{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:17:12Z","timestamp":1792455432719,"version":"4.5.0"},"reference-count":64,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2024,9,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:italic>Babesia<\/jats:italic>\n                      and\n                      <jats:italic>Plasmodium<\/jats:italic>\n                      pathogens, the causative agents of babesiosis and malaria, are vector-borne intraerythrocytic protozoan parasites, posing significant threats to both human and animal health. The widespread resistance exhibited by these pathogens to various classes of antiparasitic drugs underscores the need for the development of novel and more effective therapeutic strategies. Antifolates have long been recognized as attractive antiparasitic drugs as they target the folate pathway, which is essential for the biosynthesis of purines and pyrimidines, and thus is vital for the survival and proliferation of protozoan parasites. More efficacious and safer analogs within this class are needed to overcome challenges due to resistance to commonly used antifolates, such as pyrimethamine, and to address liabilities associated with the dihydrotriazines, WR99210 and JPC-2067. Here, we utilized an\n                      <jats:italic>in vitro<\/jats:italic>\n                      culture condition suitable for the continuous propagation of\n                      <jats:italic>Babesia duncani, Babesia divergens, Babesia MO1,<\/jats:italic>\n                      and\n                      <jats:italic>Plasmodium falciparum<\/jats:italic>\n                      in human erythrocytes to screen a library of 50 dihydrotriazines and 29 biguanides for their efficacy\n                      <jats:italic>in vitro<\/jats:italic>\n                      and compared their potency and therapeutic indices across different species and isolates. We identified nine analogs that inhibit the growth of all species, including the\n                      <jats:italic>P. falciparum<\/jats:italic>\n                      pyrimethamine-resistant strain HB3, with IC\n                      <jats:sub>50<\/jats:sub>\n                      values below 10 nM, and display excellent\n                      <jats:italic>in vitro<\/jats:italic>\n                      therapeutic indices. These compounds hold substantial promise as lead antifolates for further development as broad-spectrum antiparasitic drugs.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00423-24","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T09:02:24Z","timestamp":1723539744000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["<i>In vitro<\/i>\n                    efficacy of next-generation dihydrotriazines and biguanides against babesiosis and malaria parasites"],"prefix":"10.1128","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4944-6006","authenticated-orcid":false,"given":"Pratap","family":"Vydyam","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (Section of Infectious Diseases), Microbial Pathogenesis, and Pathology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenal","family":"Chand","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine (Section of Infectious Diseases), Microbial Pathogenesis, and Pathology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalev","family":"Gihaz","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine (Section of Infectious Diseases), Microbial Pathogenesis, and Pathology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaline","family":"Renard","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine (Section of Infectious Diseases), Microbial Pathogenesis, and Pathology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin D.","family":"Heffernan","sequence":"additional","affiliation":[{"name":"Jacobus Pharmaceutical Company Inc., Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura R.","family":"Jacobus","sequence":"additional","affiliation":[{"name":"Jacobus Pharmaceutical Company Inc., Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David P.","family":"Jacobus","sequence":"additional","affiliation":[{"name":"Jacobus Pharmaceutical Company Inc., Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt W.","family":"Saionz","sequence":"additional","affiliation":[{"name":"Jacobus Pharmaceutical Company Inc., Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raju","family":"Shah","sequence":"additional","affiliation":[{"name":"Jacobus Pharmaceutical Company Inc., Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Ming","family":"Shieh","sequence":"additional","affiliation":[{"name":"Jacobus Pharmaceutical Company Inc., Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacek","family":"Terpinski","sequence":"additional","affiliation":[{"name":"Jacobus Pharmaceutical Company Inc., Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Jacobus Pharmaceutical Company Inc., Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Cornillot","sequence":"additional","affiliation":[{"name":"Institut de Biologie Computationnelle (IBC), and Institut de Recherche en Canc\u00e9rologie de Montpellier (IRCM - INSERM U1194), Institut r\u00e9gional du Cancer Montpellier (ICM) &amp; Universit\u00e9 de Montpellier, Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5028-1400","authenticated-orcid":true,"given":"Choukri","family":"Ben Mamoun","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine (Section of Infectious Diseases), Microbial Pathogenesis, and Pathology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"World malaria report 2023","author":"World Health O","year":"2023","unstructured":"World Health O. 2023. 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