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

Abstract

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 bisacridine 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 (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.

Cytotoxic and trypanocidal activities of cinchona alkaloid derivatives

“…Interestingly, these two compounds were among the four derivatives that were highly active against the six cancer cell lines (see Table ). The selectivity of the cinchona alkaloid derivatives was determined with human leukaemia HL‐60 cells because their sensitivity for approved trypanocides is well established . Most compounds including the unmodified cinchona alkaloids showed no cytotoxicity against HL‐60 cells (Table ).…”

“…As the most trypanocidal compounds 2e and 3d were also quite cytotoxic for HL‐60 cells, their SI were only moderate (just below 10) (Table ). For comparison, drugs used for treatment of sleeping sickness have much higher SIs . For example, the reference drug suramin displayed no cytotoxicity towards HL‐60 cell and accordingly the MIC and GI 50 ratios of this trypanocide were >1,000 and >2,941, respectively (Table ).…”

New 9-aminoacridine derivatives as inhibitors of Botulinum neurotoxins and P. falciparum malaria

“…In a β-hematin inhibitory assay (BHIA), it was found that ACR derivatives formed complexes with hematin in a 3:2 molar ratio (hematin:drug). 45 However, chimeric derivatives with ART 46 or AQ, 47 as well as bis-ACR derivatives, 39,48 showed poor activities. It was also discovered that ACRs inhibit DNA topoisomerase II, 39,43 parasite folate metabolism 44 and plasmepsin II.…”

Two approaches to discovering and developing new drugs for Chagas disease

“…Multiple protease inhibitors of different scaffolds and catalytic mechanisms show activity against parasites in culture and in animal models of disease (Engel et al 1998a, Du et al 2002, Greenbaum et al 2004, Fujii et al 2005, Caffrey et al 2007, Brak et al 2008, Fricker et al 2008, McKerrow et al 2008). While gene knockout of cruzain was not achieved (presumably due to lethality), over-expression of cruzain in the parasite led to enhanced metacyclogenesis (Tomás et al 1997).…”