Multidrug resistance is a significant drawback in malaria treatment, and mutations in the active sites of the many critical antimalarial drug targets have remained challenging. Therefore, this has necessitated the global search for new drugs with new mechanisms of action. Plasmodium falciparum lactate dehydrogenase (pfLHD), a glycolytic enzyme, has emerged as a potential target for developing new drugs due to the parasite reliance on glycolysis for energy. Strong substrate‐binding is required in pfLDH enzymatic catalysis; however, there is a lack of information on small molecules’ inhibitory mechanism bound to the substrate‐binding pocket. Therefore, this study investigated a potential allosteric inhibition of pfLDH by targeting the substrate‐binding site. The structural and functional behaviour of madecassic acid (MA), the most promising among the six triterpenes bound to pfLDH, were unravelled using molecular dynamic simulations at 300 ns to gain insights into its mechanism of binding and inhibition and chloroquine as a standard drug. The docking studies identified that the substrate site has the preferred position for the compounds even in the absence of a co‐factor. The bound ligands showed comparably higher binding affinity at the substrate site than at the co‐factor site. Mechanistically, a characteristic loop implicated in the enzyme catalytic activity was identified at the substrate site. This loop accommodates key interacting residues (LYS174, MET175, LEU177 and LYS179) pivotal in the MA binding and inhibitory action. The MA‐bound pfLHD average RMSD (1.60 Å) relative to chloroquine‐bound pfLHD RMSD (2.00 Å) showed higher stability for the substrate pocket, explaining the higher binding affinity (−33.40 kcal/mol) observed in the energy calculations, indicating that MA exhibited profound inhibitory activity. The significant pfLDH loop conformational changes and the allostery substrate‐binding landscape suggested inhibiting the enzyme function, which provides an avenue for designing antimalarial compounds in the future studies of pfLDH protein as a target.

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The identification of novel molecules for the development of more effective and safe treatments to fight malaria is urgently needed. Medicinal plants are one of the main opportunities in the discovery of such new molecules. Combretaceae is a family members of which have been reported with broad spectrum of bioactivities against different diseases including malaria. The aim of this study was to screen a number Combretaceae plants, selected based on the use in ethnomedicine, for antimalarial activity. Methanolic and acetone extracts of leaves of ten different Combretaceae were screened by applying the inhibition of β-hematin synthesis, a simple and robust colorimetric assay. The analysis was conducted using a 96-well UV-vis plate reader and the absorbance was read at 405 nm. The IC 50 was calculated by analyzing the dose-response data using Graphpad Prism® (6.0). Preliminary results showed that eight plant extracts at 25mg/mL demonstrated appreciable activity by inhibiting the formation of hemozoin. The best inhibitory concentration (IC 50 2.58 ± 0.447 mg/mL) was observed in Terminalia ivorensis methanol extract (TIM) which was comparable with chloroquine standard drug (IC 50 0.55 ± 0.179 mg/mL). Moreover, the Terminalia ivorensis methanol extract showed statistically significant activity (P<0.05) at the different concentrations used, comparable to chloroquine. Activities studies of the investigated plants confirm the ethnomedicinal use of Terminalia ivorensis in the treatment of malaria. A bioassay-guided fractionation of the leaf extract of the T. ivorensis is ongoing.

Malaria remains a major public health concern which affects millions of people, particularly in SubSaharan Africa. The need for the development of alternate treatment means has become critical because of the emergence of resistance to nearly all antimalarial drugs (Kim and Schneider, 2013). Trema orientalis (L.) Blume (Ulmaceae) is used locally for the treatment of malaria. This study was designed to determine the anti-plasmodial activity of the acetone extract of T. orientalis and carry out a bio-guided separation of the extract. Acetone extract of T. orientalis leaves was investigated for its antimalarial activity in a mouse model of Plasmodium berghei using the 4 day suppressive test. Bioguided investigation was carried out by using column chromatographic fractions for in-vivo antiplasmodial screening. Preliminary spectroscopic profile of the most active fraction was obtained. Treatment with graded doses (100 to 800 mg/Kg) of acetone extract of T. orientalis resulted in significant chemosuppression of parasite growth that ranged from 44.0 to 83.8%. The most active fraction which was identified as M6 showed significant schizontocidal activity (P < 0.001). 1 H NMR and Infrared spectra data indicated that the most active fraction contained flavonoids. This study justified the folkloric use of T. orientalis. Compounds from this plant could be a potential source of antimalarial agents.