Potential Antimalarials Research Articles

Characterisation of plasmodial transketolases and identification of potential inhibitors: an in silico study

BackgroundPlasmodial transketolase (PTKT) enzyme is one of the novel pharmacological targets being explored as potential anti-malarial drug target due to its functional role and low sequence identity to the human enzyme. Despite this, features contributing to such have not been exploited for anti-malarial drug design. Additionally, there are no anti-malarial drugs targeting PTKTs whereas the broad activity of these inhibitors against PTKTs from other Plasmodium spp. is yet to be reported. This study characterises different PTKTs [Plasmodium falciparum (PfTKT), Plasmodium vivax (PvTKT), Plasmodium ovale (PoTKT), Plasmodium malariae (PmTKT) and Plasmodium knowlesi (PkTKT) and the human homolog (HsTKT)] to identify key sequence and structural based differences as well as the identification of selective potential inhibitors against PTKTs.MethodsA sequence-based study was carried out using multiple sequence alignment, phylogenetic tree calculations and motif discovery analysis. Additionally, TKT models of PfTKT, PmTKT, PoTKT, PmTKT and PkTKT were modelled using the Saccharomyces cerevisiae TKT structure as template. Based on the modelled structures, molecular docking using 623 South African natural compounds was done. The stability, conformational changes and detailed interactions of selected compounds were accessed viz all-atom molecular dynamics (MD) simulations and binding free energy (BFE) calculations.ResultsSequence alignment, evolutionary and motif analyses revealed key differences between plasmodial and the human TKTs. High quality homodimeric three-dimensional PTKTs structures were constructed. Molecular docking results identified three compounds (SANC00107, SANC00411 and SANC00620) which selectively bind in the active site of all PTKTs with the lowest (better) binding affinity ≤ − 8.5 kcal/mol. MD simulations of ligand-bound systems showed stable fluctuations upon ligand binding. In all systems, ligands bind stably throughout the simulation and form crucial interactions with key active site residues. Simulations of selected compounds in complex with human TKT showed that ligands exited their binding sites at different time steps. BFE of protein–ligand complexes showed key residues involved in binding.ConclusionsThis study highlights significant differences between plasmodial and human TKTs and may provide valuable information for the development of novel anti-malarial inhibitors. Identified compounds may provide a starting point in the rational design of PTKT inhibitors and analogues based on these scaffolds.

Evaluation of in vivo anti-malarial potential of omidun obtained from fermented maize in Ibadan, Nigeria

BackgroundThe menace of resistance to anti-malarial drugs is a great challenge to malaria control, necessitating the search for new anti-malarial agents. This search has led to the exploration of natural products for efficacy in malaria therapy. Omidun is the supernatant of fermenting maize (ogi) slurry that has been widely investigated and reported to possess several health benefits and it is used traditionally as solvent for preparing anti-malarial herbs. However, there is no information on the anti-malarial activity of omidun itself. This study was conducted to investigate the prophylactic, curative and suppressive anti-malarial potential of omidun.MethodsExperimental mice in the curative group were infected with 1 × 106 cells of Plasmodium berghei strain ANKA and treated with either 0.2 ml of omidun containing 3 × 109 cfu/ml of viable lactic acid bacteria or 0.2 ml of 5 mg/kg of chloroquine (positive control) or 0.2 ml of saline (negative control) for 4 days from day 3 post infection. The prophylactic group of mice were pre-treated with either omidun, chloroquine or saline for 4 days before infection with P. berghei, while the suppressive group was treated with omidun or chloroquine or saline and infected with P. berghei simultaneously. A group of mice were uninfected but treated (with omidun and control samples), while a final group was uninfected and untreated (controls). Parasitaemia and histopathology analysis were done in all groups.ResultsThe curative and suppressive groups showed a significant difference between the omidun-treated mice (100% parasitaemia reduction) and the untreated mice (54.5% parasitaemia increase). There was no significance difference between the omidun treatment and chloroquine (positive control) treatment in suppressive group as both treatment had 100% parasitaemia reduction. The omidun prophylactic treatment however did not show any parasitaemia suppression, but a significant difference was observed between the omidun treatment (85% increase) and the chloroquine (positive control) treatment (100% reduction) in the group. Omidun treatment is non-toxic to the kidney.ConclusionThis study provides scientific evidence supporting omidun usage in the treatment of malaria. Consequently, further work may yield the specific component of omidun responsible for the anti-malarial activity.

