Anti-malarial effect of novel chloroquine derivatives as agents for the treatment of malaria

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-1725-z) contains supplementary material, which is available to authorized users.

Malaria parasite clearance rate of crude methanol extract of Cryptolepis sanguinolenta in mice infected with chloroquine sensitive strain of Plasmodium berghei

“…The effect of methanol extract of C. sanguinolenta roots on various blood parameters such as pack cell volume (PCV), red blood cell count (RBC), white blood cell count (WBC) and haemoglobin concentration (Hb) of malariapassaged mice were evaluated. A reduction in concentration of PCV, RBC and Hb are useful indicators of clinical malarial anemia and frequently monitored as drug efficacy against Plasmodium infection (Yeo et al, 2017).…”

“…In an earlier report, Ajayi et al (2012) observed that C. sanguinolenta did not alter red cells (RBCs) and its related indices in rats treated with 250 mg/kg b.w. Changes in RBC are the most typical feature of malarial infections (Yeo et al, 2017).…”

Chloroquine analogs as antimalarial candidates with potent in vitro and in vivo activity

“…The most accepted and discussed mechanism of CQ is the inhibition of β-hematin formation in the digestive vacuole of the malaria parasite ( Combrinck et al, 2013 ; Lehane et al, 2012 ; Olafson et al, 2015 ). However, the full understanding of CQ's mechanism is still controversial, and may include alteration of digestive food vacuole pH and inhibition of lactate dehydrogenase ( Lehane et al, 2012 ; Read et al, 1999 ; Yeo et al, 2017 ). Even though there is a widespread resistance of P. falciparum and P. vivax to CQ , synthetic quinoline derivatives have remained a validated lead class for new drug discovery, since the resistance appears to be compound specific and not related to changes in the structure of the chloroquine targets ( Hu et al, 2017 ; Lawrenson et al, 2018 ; Solomon et al, 2007 ).…”

Antiproliferative evaluation of various aminoquinoline derivatives

“…Primaquine (PQ), chloroquine (CQ) and mefloquine (MQ) are 8-or 4-aminoquinoline antimalarial drugs, recognized by the World Health Organization as essential medicines (18). Numerous modifications of their structures, both at the quinoline heterocycle and at the side chain, were performed in order to avoid drug resistance, to obtain the antimalarial agents with reduced toxicity and/or increased activity or to get biologically active compounds outside the antimalarial field (19)(20)(21)(22).…”