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Antimicrobial Agents and Chemotherapy, January 2009, p. 123-128, Vol. 53, No. 1
0066-4804/09/$08.00+0     doi:10.1128/AAC.00650-07
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Activity of Indenoisoquinolines against African Trypanosomes{triangledown}

Rahul P. Bakshi,1 Dongpei Sang,1 Andrew Morrell,2 Mark Cushman,2 and Theresa A. Shapiro1*

Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,1 Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue Cancer Center, Purdue University, West Lafayette, Indiana 479072

Received 17 May 2007/ Returned for modification 26 August 2007/ Accepted 21 September 2008

African trypanosomiasis (sleeping sickness), caused by protozoan Trypanosoma brucei 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 T. brucei. 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.

* Corresponding author. Mailing address: Johns Hopkins University School of Medicine, 301 Hunterian Building, 725 N. Wolfe Street, Baltimore, MD 21205. Phone: (410) 955-1889. Fax: (410) 955-2634. E-mail: rbakshi{at}jhmi.edu

{triangledown} Published ahead of print on 29 September 2008.

Antimicrobial Agents and Chemotherapy, January 2009, p. 123-128, Vol. 53, No. 1
0066-4804/09/$08.00+0     doi:10.1128/AAC.00650-07
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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