Abstract
BackgroundThe widespread emergence of anti-malarial drug resistance has necessitated the discovery of novel anti-malarial drug candidates. In this study, chloroquine derivatives were evaluated for the improved anti-malarial activity.ResultsNovel two derivatives (SKM13 and SKM14) were synthesized based on the chloroquine (CQ) template containing modified side chains such as α,β-unsaturated amides and phenylmethyl group. The selective index indicated that SKM13 was 1.28-fold more effective than CQ against the CQ-resistant strain Plasmodium falciparum. An in vivo mouse study demonstrated that SKM13 (20 mg/kg) could completely inhibit Plasmodium berghei growth in blood and increased the survival rate from 40 to 100% at 12 days after infection. Haematological parameters [red blood cell (RBC) count, haemoglobin level, and haematocrit level] were observed as an indication of clinical malarial anaemia during an evaluation of the efficacy of SKM13 in a 4-day suppression test. An in vivo study showed a decrease of greater than 70% in the number of RBC in P. berghei-infected mice over 12 days, but the SKM13 (20 mg/kg)-treated group showed no loss of RBC.ConclusionsCQ derivatives with substituents such as α,β-unsaturated amides and phenylmethyl group have enhanced anti-malarial activity against the CQ-resistant strain P. falciparum, and SKM13 is an excellent anti-malarial drug candidate in mice model.
Highlights
The widespread emergence of anti-malarial drug resistance has necessitated the discovery of novel anti-malarial drug candidates
In the structure of CQ, there is a small methyl group on the side chain [28] but two CQ derivatives have phenylmethyl group derived from phenylalanine at the same position
A little difference of chemical structure between SKM13 and SKM14 indicates that the α,β-unsaturated amide in SKM13 is shorter than that in SKM14
Summary
The widespread emergence of anti-malarial drug resistance has necessitated the discovery of novel anti-malarial drug candidates. Successful malaria control in the past decade was dependent on treatment with efficacious anti-malarial drugs [3] Quinoline drugs such as chloroquine (CQ) and quinine were the cornerstone of malaria treatment [4]. The extensive use of CQ led to the development of a chloroquine-resistant malaria parasite Plasmodium falciparum in Southeast Asia, Oceania, and South America in the late 1950s and early 1960s [6]. This drug resistance inspired a significant effort throughout the twentieth century to identify new anti-malarial agents for the improvement of global public health. There is still a need to produce “novel” drugs with different properties, which has led to dramatic changes in the way new targets are identified [7]
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