Susceptibility of Plasmodium falciparum to five drugs: an in vitro study of isolates mainly from Thailand

Thaithong, Sodsri; Beale, G. H.; Chutmongkonkul, M.

doi:10.1016/0035-9203(83)90080-9

Cited by 119 publications

(44 citation statements)

References 12 publications

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“…In vitro activity against erythrocytic stages of P. falciparum was determined by a [ 3 H]hypoxanthine incorporation assay (21,29) using the chloroquine-and pyrimethamine-resistant strain K1, which originated from Thailand (41), and the standard drug chloroquine (C6628; Sigma). Compounds were dissolved in dimethyl sulfoxide at 10 mg/ml and were added to parasite cultures incubated in RPMI 1640 medium without hypoxanthine, supplemented with HEPES (5.94 g/liter), NaHCO 3 (2.1 g/liter), neomycin (100 U/ml), Albumax (5 g/liter), and washed A ϩ human red blood cells (RBC) at 2.5% hematocrit (0.3% parasitemia).…”

Section: Methodsmentioning

confidence: 99%

Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

Dardonville

Fernandez-Fernandez

Gibbons

et al. 2009

Antimicrob Agents Chemother

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A series of 44 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum). This screening identified 29 molecules selectively active against bloodstream-form T. b. rhodesiense trypomastigotes, with 50% inhibitory concentrations (IC 50 ) ranging from 0.12 to 10 M, and 33 compounds active against the chloroquine-and pyrimethamine-resistant K1 strain of P. falciparum (IC 50 range, 0.17 to 5 M). In addition, seven compounds displayed activity against intracellular T. cruzi amastigotes in the same range as the reference drug benznidazole (IC 50 , 1.97 M) but were also cytotoxic to L-6 cells, showing little selectivity for T. cruzi. None of the molecules tested showed interesting antileishmanial activity against axenic amastigotes of L. donovani. To our knowledge, this is the first report of the antitrypanosomal activity of molecules bearing the 4-aminopiperidine skeleton.Tropical diseases due to parasitic protozoa cause great mortality and disability in the less developed world. Malaria and kinetoplastid diseases such as human African trypanosomiasis (HAT, or sleeping sickness), Chagas' disease, and leishmaniases are among the main neglected parasitic diseases, affecting hundreds of millions of people worldwide (http://www.dndi.org /index.php/diseases.html?idsϭ2). However, the low income of the affected populations does not make it financially attractive for pharmaceutical companies to invest in the development of new drugs against these diseases. The number of antiprotozoal drugs available is limited, and they are old, toxic, and losing efficacy due to the emergence of resistant parasites. New drugs are thus urgently needed (37).The landscape of drug discovery and development for new antiparasitic drugs has changed in the past few years thanks to financial backing from not-for-profit organizations and the involvement of public-private partnerships. The collaboration of various pharmaceutical companies with the Special Programme for Research and Training in Tropical Diseases (TDR), giving access to their compound libraries to help scientists search for new antiparasitic drugs, is a good example of the pragmatic approach required for the development of new medicaments for those neglected diseases (15,32,40). The screening of compound libraries to discover new hit and lead compounds against protozoan parasites has been used very efficiently by our group for the past few years. Very potent antiprotozoal compounds, active in vitro and in vivo against Trypanosoma brucei rhodesiense and Plasmodium falciparum, were identified by our group (16,17,38). These lead compounds were discovered by screening against T. brucei and P. falciparum a small library (Ͻ100 molecules) of dicationic compounds structurally related to known antiparasitic drugs (e.g., pentamidine, diminazene) but primarily synthesized by us for different medicinal targets.Following this successful approach, we have now selected from our i...

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Section: Methodsmentioning

confidence: 99%

Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

Dardonville

Fernandez-Fernandez

Gibbons

et al. 2009

Antimicrob Agents Chemother

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“…Activity against Plasmodium falciparum In vitro activity against erythrocytic stages of P. falciparum was determined using a 3 H-hypoxanthine incorporation assay, 40,41) using the chloroquine and pyrimethamine resistant P. falciparum K1 strain that originate from Thailand (Thaitong et al) 42) and strain susceptible to known antimalarial drugs (P. falciparum NF54) (Ponnudurai et al), 31) and all the test compounds were compared for activity with the standard drug chloroquine (Sigma C6628). Compounds were dissolved in dimethyl sulfoxide (DMSO) at 10 mg/mL and added to parasite cultures incubated in RPMI 1640 medium without hypoxanthine, supplemented with N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic acid (HEPES) (5.94 g/L), NaHCO 3 (2.1 g/L), neomycin (100 U/mL), Albumax ® (5 g/L) and washed human red cells A + at 2.5% haematocrit (0.3% parasitaemia).…”

