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African trypanosomiasis and malaria are among the most severe health challenges to humans and livestock in Africa and new drugs are needed. Leaves of Hyptis suaveolens Kuntze (Lamiaceae) and Momordica charantia L. (Cucurbitaceae) were extracted with hexane, ethyl acetate, and then methanol, and subjected to silica gel column chromatography. Structures of six isolated compounds were elucidated through NMR and HR-EIMS spectrometry. Callistrisic acid, dehydroabietinol, suaveolic acid, suaveolol, and a mixture of suaveolol and suaveolic acid (SSA) were obtained from H. suaveolens, while karavilagenin D and momordicin I acetate were obtained from M. charantia. The isolated biomolecules were tested against trypomastigotes of Trypanosoma brucei brucei and T. congolense, and against Plasmodium falciparum. The most promising EC 50 values were obtained for the purified suaveolol fraction, at 2.71 ± 0.36 μg/mL, and SSA, exhibiting an EC 50 of 1.56 ± 0.17 μg/mL against T. b. brucei trypomastigotes. Suaveolic acid had low activity against T. b. brucei but displayed moderate activity against T. congolense trypomastigotes at 11.1 ± 0.5 μg/mL. Suaveolol and SSA were also tested against T. evansi, T. equiperdum, Leishmania major and L. mexicana but the antileishmanial activity was low. Neither of the active compounds, nor the mixture of the two, displayed any cytotoxic effect on human foreskin fibroblast (HFF) cells at even the highest concentration tested, being 200 μg/mL. We conclude that suaveolol and its mixture possessed significant and selective trypanocidal activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Antimalarial resistance has hampered the effective treatment of malaria, a parasitic disease caused by Plasmodium species. As part of our campaign on phenotypic screening of phenylhydrazones, a library of six phenylhydrazones was reconstructed and evaluated for their in vitro antimalarial and in silico receptor binding and pharmacokinetic properties. The structures of the phenylhydrazone hybrids were largely confirmed using nuclear magnetic resonance techniques. We identified two compounds which exhibited significant antimalarial potential against the ring stage (trophozoite) of 3D7 chloroquine-sensitive (CS) strain and DD2 chloroquine-resistant (CR) strains of Plasmodium falciparum with monosubstituted analogs bearing meta or para electron-donating groups showing significant activity in the single-digit micromolar range. Structure activity relationship is presented showing that electron-donating groups on the substituent hydrophobic pharmacophore are required for antimalarial activity. Compounds PHN6 and PHN3 were found to be the most potent with pIC 50 s (calculated form in vitro IC 50 s) of 5.37 and 5.18 against 3D7 CS and DD2 CR strains, respectively. Our selected ligands (PHN3 and PHN6) performed better when compared to chloroquine regarding binding affinity and molecular stability with the regulatory proteins of Plasmodium falciparum , hence predicted to be largely responsible for their in vitro activity. Pharmacokinetic prediction demonstrated that the phenylhydrazones may not cross the blood-brain barrier and are not P -glycoprotein (P-gp) substrates, a good absorption of 62% to 69%, and classified as a category IV compound based on toxicity grading., Competing Interests: The authors declare that no conflict of interest exists., (Copyright © 2024 Cedric Dzidzor Kodjo Amengor et al.)

Ethnopharmacological Relevance: Annickia polycarpa leaf is an effective anti-malarial agent. However, its chemical constituents have not been isolated and assayed against any pathogen., Aim of the Study: To isolate and characterize anti-malarial compound(s) from the leaf of A. polycarpa., Materials and Methods: Bioassay-guided fractionation was employed to isolated the compound (AL1) from the chloroform fraction (ALCF) of the basified ethanol extract of A. polycarpa leaf (ALE). AL1 was characterized by LC-MS, 1D and 2D NMR spectroscopic analysis. Anti-malarial activity was evaluated against drug resistance Dd2 and drug sensitive 3D7 Plasmodium falciparum strains using the SYBR green assay. Cytotoxicity and mechanistic studies were determined using tetrazolium-based colorimetric assay and molecular docking respectively., Results: AL1 was characterized as n-hexyl 1-O-rutinoside. The IC 50 values of ALE and ALCF against 3D7 and Dd2 P. falciparum strains ranges from 3.441 (0.3389) - 4.255 (0.2246) μg/mL. The IC 50 s obtained for n-hexyl 1-O-rutinoside and Artesunate (standard drug) were 7.71 (0.5473) and 0.001 (0.00008) nM against the 3D7 parasite strain respectively. Also, the efficacy of n-hexyl 1-O-rutinoside increased by 24.40% against the chloroquine resistance Dd2 P. falciparum strain whiles that of Artesunate decreased by 98.96%. Furthermore, ALE, ALCF and n-hexyl 1-O-rutinoside were weakly cytotoxic to human RBCs with high selectivity indices. N-hexyl 1-O-rutinoside inhibits P. falciparum chloroquine resistance transporter (PfCRT) and dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) better than chloroquine and pyrimethamine respectively. But, produced similar inhibition of P. falciparum 2-trans-enoyl -ACP-reductase (PfERN) as triclosan., Conclusion: These results show that A. polycarpa leaf and n-hexyl 1-O-rutinoside possessed profound anti-malarial activity and are not cytotoxic. N-hexyl 1-O-rutinoside could therefore, be developed into a new anti-malarial medicine. This is the first study to report the anti-malarial activity of n-hexyl 1-O-rutinoside and its isolation from the genus