Synthesis and antimalarial activity of sulfonamide-attached coumarin-[1,2,3]-triazoles

Drug resistance in malaria parasites is one of the major stumbling blocks hindering the goal of malaria elimination. One of the major strategies to counter drug resistance is the development of new potent antimalarial drugs. In the present study, a series of novel sulfonamide based coumarin-[1,2,3]-triazole conjugates have been synthesized via Huisgen reaction between azidosulfonamides and 4-hydroxy- or 7-hydroxymethylcoumarinoalkynes. All the compounds have been characterized spectroscopically and screened for their in vitro antimalarial activity against P. falciparum 3D7 strain. Out of the twenty five synthesized compounds, four compounds displayed significant activity (IC50 <10 µM) with the most active compound having an IC50 of 3.64 µM.

Enantioselective Synthesis of γ-Phenyl-γ-amino Vinyl Phosphonates and Sulfones and Their Application to the Synthesis of Novel Highly Potent Antimalarials.

Racemic and enantioselective syntheses of γ-phenyl-γ-amino vinyl phosphonates and sulfones have been achieved using Horner–Wadsworth–Emmons olefination of trityl protected α-phenyl-α-amino aldehydes with tetraethyl methylenediphosphonate and diethyl ((phenylsulfonyl)methyl)phosphonate, respectively, without any racemization. The present strategy has also been successfully applied to the synthesis of peptidyl vinyl phosphonate and peptidyl vinyl sulfone derivatives as potential cysteine protease inhibitors of Chagas disease, K11002, with 100% de. The developed synthetic protocol was further utilized to synthesize hybrid molecules consisting of artemisinin as an inhibitor of major cysteine protease falcipain-2 present in the food vacuole of the malarial parasite. The synthesized artemisinin–dipeptidyl vinyl sulfone hybrid compounds showed effective in vitro inhibition of falcipain-2 and potent parasiticidal efficacies against Plasmodium falciparum in nanomolar ranges. Overall, the developed synthetic protocol could be effectively utilized to design cysteine protease inhibitors not only as novel antimalarial compounds but also to be involved in other life-threatening diseases.

Screen of traditional soup broths with reported antipyretic activity towards the discovery of potential antimalarials

Screen of traditional soup broths with reported antipyretic activity towards the discovery of potential antimalarials

A Novel Series of [1,2,4]Triazolo[4,3-a]Pyridine Sulfonamides as Potential Antimalarial Agents: In Silico Studies, Synthesis and In Vitro Evaluation.

For the development of new and potent antimalarial drugs, we designed the virtual library with three points of randomization of novel [1,2,4]triazolo[4,3-a]pyridines bearing a sulfonamide fragment. The library of 1561 compounds has been investigated by both virtual screening and molecular docking methods using falcipain-2 as a target enzyme. 25 chosen hits were synthesized and evaluated for their antimalarial activity in vitro against Plasmodium falciparum. 3-Ethyl-N-(3-fluorobenzyl)-N-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide and 2-(3-chlorobenzyl)-8-(piperidin-1-ylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one showed in vitro good antimalarial activity with inhibitory concentration IC50 = 2.24 and 4.98 μM, respectively. This new series of compounds may serve as a starting point for future antimalarial drug discovery programs.

Resistance to Some But Not Other Dimeric Lindenane Sesquiterpenoid Esters Is Mediated by Mutations in a Plasmodium falciparum Esterase.

Unique lindenane sesquiterpenoid dimers from Chloranthecae spp. were recently identified with promising in vitro antiplasmodial activity and potentially novel mechanisms of action. To gain mechanistic insights to this new class of natural products, in vitro selection of Plasmodium falciparum resistance to the most active antiplasmodial compound, chlorajaponilide C, was explored. In all selected resistant clones, the half-maximal effective concentration (EC50) of chlorajaponilide C increased >250-fold, and whole genome sequencing revealed mutations in the recently discovered P.falciparum prodrug activation and resistance esterase (PfPARE). Chlorajaponilide C was highly potent (mean EC50 = 1.6 nM, n = 34) against fresh Ugandan P.falciparum isolates. The analysis of the structure-resistance relationships revealed that in vitro potency of a subset of lindenane sesquiterpenoid dimers was not mediated by PfPARE mutations. Thus, chlorajaponilide C, but not some related compounds, required parasite esterase activity for in vitro potency, and those compounds serve as the foundation for development of potent and selective antimalarials.