Section: Pharmacologymentioning

confidence: 99%

Synthesis and <i>in Vitro</i> Testing of Antimalarial Activity of Non-natural-Type Neocryptolepines: Structure–Activity Relationship Study of 2,11- and 9,11-Disubstituted 6-Methylindolo[2,3-<i>b</i>]quinolines

et al. 2013

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This report describes the synthesis and in vitro anti-malarial evaluations of certain C2 or C8 and C11-disubstituted 6-methyl-5H-indolo[2,3-b]quinoline (neocryptolepine congener) derivatives. To attain higher activities, the structure-activity relationship (SAR) studies were conducted by varying the kind of alkylamino or ω-aminoalkylamino stubstituents at C11 and with Cl at the C2 position, or CO 2 Me at the C9 position. The anti-malarial activities of the tested compounds were significantly increased compared to the 11-non(alkylamino) derivatives. The 3-aminopropylamino group at C11 was further modified to urea and thiourea, which improved the cytotoxicity against normal cells. The best results were achieved with compounds 8 and 9d against the NF54 strain with the IC 50 /SI values as of 86 nM/20 and 317 nM/370, respectively. Furthermore, the compounds were tested for β-haematin inhibition. Twelve were found to have IC 50 values below 100 µM and a linear correlation between the β-haematin inhibition and cell growth inhibition in the NF54 strain was found for those derivatives with basic amino side chains. A second correlation was identified between the NF54 activity and physico-chemical factors related to solvation and polarity.

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“…MATERIALS AND METHODS P. falciparum strain. A chloroquine-resistant strain (K-1) of P. falciparum, which was originally obtained from Thailand (14) and has been cryopreserved at the London School of Hygiene and Tropical Medicine, was used throughout.…”

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confidence: 99%

Plants as sources of antimalarial drugs: in vitro antimalarial activities of some quassinoids

O’Neill¹,

Bray²,

Boardman³

et al. 1986

Antimicrob Agents Chemother

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Fourteen quassinoids, obtained from simaroubaceous plants, were tested for in vitro antimalarial activity. All of these inhibited the incorporation of [3H]hypoxanthine into Plasmodium falciparum in vitro at concentrations below 0.41 ,Ig ml-'. The two most potent quassinoids, bruceantin and simalikalactone D, showed 50% inhibitory concentration values of 0.0008 and 0.0009 ,ug ml-1, respectively. The results are compared with the antiamoebic, antileukemic, and cytotoxic activities of these compounds reported in the literature.In the 1960s, the appearance in Southeast Asia and South America of strains of Plasmodium falciparum showing resistance to chloroquine heralded the need for alternative antiplasmodial therapy. Several hundreds of millions of people suffer from malaria, and all currently used antimalarial drugs now show limitations in their spectra of activity (17). Resistance of P. falciparum to available antimalarial drugs is an increasing world problem (10). Therefore, it is crucial that mechanistically novel antimalarial agents be added to our chemotherapeutic armamentarium as soon as possible.Certain quassinoids, obtained from simaroubaceous plants, are known to possess a variety of biological activities, including antitumor (13), antiviral (11), antifeedant (12), antiamoebic (5), and antiinflammatory (7) activities. More recently, some of these compounds, namely, bruceantin (6), simalikalactone D (16), glaucarubinone (16), soularubinone (16), and sergeolide (4), have been found to show high activity against P. falciparum in vitro. Sergeolide also markedly reduces virulence of experimentally induced P. berghei in mice (4); however, it unfortunately also shows high toxicity. In our present study, we monitored the in vitro anti-P. falciparum activities of a series of 14 quassinoids which were made available from isolations performed under the auspices of the National Cancer Institute, Bethesda, Md. Our results are considered in the light of published data for other biological activities of these quassinoids.(This report is part 2 of a study on plants as sources of antimalarial drugs. For part 1, see reference 9.) (This work was presented in part at the 122nd Annual British Pharmaceutical Conference, Leeds, United Kingdom, 1985.) MATERIALS AND METHODS P. falciparum strain. A chloroquine-resistant strain (K-1) of P. falciparum, which was originally obtained from Thailand (14) and has been cryopreserved at the London School of Hygiene and Tropical Medicine, was used throughout.Maintenance of cultures. Cultures of P. falciparum were maintained in vitro in human blood cells (O+ve) was achieved with 12 2-fold dilutions at concentrations around the range of the value obtained by 10-fold dilutions. All tests were performed in duplicate. To each well was added 50 ptl of human erythrocytes (O+ve, diluted to 5% hematocrit) with 1% parasitemia (dilutions to 1% parasitemia were made with uninfected washed erythrocytes). Two series of controls were performed, one with parasitized blood without quassinoid and anothe...

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Susceptibility of Plasmodium falciparum to five drugs: an in vitro study of isolates mainly from Thailand

Cited by 119 publications

References 12 publications

Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

Synthesis and <i>in Vitro</i> Testing of Antimalarial Activity of Non-natural-Type Neocryptolepines: Structure–Activity Relationship Study of 2,11- and 9,11-Disubstituted 6-Methylindolo[2,3-<i>b</i>]quinolines

Plants as sources of antimalarial drugs: in vitro antimalarial activities of some quassinoids

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