBrucei","volume":"91","author":"Pays","year":"1998","journal-title":"Mol. Biochem. Parasitol"},{"issue":"2","key":"2026100610465498600_cit10","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/S0304-4017(00)00427-1","article-title":"Drug Resistance\nin Pathogenic African\nTrypanosomes: What Hopes for the Future?","volume":"96","author":"Anene","year":"2001","journal-title":"Vet.\nParasitol"},{"key":"2026100610465498600_cit11","volume-title":"Ending the Neglect to Attain the Sustainable\nDevelopment Goals (A Road Map for Neglected Tropical Disease 2021-2030)\nOverview","author":"WHO.","year":"2020"},{"issue":"1","key":"2026100610465498600_cit12","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/1756-3305-3-15","article-title":"The Development\nof Drugs for Treatment of Sleeping Sickness: A Historical Review","volume":"3","author":"Steverding","year":"2010","journal-title":"Parasites Vectors"},{"issue":"3","key":"2026100610465498600_cit13","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/0924-8579(94)90012-4","article-title":"Drug Used\nin the Treatment of Sleeping Sickness (Human African Trypanosomiasis:\nHAT)","volume":"4","author":"We\u0301ry","year":"1994","journal-title":"Int. J. Antimicrob. Agents"},{"issue":"5","key":"2026100610465498600_cit14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0008261","article-title":"Monitoring\nthe Elimination of Human African Trypanosomiasis at Continental and\nCountry Level: Update to 2018","volume":"14","author":"Franco","year":"2020","journal-title":"PLoS Negl. Trop.\nDis"},{"issue":"12","key":"2026100610465498600_cit15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0000923","article-title":"Fexinidazole\n\u2013 A New Oral Nitroimidazole Drug Candidate Entering Clinical\nDevelopment for the Treatment of Sleeping Sickness","volume":"4","author":"Torreele","year":"2010","journal-title":"PLoS Negl. Trop. Dis"},{"key":"2026100610465498600_cit16","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.16881","article-title":"Efficacy and\nToxicity of Fexinidazole and Nifurtimox Plus Eflornithine in the Treatment\nof African Trypanosomiasis","volume":"13","author":"Hidalgo","year":"2021","journal-title":"Cureus"},{"issue":"4","key":"2026100610465498600_cit17","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02515-18","article-title":"Pharmacokinetic-Pharmacodynamic\nAssessment of the Hepatic\nand Bone Marrow Toxicities of the New Trypanoside Fexinidazole","volume":"63","author":"Watson","year":"2019","journal-title":"Antimicrob. Agents Chemother"},{"issue":"10","key":"2026100610465498600_cit18","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.3390\/pathogens11101100","article-title":"Systematic\nReview and Meta-Analysis\non Human African Trypanocide Resistance","volume":"11","author":"Kasozi","year":"2022","journal-title":"Pathogens"},{"issue":"3","key":"2026100610465498600_cit19","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1093\/jac\/dkv376","article-title":"Nitroheterocyclic\nDrug Resistance Mechanisms in Trypanosoma\nBrucei","volume":"71","author":"Wyllie","year":"2016","journal-title":"J. Antimicrob. Chemother"},{"issue":"6","key":"2026100610465498600_cit20","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.pt.2014.04.003","article-title":"Nitro Drugs for the\nTreatment of Trypanosomatid Diseases:\nPast, Present, and Future Prospects","volume":"30","author":"Patterson","year":"2014","journal-title":"Trends\nParasitol"},{"issue":"7","key":"2026100610465498600_cit21","doi-asserted-by":"publisher","first-page":"2893","DOI":"10.1128\/AAC.00332-10","article-title":"Cross-Resistance\nto Nitro Drugs and Implications for\nTreatment of Human African Trypanosomiasis","volume":"54","author":"Sokolova","year":"2010","journal-title":"Antimicrob. Agents Chemother"},{"issue":"8","key":"2026100610465498600_cit22","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.1021\/acsinfecdis.2c00331","article-title":"Identification\nof Prazosin as a Potential Flagellum\nAttachment Zone 1(FAZ1) Inhibitor for the Treatment of Human African\nTrypanosomiasis","volume":"8","author":"Orahoske","year":"2022","journal-title":"ACS Infect. Dis"},{"issue":"1","key":"2026100610465498600_cit23","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1172\/JCI117309","article-title":"Alpha 1 adrenergic\nreceptor-induced c-fos gene expression in rat aorta and cultured vascular\nsmooth muscle cells","volume":"94","author":"Okazaki","year":"1994","journal-title":"J. Clin. Invest"},{"issue":"27","key":"2026100610465498600_cit24","doi-asserted-by":"publisher","first-page":"11105","DOI":"10.1073\/pnas.1103634108","article-title":"Structure of Trypanosoma\nBrucei Flagellum