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Antimicrobial Agents and Chemotherapy, June 2007, p. 2164-2172, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01418-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Bis-Acridines as Lead Antiparasitic Agents: Structure-Activity Analysis of a Discrete Compound Library In Vitro{triangledown}

Conor R. Caffrey,1* Dietmar Steverding,2,{dagger} Ryan K. Swenerton,1 Ben Kelly,1 Deirdre Walshe,1 Anjan Debnath,1 Yuan-Min Zhou,1 Patricia S. Doyle,1 Aaron T. Fafarman,3 Julie A. Zorn,3 Kirkwood M. Land,4 Jessica Beauchene,4 Kimberly Schreiber,4 Heidrun Moll,5 Alicia Ponte-Sucre,5,6 Tanja Schirmeister,7 Ahilan Saravanamuthu,8 Alan H. Fairlamb,8 Fred E. Cohen,9 James H. McKerrow,1 Jennifer L. Weisman,3 and Barnaby C. H. May9

Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, 1700 4th Street, San Francisco, California 94158-2330,1 School of Biological Sciences, University of Bristol, Woodland Road, Bristol BS8 1UG, United Kingdom,2 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 1700 4th Street, San Francisco, California 94158-2330,3 Department of Biological Sciences, University of the Pacific, Stockton, California 95211,4 Institute for Molecular Infection Biology, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany,5 Laboratory of Molecular Physiology, Universidad Central de Venezuela, Apdo. 68256, Caracas 1062-A, Venezuela,6 Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany,7 Division of Biological Chemistry and Molecular Biology, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, DD1 5EH Scotland, United Kingdom,8 Institute for Neurodegenerative Diseases and Department of Neurology, University of California, San Francisco, 513 Parnassus Ave., San Francisco, California 94143-05189

Received 13 November 2006/ Returned for modification 28 January 2007/ Accepted 12 March 2007

Parasitic diseases are of enormous public health significance in developing countries—a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bis-acridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 Å. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC50) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low- to mid-nanomolar EC50 values against Plasmodium falciparum and Trypanosoma brucei; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent of P. falciparum resistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent useful starting points for further lead optimization.

* Corresponding author. Mailing address: Sandler Center for Basic Research in Parasitic Diseases, BH508, University of California, San Francisco, 1700 4th Street, San Francisco, CA 94158-2330. Phone: (415) 502-6866. Fax: (415) 514-8193. E-mail: caffrey{at}cgl.ucsf.edu

{triangledown} Published ahead of print on 19 March 2007.

{dagger} Present address: Biomedical Research Centre, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich NR4 7TJ, United Kingdom.

Antimicrobial Agents and Chemotherapy, June 2007, p. 2164-2172, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01418-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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