Anti-malarial activity of HCl salt of SKM13 (SKM13-2HCl)

Abstract

Malaria is among the most devastating and widespread tropical parasitic diseases in developing countries. To prevent a potential public health emergency, there is an urgent need for new antimalarial drugs, with single-dose cures, broad therapeutic potential, and novel mechanism of action. We synthesized HCl salt of SKM13 (SKM13-2HCl) based on the modification of SKM13 to improve solubility in water. The anti-malarial activity of the synthesized drug was evaluated in both in vitro and in vivo models. The selective index indicated that SKM13-2HCl showed the same effectiveness with SKM13 in Plasmodium falciparum in in-vitro. Even though, in vivo mouse study demonstrated that SKM13 (20 mg/kg) at single dose could not completely inhibit P. berghei growth in blood. The survival rate increased from 33 to 90% at 15 days after infection. However, SKM13-2HCl (20 mg/kg) at a single dose increased the survival rate up to 100% at the same duration. Ultra-High-Performance Liquid Chromatography (UHPLC) showed that solubility in water of SKM13 and SKM13-2HCL was 0.389 mg/mL and 417 mg/mL, respectively. Pharmacokinetics (PK) analysis corresponded to the increased solubility of SKM13-2HCl over SKM13. Haematological parameters [red blood cell (RBC) count, haemoglobin level, and haematocrit level] supported the comparable efficacy of SKM13 and SKM13-2HCl in a 4-day suppression test. One mode of these drugs was found to be activating phosphorylation of eIF2α, hallmark of ER-stress, to kill parasite. Novel salt derivative of SKM13 (SKM13-2HCl) have enhanced anti-malarial activity against P. falciparum with endoplasmic reticulum (ER)-stress and salt form of SKM13 is an excellent direction to develop anti-malarial drug candidate in mice model.

Keywords: Antimalarial drugs; Endoplasmic reticulum (ER)-Stress; Malaria; Pharmacokinetics; SKM13-2HCl salt.