Annickia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The emergence of drug-resistant parasites impedes disease management and eradication efforts. Hence, a reinvigorated attempt to search for potent lead compounds in the mangroves is imperative., Aim: This study evaluates in vitro antiplasmodial activity, antioxidant properties, and cytotoxicity of A. africana leaf alkaloidal extracts., Methods: The A. africana leaves were macerated with 70% ethanol to obtain a total crude extract. Dichloromethane and chloroform-isopropanol (3 : 1, v/v) were used to extract the crude alkaloids and quaternary alkaloids from the total crude. The antiplasmodial activities of the alkaloidal extracts were performed against 3D7 P. falciparum chloroquine-sensitive clone via the SYBR Green I fluorescence assay with artesunate serving as the reference drug. The alkaloidal extracts were further evaluated for antioxidant properties via the total antioxidant capacity (TAC), the total glutathione concentration (GSH), the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay, and the ferric-reducing antioxidant power (FRAP) methods. The cytotoxic activity of the alkaloidal extracts was tested on erythrocytes using a 3-(4,5-dimethylthiazol-2-yl)-5-diphenyltetrazolium bromide-MTT assay with little modification. The phytocompounds in the alkaloidal extracts were identified via gas chromatography-mass spectrometry (GC-MS) techniques., Results: The total crude extract showed good antiplasmodial activity (IC 50  = 11.890  µ g/mL). The crude and quaternary alkaloidal extracts demonstrated promising antiplasmodial effects with IC 50 values of 6.217 and 6.285  µ g/mL, respectively. The total crude and alkaloidal extracts showed good antioxidant properties with negligible cytotoxicity on erythrocytes with good selectivity indices. The GC-MS spectral analysis of crude alkaloidal extracts gave indole and isoquinoline alkaloids and several other compounds. Dexrazoxane was found to be the main compound predicted, with an 86% peak area in the quaternary alkaloidal extract., Conclusion: The crude and quaternary alkaloidal extracts exhibited antiplasmodial activities and ability to inhibit oxidative stress with negligible toxicity on erythrocytes. This may be good characteristics to avoid oxidative stress related to Plasmodium infection in the treatment of malaria., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Mustapha A. Ahmed et al.)

Background: The erythrocytic stage of the life cycle of the malaria parasite, Plasmodium falciparum, consists of trophozoite, schizont and gametocyte stages in humans. Various anti-malarial agents target different stages of the parasite to produce treatment outcomes. This study reports on the stage-specific anti-malarial activity of heptaphylline and imperatorin against human P. falciparum in addition to their cytotoxicity and selectivity indices (SI)., Methods: The compounds were isolated from Clausena anisata using column chromatography and their structures elucidated using NMR spectroscopy. The anti-malarial activity was determined by measuring the trophozoitocidal, schizonticidal and gametocytocidal activities of the compounds using the SYBR green assay. Cytotoxicity was evaluated using the tetrazolium-based colorimetric assay., Results: Heptaphylline and imperatorin produced trophozoitocidal, schizonticidal and gametocytocidal activities with IC 50 s of 1.57 (0.2317)-26.92 (0.3144) µM with those of artesunate (the standard drug) being 0.00024 (0.0036)-0.0070 (0.0013) µM. In the cytotoxicity assay, the compounds produced CC 50S greater than 350 µM and SI of 13.76-235.90. Also, the trophozoitocidal and schizonticidal activities of the compounds were more pronounced than their gametocytocidal activity. Imperatorin was 42.04% more trophozoitocidal than hepthaphyline. However, hepthaphyline has more schizonticidal and gametocytocidal properties than imperatorin., Conclusion: Heptaphylline and imperatorin are promising anti-malarial agents, since they possess potent anti-malarial activity with weak cytotoxicity on RBCs. However, imperatorin is a better anti-malarial prophylactic agent whereas heptaphylline is a better malaria treatment agent., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Human malaria parasites have complex but poorly understood population dynamics inside their human host. In some but not all infections, parasites progress synchronously through the 48 h lifecycle following erythrocyte invasion, such that at any one time there is a limited spread of parasites at a particular time (hours) post-invasion. Patients presenting with older parasites, and with asynchronous infections, have been reported to have higher risks of fatal outcomes, associated with higher parasite biomass and multiplication rates respectively. However, practical tools to assess synchrony and estimate parasite age post-invasion in patient samples are lacking. We have developed a novel method based on three genes differentially expressed over the parasite intra-erythrocytic lifecycle, and applied it to samples from patients with uncomplicated malaria attending two health clinics in Ghana. We found that most patients presented with synchronous infections, and with parasites within 12 h of erythrocyte invasion. Finally we investigated if clinical features such as fever and parasite density could act as predictors of parasite age and synchrony. The new method is a simple and practicable approach to study parasite dynamics in naturally-infected patients, and is a significant improvement on the subjective microscopical methods for parasite staging in vivo, aiding patient management.