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African trypanosomes are unique among eukaryotes in having an RNA Polymerase 1 that transcribes not only rRNA but also mRNA that encodes the abundant variable surface glycoprotein (VSG) that coats the cell membrane of bloodstream-form parasites and allows them to evade host immune defenses. RNA Pol 1 inhibitor BMH-21, an intercalator not associated with DNA damage and a lead for new cancer therapy, has reported activity against the synthesis of rRNA and VSG mRNA in\n                      <jats:italic toggle=\"yes\">Trypanosoma brucei brucei<\/jats:italic>\n                      . We evaluated a library of BMH-21 analogs against bloodstream-form\n                      <jats:italic toggle=\"yes\">T. b. brucei in vitro<\/jats:italic>\n                      and found limited tolerance for structural modification. Striking and time-dependent bimodal dose-response curves indicate these compounds have a complex mechanism of action. Most potent against\n                      <jats:italic toggle=\"yes\">T. b. brucei<\/jats:italic>\n                      was benzopyridoquinazoline Compound\n                      <jats:bold>2<\/jats:bold>\n                      , with an EC\n                      <jats:sub>50<\/jats:sub>\n                      of 84 nM. Analysis of\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      pharmacokinetic-pharmacodynamic (PK-PD) relationships by a hollow fiber model system revealed that in\n                      <jats:italic toggle=\"yes\">T. b. brucei<\/jats:italic>\n                      , the kinetic driver of Compound\n                      <jats:bold>2<\/jats:bold>\n                      is drug concentration, a finding that was confirmed by dose fractionation in infected mice and that highlights the utility of the\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      system for assessing antitrypanosomal PK-PD. Although Compound\n                      <jats:bold>2<\/jats:bold>\n                      accumulates 20-fold in mouse brain tissue vs plasma, efficacy against CNS\n                      <jats:italic toggle=\"yes\">T. b. brucei<\/jats:italic>\n                      in mice was limited. RNA Pol 1 remains an attractive target for developing new and more selectively toxic antitrypanosomal agents.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01492-25","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T13:00:19Z","timestamp":1774616419000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["RNA Polymerase 1 inhibitors against African trypanosomes\n                    <i>in vitro<\/i>\n                    and in mice"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7907-7165","authenticated-orcid":false,"given":"Alexander V.","family":"Cumming","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine","place":["Baltimore, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathaniel P.","family":"Nenortas","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine","place":["Baltimore, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Nenortas","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine","place":["Baltimore, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rahul P.","family":"Bakshi","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine","place":["Baltimore, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily R.","family":"Caton","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine","place":["Baltimore, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Estefany","family":"Rios-Guzman","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine","place":["Baltimore, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary E.","family":"Barry","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine","place":["Baltimore, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James C.","family":"Barrow","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Lieber Institute for Brain Development, The Johns Hopkins University School of Medicine","place":["Baltimore, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marikki","family":"Laiho","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine","place":["Baltimore, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6823-7536","authenticated-orcid":true,"given":"Theresa A.","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine","place":["Baltimore, USA"]},{"name":"Department of Physiology, Pharmacology and Therapeutics, The Johns Hopkins University School of Medicine","place":["Baltimore, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60829-1"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hcad273"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(25)00107-2"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(24)00581-4"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/cmr.00153-23"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(25)00016-6"},{"key":"e_1_3_5_8_2","unstructured":"Center for Drug Evaluation and Research US Food and Drug Administration. 2021. 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