New enantiomerically pure 1,2,4-trioxepanes 10a,b/11a,b were synthesized from d-glucose. Their conformational behavior was studied by low-temperature NMR and substantiated by DFT calculations. On ...evaluation of in vitro antimalarial activity, the adamantyl derivative 11b showed IC50 values in the low micromolar range, particularly against the W2 chloroquine-resistant Plasmodium falciparum strain (IC50 = 0.15 ± 0.12 μM).
A new series of nineteen 3-methoxy-1,2-dioxanes containing an amino moiety at C4 was designed, synthesized and tested for in vitro antimalarial activity against chloroquine sensitive (CQ-S) D10 and ...chloroquine resistant (CQ-R) W2 strains of Plasmodium falciparum (Pf). Cytotoxicity against the human endothelial cell line (HMEC-1) was also evaluated. The introduced modifications resulted in a notable improvement of the antimalarial activity. In particular, compound 9a with an amino-imidazole side-chain at C4 displays antimalarial activity in the high nanomolar range against the CQ-R Pf strain (W2 IC50 = 200 nM), being more active against CQ-R than CQ-S Pf strains and devoid of cytotoxicity against human HMEC-1 cells. On the other hand, some of the hybrids with 4-amino-7-chloroquinoline (9k-p) show an IC50 comparable to that of chloroquine against the CQ-S Pf strain (9k-p, D10 IC50 = 50-90 nM) but without losing potency against the CQ-R Pf strain (9k-p, resistance index = 1.2-2.6), with low cytotoxicity against HMEC-1. Structure-activity relationship studies show that the improved antimalarial activity of the new compounds is the result of a combination of cellular pharmacokinetics and pharmacodynamics effects.
In the search for new antimalarials, we used the quinone scaffold of marine secondary metabolites as a chemical starting point to synthesize new thiazinoquinone compounds. Most of synthetic ...derivatives have shown a significant pharmacological activity and some structural requirements, critical for both the antiplasmodial effect and cytotoxicity, have been evidenced. The redox properties of the prepared compounds have been investigated by computational studies and electrochemical assays, which indicated that a higher antiplasmodial activity of some thiazinoquinones is related to their greater ability to form the semiquinone species and strongly interact with free Fe(iii)-protoporphyrin IX.
Artemisinin derivatives, the current cornerstone of malaria treatment, possess also anti-angiogenic and anti-tumor activity. Hypoxia plays a crucial role both in severe malaria (as a consequence of ...the cytoadherence of infected erythrocytes to the microvasculature) and in cancer (due to the restricted blood supply in the growing tumor mass). However, the consequences of hypoxia onto the effects of artemisinins is under-researched.
This study aimed at assessing how the inhibition of microvascular endothelial cell (HMEC-1) growth induced by dihydroartemisinin (DHA, an antimalarial drug and the active metabolite of currently in-use artemisinins) is affected by oxygen tension.
Low doses of DHA (achieved in the patients’ plasma when treating malaria) were more inhibitory in hypoxia, whereas high doses (required for anti-angiogenic or anti-tumor activity) were more effective in normoxia. The peroxide bridge is essential for cellular toxicity (deoxyDHA was inactive). High doses of DHA caused HMEC-1 apoptosis and G2 cell cycle arrest. Effects were mediated by the generation of oxidative stress as demonstrated by DCF-DA fluorescence and membrane lipid peroxidation analysis.
Overall, these results suggest that DHA inhibition of endothelial cell growth is related to the level of tissue oxygenation and drug concentration. This should be considered when studying both the effects of artemisinin derivatives as antimalarials and the potential therapeutic applications of these drugs as anti-tumor agents.
We have previously described several potent dual inhibitors of
Plasmodium falciparum
(
Pf
) growth characterized by the presence of statine, a β-hydroxyl amino acid able to inhibit parasite's ...plasmepsins (PLMs). While investigating the mechanism of action of these inhibitors, new compounds derived from statine were synthesized, which lost the ability to inhibit PLMs, but retained a significant
Pf
growth inhibition. Further structural simplifications showed that the inhibition of
Pf
viability was ascribed to a new pharmacophore never described before as antimalarial.
Curcumin is a natural plant product with antimalarial activity and immunomodulatory properties. In this study we aimed to investigate its effects on CD36 expression and CD36-mediated Plasmodium ...falciparum phagocytosis as well as the role played by reactive oxygen species (ROS) and the peroxisome proliferator-activated receptor γ retinoid X receptor (PPARγ-RXR) in these processes.
In vitro antimalarial activity was evaluated by the ³Hhypoxanthine assay. ROS production and surface CD36 in human monocyte/macrophages were measured by flow cytometry. PPARγ and CD36 mRNA expression was determined by the QuantiGene Plex® assay and RT-qPCR. Nuclear PPARγ activation was analysed by a DNA-binding ELISA while nuclear erythroid-related factor 2 (Nrf2) expression was analysed by western blotting. P. falciparum phagocytosis was assessed by light microscopy.
