Sensitivity of Plasmodium falciparum field-isolates from Tanzania to chloroquine, mefloquine and pyrimethamine during in vitro cultivation

216

119

We have synthesized several 4-aminoquinolines with shortened side chains that retain activity against chloroquine-resistant isolates of Plasmodium falciparum malaria (W. Hofheinz, C. Jaquet, and S. Jolidon, European patent 94116281.0, June 1995). We report here an assessment of the activities of four selected compounds containing ethyl, propyl, and isopropyl side chains. Reasonable in vitro activity (50% inhibitory concentration, < 100 nM) against chloroquine-resistant P. falciparum strains was consistently observed, and the compounds performed well in a variety of plasmodium berghei animal models. However, some potential drawbacks of these compounds became evident upon in-depth testing. In vitro analysis of more than 70 isolates of P. falciparum and studies with a mouse in vivo model suggested a degree of cross-resistance with chloroquine. In addition, pharmacokinetic analysis demonstrated the formation of N-dealkylated metabolites of these compounds. These metabolites are similarly active against chloroquine-susceptible strains but are much less active against chloroquine-resistant strains. Thus, the clinical dosing required for these compounds would probably be greater for chloroquine-resistant strains than for chloroquine-susceptible strains. The clinical potential of these compounds is discussed within the context of chloroquine's low therapeutic ratio and toxicity.

Section: Resultsmentioning

confidence: 99%

Section: Consentmentioning

confidence: 99%

4-aminoquinoline analogs of chloroquine with shortened side chains retain activity against chloroquine-resistant Plasmodium falciparum

Ridley

Hofheinz

Matile

et al. 1996

216

119

“…Other standard strains tested were (i) the chloroquine-sensitive strains FCH-5-C2 (clone of FCH-5; Tanzania), HB3 (Honduras; resistant to pyrimethamine), RF MEF3 (a laboratory strain made resistant to mefloquine), and Ro73 (Kenya) and (ii) the chloroquineresistant strains RFCR-3 (The Gambia), ItG2F6 (Brazil), INDO (Indochina), W2 (Indochina), W2MEF (a mefloquine-resistant line derived from W2), 7G8 (Brazil), and T9/94 (Thailand). In addition, 32 isolates from Thailand (20) and 33 isolates from Tanzania (8,20) were also tested. The Thai strains tested were T116, T120, TD378, TD379, TD380, TD381, TD385, TD386, TD388, TM01, TM02, TM03, TM04, TM05, TM06, TM08, TM19, TM20, TM25, TM28, TM41, TM43, TM52, TM53, TM56, TM57, TM58, TM62, TM67, TM69, and TM79.…”

Section: Methodsmentioning

confidence: 99%

Antimalarial activity of the bisquinoline trans-N1,N2-bis (7-chloroquinolin-4-yl)cyclohexane-1,2-diamine: comparison of two stereoisomers and detailed evaluation of the S,S enantiomer, Ro 47-7737

Ridley

Matile

Jaquet

et al. 1997

The S,S enantiomer of the bisquinoline trans-N1,N2-bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamine, Ro 47-7737, is significantly more potent against chloroquine-resistant Plasmodium falciparum than the R,R enantiomer and the previously described racemate. Both the enantiomers and the racemate are more potent inhibitors of heme polymerization than chloroquine, and their activities are probably mediated by inhibition of this parasite-specific process. The S,S enantiomer, Ro 47-7737, was studied in more detail and proved to be a potent antimalarial in the treatment of P. vivax ex vivo and P. berghei in vivo. Its suppression of P. berghei growth in a mouse model (50% effective dose, 2.3 mg/kg of body weight) was equal to that of chloroquine and mefloquine, and Ro 47-7737 was found to be more potent than these two drugs in the Rane test, in which the curative effect of a single dose is monitored. The dose at which 50% of animals were permanently cured (34 mg/kg) was markedly superior to those of chloroquine (285 mg/kg) and mefloquine (> 250 mg/kg). When administered orally at 50 mg/kg, Ro 47-7737 also showed a faster clearance of parasites than either chloroquine or mefloquine, and unlike the other two compounds, Ro 47-7737 showed no recrudescence. In a study to compare prophylactic efficacies of oral doses of 50 mg/kg, Ro 47-7737 provided protection for 14 days compared to 3 days for mefloquine and 1 day for chloroquine. The good curative and prophylactic properties of the compound can be explained in part by its long terminal half-life. The ability to generate parasite resistance to Ro 47-7737 was also assessed. With a rodent model, resistance could be generated over eight passages. This rate of resistance generation is comparable to that of mefloquine, which has proved to be an effective antimalarial for many years. Toxicity liabilities, however, ruled out this compound as a candidate for drug development.

“…The radioactivity was counted using a Betaplate liquid scintillation counter (Wallac, Zürich), and the results were recorded as counts per minute (cpm) per well at each drug concentration and expressed as a percentage of the untreated controls. Fifty percent inhibitory concentrations (IC 50 ) were estimated by linear interpolation (13).…”

Section: Methodsmentioning

confidence: 99%

In Vitro and In Vivo Activity of Solithromycin (CEM-101) against Plasmodium Species

Wittlin

Ekland

Craft

et al. 2012

With the emergence of Plasmodium falciparum infections exhibiting increased parasite clearance times in response to treatment with artemisinin-based combination therapies, the need for new therapeutic agents is urgent. Solithromycin, a potent new fluoroketolide currently in development, has been shown to be an effective, broad-spectrum antimicrobial agent. Malarial parasites possess an unusual organelle, termed the apicoplast, which carries a cryptic genome of prokaryotic origin that encodes its own translation and transcription machinery. Given the similarity of apicoplast and bacterial ribosomes, we have examined solithromycin for antimalarial activity. Other antibiotics known to target the apicoplast, such as the macrolide azithromycin, demonstrate a delayed-death effect, whereby treated asexual blood-stage parasites die in the second generation of drug exposure. Solithromycin demonstrated potent in vitro activity against the NF54 strain of P. falciparum, as well as against two multidrugresistant strains, Dd2 and 7G8. The dramatic increase in potency observed after two generations of exposure suggests that it targets the apicoplast. Solithromycin also retained potency against azithromycin-resistant parasites derived from Dd2 and 7G8, although these lines did demonstrate a degree of cross-resistance. In an in vivo model of P. berghei infection in mice, solithromycin demonstrated a 100% cure rate when administered as a dosage regimen of four doses of 100 mg/kg of body weight, the same dose required for artesunate or chloroquine to achieve 100% cure rates in this rodent malaria model. These promising in vitro and in vivo data support further investigations into the development of solithromycin as an antimalarial agent.