Acute oral toxicity and antimalarial studies of 7-[(7-methoxy-4,5-dihydro-1H-benzo[g]indazol-3-yl)carbonyl]-2-phenyl-5,6,7,8-tetrahydropyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(1H)-one in mouse models

Abstract

Reports of resistance to current antimalarial combination therapies (ACTs) have necessitated the discovery of new antimalarial drugs, most importantly with new mechanisms of action. From our molecular docking study, the small molecule 7-[(7-methoxy-4,5-dihydro-1H-benzo[g]indazol-3-yl)carbonyl]-2-phenyl-5,6,7,8-tetrahydropyrazolo[1,5 a]pyrido[4,3-d]pyrimidin-9(1H)-one (MCL) was identified to be capable of inhibiting an essential protein in Plasmodium falciparum (Apetala 2-invasion transcription factor) involved in red blood cell invasion. This study determined MCL's acute oral toxicity and therapeutic effect against malaria infection in vivo. Thirty-five 6-week-old Swiss albino mice were grouped into seven (n = 5 mice per group). The first group served as control, and the other six groups were administered a single oral dose of 1, 10, 20, 30, 40, and 50 µM MCL to determine acute oral toxicity. Effects on body and organ weight, morbidity, mortality rate, and biochemical, hematological, and histopathological outcomes were assessed. A single oral dose and a combination therapy with 14.17 µM artemisinin and MCL (50 µM) were also administered to another set of fifty-five P. berghei-infected mice for 3 and 7 days to determine the parasite inhibitory potential. Parasite density, suppression rate, and EC50 were assessed by parasite inhibitory assay. The acute oral toxicity study of MCL showed moderate toxicity in the experimental animals after 14 days. Parasite inhibitory study showed that MCL reduced malaria parasite significantly with an EC50 value of 37.32 on day 3 and 22.26 on day 7 and 83.75 % parasite clearance rate at a maximum dose of 50 μM. Furthermore, MCL in combination with artemisinin, showed a parasite suppression rate of 48 % after a 3-day single oral dose. These results show MCL can act as a schizonticidal drug and disrupt P. berghei red blood cell invasion and reinvasion. Hence, it can be combined with artemisinin to replace artemisinin partner drugs, which have shown high-grade resistance in endemic African regions.

Keywords

• Malaria
• Malaria parasites
• Drug discovery
• Small molecules
• Toxicity
• Parasite suppression