Jacobs Journal of Medicinal Chemistry

Antimalarial Activity of 2 -Aryl- 3H-indol-3-one Formulated in Albumin-based Nanosuspensions

Published on: 2017-06-30


Bioreducible indolone-N-oxides have demonstrated their potent antimalarial activities with, however, a short half-life. The deoxygenated analogues, 2-aryl-3H-indol-3-ones, a reduced chemical form obtained by synthesis, have similar antiplasmodial properties against the blood stages of Plasmodium falciparum in vitro, with, however, a low aqueous solubility in vivo. Albumin-based nanosuspensions were used to solubilize these new compounds to conduct experiments in vivo using the P. berghei ANKA murine model to determine the antimalarial activity of the most active derivative of this deoxygenated series, the 5-methoxy-2-(4- methoxyphenyl)-3H-indol-3-one (IND-1). Results were compared with its oxygenated analogue tested in the same conditions. Albumin-based nano-suspensions were prepared by precipitation, high-pressure homogenization and lyophilisation to yield nanoparticles of controlled diameter (350 nm) and polydispersity index (0.223) suitable for intravenous administration. The efficacy of IND-1, free and formulated in albumin-based nanosuspensions, was evaluated on a murine model infected with P. berghei ANKA. Assays revealed that the nanoformulation is much more potent (ED50 7.3 mg/kg/day, ip) than the non-formulated IND-1 (ED50 49.5 mg/kg/day, ip). Moreover, the albumin-based formulated nanosuspensions of IND-1 showed 100 % parasitemia inhibition when administered iv and ip at 50 and 100 mg/kg/day, respectively. This inhibition was not reached with the classical solvent/cosolvent methods. In conclusion, the albumin-based nanosuspensions of 2-aryl-3H-indol-3-ones greatly enhanced their antimalarial activities in vivo with a 7-fold decrease of the ED50 on ip administration compared to the free compound. However, the reduction of the NO moiety did not significantly improve in vivo properties of the IND-1 compound compared, in the same conditions, to the INOD-1 compound.


Albumin-based Nanosuspensions, Antimalarial, 2-aryl-3H-indol-3-ones, Plasmodium berghei