{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T16:49:31Z","timestamp":1761929371922},"reference-count":41,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2009,1,1]],"date-time":"2009-01-01T00:00:00Z","timestamp":1230768000000},"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":[[2009,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>African trypanosomiasis (sleeping sickness), caused by protozoan<jats:italic>Trypanosoma brucei<\/jats:italic>species, is a debilitating disease that is lethal if untreated. Available drugs are antiquated, toxic, and compromised by emerging resistance. The indenoisoquinolines are a class of noncamptothecin topoisomerase IB poisons that are under development as anticancer agents. We tested a variety of indenoisoquinolines for their ability to kill<jats:italic>T. brucei<\/jats:italic>. Indenoisoquinolines proved trypanocidal at submicromolar concentrations in vitro. Structure-activity analysis yielded motifs that enhanced potency, including alkylamino substitutions on N-6, methoxy groups on C-2 and C-3, and a methylenedioxy bridge between C-8 and C-9. Detailed analysis of eight water-soluble indenoisoquinolines demonstrated that in trypanosomes the compounds inhibited DNA synthesis and acted as topoisomerase poisons. Testing these compounds on L1210 mouse leukemia cells revealed that all eight were more effective against trypanosomes than against mammalian cells. In preliminary in vivo experiments one compound delayed parasitemia and extended survival in mice subjected to a lethal trypanosome challenge. The indenoisoquinolines provide a promising lead for the development of drugs against sleeping sickness.<\/jats:p>","DOI":"10.1128\/aac.00650-07","type":"journal-article","created":{"date-parts":[[2008,9,30]],"date-time":"2008-09-30T00:54:41Z","timestamp":1222736081000},"page":"123-128","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["Activity of Indenoisoquinolines against African Trypanosomes"],"prefix":"10.1128","volume":"53","author":[{"given":"Rahul P.","family":"Bakshi","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongpei","family":"Sang","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Morrell","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Cushman","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theresa A.","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"10397","DOI":"10.1158\/0008-5472.CAN-07-0938","volume":"67","year":"2007","unstructured":"Antony, S., K. 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