Multinormal in vitro distribution of Plasmodium falciparum susceptibility to piperaquine and pyronaridine.

BACKGROUND: In 2002, the World Health Organization recommended that artemisinin-based combination therapy (ACT) be used to treat uncomplicated malaria. Dihydroartemisinin-piperaquine and artesunate-pyronaridine are two of these new combinations. The aim of the present work was to assess the distribution of the in vitro values of pyronaridine (PND) and piperaquine (PPQ) and to define a cut-off for reduced susceptibility for the two anti-malarial drugs. METHODS: The distribution and range of the 50% inhibitory concentration values (IC50) of PND and PPQ were determined for 313 isolates obtained between 2008 and 2012 from patients hospitalized in France for imported malaria. The statistical Bayesian analysis was designed to answer the specific question of whether Plasmodium falciparum has different phenotypes of susceptibility to PND and PPQ. RESULTS: The PND IC50 values ranged from 0.6 to 84.6 nM, with a geometric mean of 21.1 ± 16.0 nM (standard deviation). These values were classified into three components. The PPQ IC50 values ranged from 9.8 to 217.3 nM, and the geometric mean was 58.0 ± 34.5 nM. All 313 PPQ values were classified into four components. Isolates with IC50 values greater than 60 nM or four-fold greater than 3D7 IC50 are considered isolates that have reduced susceptibility to PND and those with IC50 values greater than 135 nM or 2.3-fold greater than 3D7 IC50 are considered isolates that have reduced susceptibility to PPQ. CONCLUSION: The existence of at least three phenotypes for PND and four phenotypes for PPQ was demonstrated. Based on the cut-off values, 18 isolates (5.8%) and 13 isolates (4.2%) demonstrated reduced susceptibility to PND and PPQ, respectively.

Metal-chloroquine derivatives as possible anti-malarial drugs: evaluation of anti-malarial activity and mode of action.

BACKGROUND: Malaria still has significant impacts on the world; particularly in Africa, South America and Asia where spread over several millions of people and is one of the major causes of death. When chloroquine diphosphate (CQDP) lost its efficiency as a first-line anti-malarial drug, this was a major setback in the effective control of malaria. Currently, malaria is treated with a combination of two or more drugs with different modes of action to provide an adequate cure rate and delay the development of resistance. Clearly, a new effective and non-toxic anti-malarial drug is urgently needed. METHODS: All metal-chloroquine (CQ) and metal-CQDP complexes were synthesized under N(2) using Schlenk techniques. Their interactions with haematin and the inhibition of ß-haematin formation were examined, in both aqueous medium and near water/n-octanol interfaces at pH 5. The anti-malarial activities of these metal- CQ and metal-CQDP complexes were evaluated in vitro against two strains, the CQ-susceptible strain (CQS) 3D7 and the CQ-resistant strain (CQR) W2. RESULTS: The previously synthesized Au(CQ)(Cl) (1), Au(CQ)(TaTg) (2), Pt(CQDP)(2)Cl(2) (3), Pt(CQDP)(2)I(2) (4), Pd(CQ)(2)Cl(2) (5) and the new one Pd(CQDP)(2)I(2) (6) showed better anti-malarial activity than CQ, against the CQS strain; moreover, complexes 2, 3 and 4 were very active against CQR strain. These complexes (1-6) interacted with haem and inhibited ß-haematin formation both in aqueous medium and near water/n-octanol interfaces at pH 5 to a greater extent than chloroquine diphosphate (CQDP) and other known metal-based anti-malarial agents. CONCLUSIONS: The high anti-malarial activity displayed for these metal-CQ and metal-CQDP complexes (1-6) could be attributable to their effective interaction with haem and the inhibition of ß-haematin formation in both aqueous medium and near water/n-octanol interfaces at pH 5.

1H-1,2,3-triazole tethered isatin-ferrocene conjugates: Synthesis and in vitro antimalarial evaluation.

1H-1,2,3-triazole tethered isatin-ferrocene conjugates were synthesized and evaluated for their antiplasmodial activities against chloroquine-susceptible (3D7) and chloroquine-resistant (W2) strains of Plasmodium falciparum. The conjugates 5f and 5h with an optimum combination of electron-withdrawing halogen substituent at C-5 position of isatin ring and a propyl chain, introduced as linker, proved to be most potent and non-cytotoxic among the series with IC50 values of 3.76 and 4.58 µM against 3D7 and W2 strains, respectively.

1H-1,2,3-triazole tethered mono- and bis-ferrocenylchalcone-ß-lactam conjugates: synthesis and antimalarial evaluation.

A series of ferrocenylchalcone-ß-lactam conjugates were synthesized and evaluated against 3D7 (CQ-Sensitive) and W2 (CQ-Resistant) strains of Plasmodium falciparum. The SAR studies revealed the dependence of activities at N-1 substituent of ß-lactam ring with compounds being more potent on resistant strain. The compound 9f and 9l with N-cyclohexyl substituent proved to be the most potent and non-cytotoxic among the series exhibiting IC50 values of 2.36 and 2.43 µM respectively, against W2 strain of P. falciparum.

In vitro piperaquine susceptibility is not associated with the Plasmodium falciparum chloroquine resistance transporter gene.

BACKGROUND: Dihydroartemisinin-piperaquine is a new ACT that is administered as single daily dose for three days and has been demonstrated to be tolerated and highly effective for the treatment of uncomplicated Plasmodium falciparum malaria. Piperaquine was used alone to replace chloroquine as the first-line treatment for uncomplicated malaria in China in response to increasing chloroquine resistance in the 1970s. However, the rapid emergence of piperaquine-resistant strains that resulted in the cessation of its use in China in the 1980s, suggests that there is cross-resistance between piperaquine and chloroquine. Very few data are available on cross-resistance between piperaquine and chloroquine, and the data that do exist are often contradictory. METHODS: In total, 280 P. falciparum isolates, collected between April 2008 and June 2012 from patients hospitalized in France with imported malaria from a malaria-endemic country, were assessed ex vivo for piperaquine and chloroquine susceptibilities by using the standard 42-hour 3H-hypoxanthine uptake inhibition method. The chloroquine resistance-associated mutation K76T in pfcrt was also investigated for the 280 isolates. RESULTS: The IC50 for piperaquine ranged from 9.8 nM to 217.3 nM (mean = 81.3 nM. The IC50 for chloroquine ranged from 5.0 nM to 1,918 nM (mean = 83.6 nM. A significant but low correlation was observed between the Log IC50 values for piperaquine and chloroquine (r = 0.145, p < 0.001). However, the coefficient of determination of 0.021 indicates that only 2.1% of the variation in the response to piperaquine is explained by the variation in the response to chloroquine. The mean value for piperaquine was 74.0 nM in the Pfcrt K76 wild-type group (no = 125) and 87.7 nM in the 76 T mutant group (no = 155). This difference was not significant (p = 0.875, Mann Whitney U test). CONCLUSIONS: The present work demonstrates that there was no cross-resistance between piperaquine and chloroquine among 280 P. falciparum isolates and that piperaquine susceptibility is not associated with pfcrt, the gene involved in chloroquine resistance. These results confirm the efficacy of piperaquine in association with dihydroartemisinin and support its use in areas in which parasites are resistant to chloroquine.