Antimalarial 9-Anilinoacridine Compounds Directed atHematin

Auparakkitanon, Saranya; Noonpakdee, Wilai; Ralph, R.K.; Denny, William A.; Wilairat, Prapon

doi:10.1128/aac.47.12.3708-3712.2003

Cited by 50 publications

(41 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The most effective bis-acridines gave bioactivities comparable to those of the antimalarial drugs CQ and QA. These drugs are thought to act on P. falciparum by disrupting the storage of toxic heme as polymeric hematin (3,10,35). Given that the acridine heterocycle is a common structural feature of both QA and the bis-acridine compounds, it is conceivable that the present compounds operate via a similar mechanism.…”

Section: Discussionmentioning

confidence: 99%

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

Caffrey

Steverding

Swenerton

et al. 2007

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Caffrey

Steverding

Swenerton

et al. 2007

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…11 Given that both QA and compounds 6 share the acridine moiety as a central scaffold, it was conceivable that they operated via a similar mechanism. Thus, compounds 6 were evaluated in vitro as inhibitors of heme biocrystallization, by methods previously reported by us, [4][5][6] but none of them was found to be capable of inhibiting this process (data not shown).…”

Section: Introductionmentioning

confidence: 99%

In vitro efficiency of 9-(N-cinnamoylbutyl)aminoacridines against blood- and liver-stage malaria parasites

Pérez

Teixeira

Gomes

et al. 2013

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

a b s t r a c tNovel 9-aminoacridine derivatives were synthesized by linking the heteroaromatic core to different cinnamic acids through an aminobutyl chain. The test compounds demonstrated mid-nanomolar in vitro activity against erythrocytic stages of the chloroquine-resistant W2 strain of the human malaria parasite Plasmodium falciparum. Two of the most active derivatives also showed in vitro activity against liver-stage Plasmodium berghei, with activity greater than that of the reference liver-stage antimalarial primaquine.The compounds were not toxic to human hepatoma cells at concentrations up to 5 lM. Hence, 9-(N-cinnamoylbutyl)aminoacridines are a new class of leads for prevention and treatment of malaria.

show abstract

“…FP (15 M, final concentration) was diluted in 10 mM sodium phosphate buffer, pH 6.0, containing 40% dimethyl sulfoxide (DMSO) (binding buffer) alone or in the presence of increasing concentrations of the compounds (1 to 200 M) and absorption spectra were recorded after 2 min (21). In parallel, the spectral changes were determined by a continuous-variation technique (Job's plot) (1). Solutions containing different drug/FP (molar) combinations were prepared.…”

mentioning

confidence: 99%

Novel Antimalarial Aminoquinolines: Heme Binding and Effects on Normal or Plasmodium falciparum -Parasitized Human Erythrocytes

Omodeo‐Salè¹,

Cortelezzi²,

Basilico³

et al. 2009

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Two new quinolizidinyl-alkyl derivatives of 7-chloro-4-aminoquinoline, named AM-1 and AP4b, which are highly effective in vitro against both the D10 (chloroquine [CQ] susceptible) and W2 (CQ resistant) strains of Plasmodium falciparum and in vivo in the rodent malaria model, have been studied for their ability to bind to and be internalized by normal or parasitized human red blood cells (RBC) and for their effects on RBC membrane stability. In addition, an analysis of the heme binding properties of these compounds and of their ability to inhibit beta-hematin formation in vitro has been performed. Binding of AM1 or AP4b to RBC is rapid, dose dependent, and linearly related to RBC density. Their accumulation in parasitized RBC (pRBC) is increased twofold compared to levels in normal RBC. Binding of AM1 or AP4b to both normal and pRBC is higher than that of CQ, in agreement with the lower pK a and higher lipophilicity of the compounds. AM1 or AP4b is not hemolytic per se and is less hemolytic than CQ when hemolysis is accelerated (induced) by hematin. Moreover, AM-1 and AP4b bind heme with a stoichiometry of interaction similar to that of CQ (about 1:1.7) but with a lower affinity. They both inhibit dose dependently the formation of beta-hematin in vitro with a 50% inhibitory concentration comparable to that of CQ. Taken together, these results suggest that the antimalarial activity of AM1 or AP4b is likely due to inhibition of hemozoin formation and that the efficacy of these compounds against the CQ-resistant strains can be ascribed to their hydrophobicity and capacity to accumulate in the vacuolar lipid (elevated lipid accumulation ratios).Chloroquine (CQ) has been effectively used for decades as an antimalarial drug for its efficacy, safety, and stability but is now largely ineffective because of widespread parasite resistance. This has led to the necessity of utilizing artemisininbased combination therapy as a first-line treatment for uncomplicated malaria (20). However, the recent reports of artemisinin-based combination therapy treatment failure in southeast Asia and the potential emergence of artemisinin resistance (26) indicate that the search for new drugs or new drug combinations is still highly necessary (40, 41). Quinolinetype antimalarials remain an attractive class of compounds because their mechanism of action and resistance are unrelated (14) and resistance has emerged very slowly over time. CQ and quinoline antimalarial drugs are thought to kill parasites by inhibiting the process of crystallization necessary to detoxify ferriprotoporphyrin IX (FP) into hemozoin (HZ) (5,30,34). This process is vital for Plasmodium falciparum and can be reproduced in vitro with hematin under acidic conditions, leading to the formation of beta-hematin (BH), a crystal product showing physicochemical properties identical to those of HZ (29).FP in the food vacuole of the parasite is considered the target of quinoline antimalarials (6, 15). The inhibition of HZ formation leads to the accumulation of free FP, potentially...

show abstract

Antimalarial 9-Anilinoacridine Compounds Directed atHematin

Cited by 50 publications

References 33 publications

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

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

In vitro efficiency of 9-(N-cinnamoylbutyl)aminoacridines against blood- and liver-stage malaria parasites

Novel Antimalarial Aminoquinolines: Heme Binding and Effects on Normal or Plasmodium falciparum -Parasitized Human Erythrocytes

Contact Info

Product

Resources

About