Accounts for Its Bihelical Motion","volume":"108","author":"Koyfman","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A"},{"key":"2026100610465498600_cit25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1722618115","article-title":"Flagellum\nCouples Cell Shape to Motility in Trypanosoma Brucei","volume":"115","author":"Sun","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A"},{"issue":"1","key":"2026100610465498600_cit26","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.protis.2007.08.005","article-title":"A Repetitive\nProtein Essential for the Flagellum Attachment Zone Filament Structure\nand Function in Trypanosoma Brucei","volume":"159","author":"Vaughan","year":"2008","journal-title":"Protist"},{"issue":"8\u20139","key":"2026100610465498600_cit27","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1016\/j.ijpara.2008.03.003","article-title":"The Flagellum of Trypanosoma Brucei: New Tricks from\nan Old Dog","volume":"38","author":"Ralston","year":"2008","journal-title":"Int. J. Parasitol"},{"issue":"10","key":"2026100610465498600_cit28","doi-asserted-by":"publisher","first-page":"ar103","DOI":"10.1091\/mbc.E23-01-0022","article-title":"FAZ assembly in bloodstream form\nTrypanosoma brucei requires kinesin KIN-E","volume":"34","author":"Albisetti","year":"2023","journal-title":"Mol.\nBiol. Cell"},{"key":"2026100610465498600_cit29","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/s41564-022-01295-6","article-title":"Genome-wide subcellular protein map for the flagellate\nparasite Trypanosoma brucei","volume":"8","author":"Billington","year":"2023","journal-title":"Nat. Microbiol"},{"issue":"11","key":"2026100610465498600_cit30","doi-asserted-by":"publisher","first-page":"107856","DOI":"10.1016\/j.jbc.2024.107856","article-title":"A putative\ncAMP-binding protein in\nTrypanosoma brucei cooperates with FLAM3 to promote flagellar connection\nand cell morphogenesis","volume":"300","author":"Zhou","year":"2024","journal-title":"J. Biol. Chem"},{"issue":"13","key":"2026100610465498600_cit31","doi-asserted-by":"publisher","first-page":"2361","DOI":"10.1242\/jcs.168377","article-title":"Assembly and Maintenance of the Flagellum\nAttachment Zone Filament in Trypanosoma Brucei","volume":"128","author":"Zhou","year":"2015","journal-title":"J. Cell Sci"},{"issue":"3","key":"2026100610465498600_cit32","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/s41564-022-01295-6","article-title":"Genome-Wide\nSubcellular Protein Map for the Flagellate Parasite Trypanosoma Brucei","volume":"8","author":"Billington","year":"2023","journal-title":"Nat. Microbiol"},{"key":"2026100610465498600_cit33","doi-asserted-by":"publisher","first-page":"117751","DOI":"10.1016\/j.bmc.2024.117751","article-title":"Synthesis\nand Biological\nEvaluation of Orally Active Anti-Trypanosoma Agents","volume":"107","author":"Salem","year":"2024","journal-title":"Bioorg. Med. Chem"},{"issue":"8016","key":"2026100610465498600_cit34","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate Structure Prediction of\nBiomolecular Interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"issue":"D1","key":"2026100610465498600_cit35","doi-asserted-by":"publisher","first-page":"D204","DOI":"10.1093\/nar\/gku989","volume":"43","author":"UniProt: A Hub for Protein Information.","year":"2015","journal-title":"Nucleic\nAcids Res"},{"issue":"8","key":"2026100610465498600_cit36","doi-asserted-by":"publisher","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","article-title":"AutoDock Vina 1.2.0:\nNew Docking Methods, Expanded Force Field, and Python Bindings","volume":"61","author":"Eberhardt","year":"2021","journal-title":"J. Chem. Inf. Model"},{"issue":"11","key":"2026100610465498600_cit37","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4792","article-title":"UCSF ChimeraX:\nTools for Structure\nBuilding and Analysis","volume":"32","author":"Meng","year":"2023","journal-title":"Protein Sci"}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c03993","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/39\/58918\/68653166\/acsomega.6c03993.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/39\/58918\/68653166\/acsomega.6c03993.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:30:07Z","timestamp":1791300607000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/39\/58918\/5438527\/Synthesis-and-Biological-Evaluation-of-Prazosin"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":37,"journal-issue":{"issue":"39","published-online":{"date-parts":[[2026,9,25]]},"published-print":{"date-parts":[[2026,10,6]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c03993","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]}}}