Synthesis and Evaluation of 1‐Amino‐6‐halo‐β‐carbolines as Antimalarial and Antiprion Agents
Mark J. ThompsonJennifer LouthSusan LittleMatthew P. JacksonYohan BoursereauBeining ChenIain Coldham
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Abstract Malaria is one of the world’s most devastating parasitic diseases, causing almost one million deaths each year. Growing resistance to classical antimalarial drugs, such as chloroquine, necessitates the discovery of new therapeutic agents for successful control of this global disease. Here, we report the synthesis of some 6‐halo‐β‐carbolines as analogues of the potent antimalarial natural product, manzamine A, retaining its heteroaromatic core whilst providing compounds with much improved synthetic accessibility. Two compounds displayed superior activity to chloroquine itself against a resistant Plasmodium falciparum strain, identifying them as promising leads for future development. Furthermore, in line with previous reports of similarities in antimalarial and antiprion effects of aminoaryl‐based antimalarial agents, the 1‐amino‐β‐carboline libraries were also found to possess significant bioactivity against a prion‐infected cell line.Keywords:
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The response in vitro of Plasmodium falciparum to chloroquine, mefloquine and quinine was studied in a hyperendemic peri-urban area of Accra, Ghana, during the fourth quarter of 1991, yielding a total of 159 valid tests. Schizont maturation in drug-free controls and effective chloroquine concentrations were strongly correlated. This was not seen with mefloquine or quinine. Higher mean parasitaemia in untreated oligo-symptomatic carriers of overtly chloroquine-resistant P. falciparum than in carriers of more sensitive parasites was another indication of higher viability and biological advantage of chloroquine-resistant P. falciparum that may conceivably have clinical implications.
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The antimalarial activity of four chloroquine derivatives has been assessed in vitro by the Trager and Jensen technique against the strain of Plasmodium falciparum FCC, 2spp. Monodesethyl-chloroquine possessed a significant activity, reducing the parasitaemia to 5% with 2 nM ml−1 (base). The hydroxy-metabolite showed a slight activity, reducing the parasitaemia to 39·5% with 2 nM ml−1 (base). No activity was found with the amino-metabolite and the pyrrolidinyl chemical derivative. The antimalarial activity of monodesethyl-chloroquine should be considered for pharmacokinetics and for optimizing chloroquine treatments.
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Polymorphism in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report, we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3-bromo, and 3-iodo) against chloroquine-susceptible and -resistant P. falciparum. All three derivatives inhibited the proliferation of P. falciparum; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistant P. falciparum.
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A 48 h in vitro test was conducted to compare the susceptibility of two strains of Plasmodium falciparum to chloroquine, the two enantiomers of chloroquine, desethylchloroquine and the new antimalarial drug pyronaridine. The five compounds similarly inhibited the chloroquine sensitive strain. However, desethylchloroquine was less active and pyronaridine was much more active than chloroquine and its enantiomers against the chloroquine resistant strain.
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A series of 3-amino- and polyaminosterol analogues of squalamine and trodusquemine were evaluated for their in vitro antimalarial properties against chloroquine-susceptible and -resistant Plasmodium falciparum. These derivatives were designed possessing a good therapeutic index compared to chloroquine with IC50 varying from 2 to 22 μM. These compounds as well as the underlying design rationale may find usefulness in the discovery and development of new antimalarial drugs. Keywords: Squalamine, Trodusquemine, Aminosterol derivatives, Antimalarial activity
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With the test in vivo and the bleeding dosage of chloroquine, authors report the rate of resistance of chloroquine to Plasmodium falciparum. 2.3% of Plasmodium falciparum in Kinshasa are resistant to chloroquine.
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Glucose stimulates the high-affinity processes of chloroquine and amodiaquin accumulation in owl monkey erythrocytes infected with a chloroquine-susceptible strain of Plasmodium falciparum . Although these erythrocytes have greater ability to accumulate amodiaquin than chloroquine, glucose has relatively less effect on amodiaquin accumulation than on chloroquine accumulation. In contrast to these findings with chloroquine-susceptible P. falciparum , glucose stimulates amodiaquin but not chloroquine accumulation in erythrocytes infected with chloroquine-resistant P. falciparum . This lack of function of a substrate-dependent component of chloroquine accumulation distinguishes chloroquine-resistant from chloroquine-susceptible P. falciparum .
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