Curcumin's antimalarial activity was confirmed and did not differ between drug-susceptible and -resistant P. falciparum strains. Curcumin increased monocyte ROS production and expression of PPARγ and CD36 at the mRNA and protein levels. Although PPARγ activation was blocked by the PPARγ antagonist GW9662, CD36 expression and CD36-mediated P. falciparum phagocytosis were only inhibited by N-acetylcysteine (NAC), suggesting a PPARγ-independent CD36 expression pathway. We then identified seven putative Nrf2 antioxidant response elements on the CD36 gene promoter and showed that NAC inhibited curcumin-induced Nrf2 protein expression.
CD36 expression and CD36-mediated P. falciparum phagocytosis by curcumin are dependent on ROS production and probably involve the Nrf2 pathway. The dual immunomodulatory and antimalarial mechanisms of curcumin action may mean that curcumin has potential as an adjuvant treatment limiting the risk of recrudescence following standard antimalarial therapy.
Antiplasmodial activities versus the chloroquine sensitive D10 strain of Plasmodium falciparum of a series of N ,N 1-diethyl-N -(4-quinolinyl)-1,2-ethanediamines with 11 different substituents at the ...7-position on the quinoline ring have been investigated in vitro. Electron-withdrawing groups at the 7-position have been shown to lower the pK a of both the quinoline ring nitrogen atom and the tertiary amino nitrogen in the alkyl side chain. The quinoline nitrogen pK a ranges from 6.28 in the nitro derivative to 8.36 in the amino derivative, while the tertiary amino nitrogen has a pK a ranging between 7.65 in the trifluoromethyl derivative and 10.02 in the amino derivative. Calculation suggests that the resulting pH trapping of these compounds in the parasite food vacuole ranges between about 7% of that observed in chloroquine for the NO2 derivative and 97% in the amino derivative. A direct proportionality between antiplasmodial activity normalized for pH trapping and β-hematin inhibitory activity was observed. Activity could not be correlated with any other observed physical parameter. The β-hematin inhibitory activity of these derivatives appears to correlate with both the hematin−quinoline association constant and the electron-withdrawing capacity of the group at the 7-position (Hammett constant). For the compounds under investigation, the hematin association constant is in turn influenced by the lipophilicity of the group at the 7-position.
There is mounting evidence that the release of haemozoin (β-haematin), which is produced in large amounts during malaria infection and is released into the circulation during schizont rupture, is ...associated with damage to cell membranes through an oxidative mechanism. The red blood cell membrane is thus oxidised, causing rigidity of the cell. This can contribute to the pathophysiology of severe malaria, since red blood cells will have to deform considerably in order to squeeze through the microcirculation, the patency of which is disturbed by sequestered red blood cells containing the mature forms of the parasite. Rigidity of red blood cells forms a new target for intervention. Since this seems to be caused by oxidative damage to the red blood cell membrane, the anti-oxidant N-acetylcysteine is a promising candidate for adjunctive treatment in severe malaria, which still has a mortality rate as high as 20%.
Continuous efforts into the discovery and development of new antimalarials are required to face the emerging resistance of the parasite to available treatments. Thus, new effective drugs, ideally ...able to inhibit the
life-cycle stages that cause the disease as well as those responsible for its transmission, are needed. Eight compounds from the Medicines for Malaria Venture (MMV) Malaria Box, potentially interfering with the parasite polyamine biosynthesis were selected and assessed in vitro for activity against malaria transmissible stages, namely mature gametocytes and early sporogonic stages.
Compound activity against asexual blood stages of chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains of
was tested measuring the parasite lactate dehydrogenase activity. The gametocytocidal effect was determined against the
3D7elo1-pfs16-CBG99 strain with a luminescent method. The murine
CTRP.GFP strain was employed to assess compounds activities against early sporogonic stage development in an in vitro assay simulating mosquito midgut conditions.
Among the eight tested molecules, MMV000642, MMV000662 and MMV006429, containing a 1,2,3,4-tetrahydroisoquinoline-4-carboxamide chemical skeleton substituted at N-2, C-3 and C-4, displayed multi-stage activity. Activity against asexual blood stages of both strains was confirmed with values of IC
(50% inhibitory concentration) in the range of 0.07-0.13 µM. They were also active against mature stage V gametocytes with IC
values below 5 µM (range: 3.43-4.42 µM). These molecules exhibited moderate effects on early sporogonic stage development, displaying IC
values between 20 and 40 µM.
Given the multi-stage, transmission-blocking profiles of MMV000642, MMV000662, MMV006429, and their chemical characteristics, these compounds can be considered worthy for further optimisation toward a TCP5 or TCP6 target product profile proposed by MMV for transmission-blocking antimalarials.
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