IN VIVO IN VITRO ANTI-PLASMODIAL ACTIVITY OF CHEMICALLY SYNTHESISED IMIDAZOLE COMPOUNDS

Abstract

Malaria remains a leading cause of morbidity and mortality globally, with the continued emergence of Plasmodium falciparum resistance to artemisinin-based therapies rendering the identification of novel chemotherapeutic scaffolds an urgent priority. The imidazole family of compounds, with their adaptable framework and ability to engage parasite-specific targets such as falcipain-2 and hemozoin biosynthesis machinery, represent compelling synthetic leads. This study evaluates the in vitro anti-plasmodial activity and in vivo efficacy and safety profiles of two newly synthesised compounds: 4,5-diphenyl-2-(m-tolyl)-1H-imidazole (IM1) and 4,5-diphenyl-2- (m-tolyl)-1-tosyl-1H-imidazole (IM2). In vitro susceptibility was assessed using a schizont maturation inhibition assay against the chloroquine-sensitive P. falciparum 3D7 strain. In vivo evaluation employed Peter's 4-d suppressive test in P. berghei ANKA-infected Swiss albino mice administered oral doses of 20–400 mg/kg. Acute toxicity was assessed according to the OECD 423 guidelines through haematological, biochemical, oxidative stress, and histopathological analyses. In vitro, IM1 demonstrated higher intrinsic potency, exhibiting a half-maximal inhibitory concentration (IC50) of 3.6 ± 0.2 μg/mL compared to 7.8 ± 0.5 μg/mL for IM2. However, in vivo evaluation revealed a distinct efficacy paradox: IM2 demonstrated superior systemic efficacy, achieving up to 68% parasitaemia suppression at 400 mg/kg, surpassing the 52% suppression observed with IM1. IM2 also significantly extended the mean survival time of infected mice to 12.3 d, compared with 8.1 d for untreated controls. Systemically, IM2 maintained physiological homeostasis, preserved hepatic and renal architecture, and induced significant modulation and stabilization of circulating lymphocytes (p=0.049), compared with the abnormal increase observed in untreated infections. A strong positive correlation between malondialdehyde and glutathione (r=0.839, p=0.005) indicated a well-tolerated, reactive oxygen species-mediated parasiticidal mechanism for IM2. On the other hand, high-dose IM1 (400 mg/kg) induced dose-dependent hepatotoxicity, as evidenced by elevated alanine aminotransferase (44.47 U/L) and histopathological evidence of hepatocyte vacuolation. Ultimately, whilst IM1's highly lipophilic core necessitates structural optimization to mitigate hepatic stress, IM2 represents a promising lead compound that requires further pre-clinical investigations.