New antimalarial agents derived from nonlinear phenoxazine ring system

In vivo antimalarial screening of nine nonlinear phenoxazine compounds was carried out on the blood stages of Plasmodium berghei using standard methods. The activities of the compounds were compared with that of quinine as a standard antimalarial drug. LD50 and histopathological studies were also done. Molecular docking studies were carried out on four different protein targets of Plasmodium spp. The effects of these compounds on the hematological parameters (Hemoglobin, Hb; packed cell volume, PCV; white blood cells, WBC; and red blood cells, RBC) were also evaluated. The in vivo antimalarial studies showed that all the synthesized compounds had significant parasitaemia load reduction (89.00–94.05%) at 200 mg/ml when compared with the control, with (2-aminophenoxyl)benzo[a]phenoxazin-5-one 3b showing the highest activity. There was no significant difference in the activities of these compounds compared with the standard drug used (96%). The LD50 was found to be ≥5000 mg/kg. Histopathological studies showed a significant restoration of the liver intoxicated with malaria parasite after 5 days. The hematological analysis showed normal values for Hb, PCV, WBC, and RBC in the course of the treatment. The compounds showed more binding affinities for the P. falciparum receptors than the standard drug. The nine synthesized nonliner phenoxazine compounds had significant antimalarial activities and did not significantly affect the hematological parameters. They showed strong binding affinity to the parasite receptors. Hence, they are good candidates for antimalarial drugs. More preclinical investigations are needed.