The fight against malaria: Diminishing gains and growing challenges

Abstract

Since the year 2000, historic reductions in malaria incidence and mortality have been driven by the widespread distribution of bed nets, drugs, and insecticides for the prevention and treatment of malaria. Scale-up of these tools has been enabled by an increase in malaria financing compounded by price reductions, yet these trends are unlikely to continue at the same rate. Rapid population growth in high-endemic areas requires procurement of more of these tools just to maintain current coverage, even as prices are likely to increase as resistance to drugs and insecticides forces shifts to newer products. Further progress toward the long-term goal of malaria eradication requires a combination of greater funding, more cost-effective resource allocation, and fundamental changes to the global malaria control strategy.

Antimalarial Pyrido[1,2-a]benzimidazoles Exert Strong Parasiticidal Effects by Achieving High Cellular Uptake and Suppressing Heme Detoxification

“…At this same drug dosage, but administered orally by gavage, CQ did not cure, while PBI (1), tested in parallel, did. PBI compounds (2) and (3) also showed efficacy in suppressing parasitemia (Table S2) albeit approximately half the efficacy of PBI (1). From two independent experiments, the parasiticidal efficacy after oral administration was 71.0 ± 4.4% for CQ and 80.5 ± 5.5% for PBI (1) (Figure 3).…”

“…Based on this, we infer that both CQ and PBI (1) are able to kill all rings and trophozoites of P. falciparum. While both MFQ and PBI (1) have a similar speed of action, with a peak in activity at 48 h, PBI (1) does not share the same limited activity in terms of only killing trophozoites of P. falciparum as observed for MFQ. Moreover, the PBIs are hundreds of times more toxic to parasite cells than mammalian cells (Table S1) and do not have a chemical liability with respect to glutathione conjugation as AQ (Figure S2).…”

“…PBI (1) is fast-acting in comparison to atovaquone and has a speed of activity that is similar to MFQ, displaying potent inhibitory activity after 48 h of parasite exposure and a peak in activity after 72 h (Figure 2A). Given that the speed of action of PBI (1) was similar to MFQ, we determined whether or not PBIs have the same antimalarial phenotype as MFQ, a drug that acts more specifically on trophozoites of ABS and, conversely, a drug of lower activity against ring-stage parasites.…”

“…PBI (1) is fast-acting in comparison to atovaquone and has a speed of activity that is similar to MFQ, displaying potent inhibitory activity after 48 h of parasite exposure and a peak in activity after 72 h (Figure 2A). Given that the speed of action of PBI (1) was similar to MFQ, we determined whether or not PBIs have the same antimalarial phenotype as MFQ, a drug that acts more specifically on trophozoites of ABS and, conversely, a drug of lower activity against ring-stage parasites. 16−18 Thus, asynchronous parasites were treated under continuous drug exposure (IC 50 ) or under 6 h of drug exposure (IC 50 w) followed by a standard parasite washing method of three washes with RPMI medium and incubated for 48 h. A timeframe of 6 h is considered a short pulse of drug exposure as it does not reduce parasite growth.…”

“…Malaria, caused by the unicellular pathogen Plasmodium, represents a major public health problem worldwide. , To assist in the current global effort to eradicate the disease, new antiparasitic drugs acting on validated targets are needed, especially with activity spanning multiple stages of the Plasmodium life cycle , and against drug-resistant parasite strains. , As a validated drug target, the heme detoxification process is an example of the masterly evolutionary adaptation of Plasmodium , in which the parasite digests approximately 80% of red blood cell hemoglobin and releases cytotoxic heme, which is transient and then oxidized to ferric hematin and detoxified by hematin biomineralization to an inert form known as hemozoin (Hz), which is harmless to the parasite. − …”