Bis-acridines as lead anti-parasitic agents: structure activity analysis of a discrete compound library in vitro

Caffrey, Conor R., Steverding, Dietmar, Swenerton, Ryan K., Kelly, Ben, Walshe, Deirdre, Debnath, Anjan, Zhou, Yuan-Min, Doyle, Patricia S., Fafarman, Aaron T., Zorn, Julie A., Land, Kirkwood M., Beauchene, Jessica, Schreiber, Kimberly, Moll, Heidrun, Ponte-Sucre, Alicia, Schirmeister, Tanja, Saravanamuthu, Ahilan, Fairlamb, Alan H., Cohen, Fred E., McKerrow, James H., Weisman, Jennifer L. and May, Barnaby C. H. (2007) Bis-acridines as lead anti-parasitic agents: structure activity analysis of a discrete compound library in vitro. Antimicrobial Agents and Chemotherapy, 51 (6). pp. 2164-2172. ISSN 0066-4804

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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 A. 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 (EC(50)) 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 EC(50) 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.

Item Type: Article
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Depositing User: EPrints Services
Date Deposited: 25 Nov 2010 11:13
Last Modified: 24 Oct 2022 01:17
DOI: 10.1128/AAC.01418-06

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