6-Aza-artemisinins as Potent Antimalarial Drugs

6-Aza-artemisinins as Potent Antimalarial Drugs

Visible‐Light‐Induced C2 Alkylation of Heterocyclic N‐Oxides with N‐Hydroxyphthalimide Esters under Metal‐Free Conditions

AbstractA visible‐light‐induced site selective C−H alkylation of heterocyclic N‐oxides with N‐hydroxyphthalimide esters was developed using Eosin Y as the photocatalyst in the presence of Cs2CO3 under redox‐neutral and mild conditions. Using N‐hydroxyphthalimide esters as the radical precursors, quinoline and pyridine N‐oxides were readily coupled with a wide range of primary, secondary, and tertiary radicals to afford the desired alkylated heterocyclic N‐oxides in moderated to excellent yields. Importantly, this reaction protocol also successfully demonstrated its applications for the construction of glycosyl or bioactive natural dehydroabietic acid containing heterocyclic N‐oxides, as well as the pharmaceutical and agrochemical active alkylated quinine‐based functional molecules (potential antimalarial drug).magnified image

Exploration of Anti-plasmodial Activity of Prunus cerasoides Buch.-Ham. ex D. Don (family: Rosaceae) and Its Wood Chromatographic Fractions.

Increasing resistance to the currently available antimalarial drugs is a leading cause of failure to control malaria. Plant-based medicines are commonly used to manage numerous infections, making medicinal plants the best possible source of alternative antimalarial drugs. The objective of this study is therefore to identify antimalarial potential of Prunus cerasoides. Here, anti-plasmodial activity of crude methanolic and aqueous extracts of Prunus cerasoides and fractions obtained by reverse-phase high performance liquid chromatography (RPHPLC) were tested for in vitro activity against chloroquine sensitive Plasmodium falciparum 3D7 and chloroquine resistant INDO & Dd2 strains using SYBR Green I assay. The cytotoxic activity of active extracts/fractions was evaluated against mammalian cell lines-HeLa using MTT assay. Aqueous extracts of leaves, wood, bark and fruit of P. cerasoides showed poor to no activity up to 100µg/ml, however methanolic extract showed moderate (IC50: 21-60µg/ml) to poor (IC50: 61-100µg/ml) anti-plasmodial activity. Fractionation of wood methanolic extract led to enrichment in antimalarial activity in some of its fractions as out of 17 fractions collected, good anti-plasmodial activity (IC50: 1-20µg/ml) was shown by three fractions and nine fractions showed moderate anti-plasmodial activity. However, five fractions showed poor to no activity against Plasmodium falciparum (IC50:61-100and >100 µg/ml respectively). Furthermore, these active fractions showed no cytotoxic effects on mammalian cell lines. Findings of this study elucidate the anti-plasmodial potential of P. cerasoides and validate its traditional usage suggesting that it could be a possible source of a drug candidate in combating this disease.

Toxicity and deleterious effects of Artemisia annua essential oil extracts on mulberry pyralid (Glyphodes pyloalis)

Botanical extracts are an important source of bio-pesticides and are generally considered safe to the environment. Artemisia annua L, a medicinal plant, well known for its antimalarial potential, was evaluated as a source of a type of essential oil collected during vegetative growth stage against Glyphodes pyloalis Walker. The main chemical components of the essential oil at vegetative stage of Artemisia annua was analyzed by GC- MS and contained 1,8-cineole (18.68%), Camphor (11.4%), α-Pinene (9.3%) and 3-Carene (6.3%). The LC50 of this plant oil was estimated to be 0.652% W/V and 2.585 μL/L air incorporated orally and fumigation, respectively. The digestive enzymes such as α-amylases, Proteases, Lipases and α- and β-glucosidases were considereably inhibited in treated larvae compared with controls. Similarly, the amount of protein, glucose, and triglyceride were decreased in the treated larvae by methods used. The lower hemocyte numbers, nodule formation and activity of phenoloxidases after injection of Beauveria bassiana and latex beads showed its EO effect on immunity. The anatomy of the larval midgut after treatment showed degeneration in digestive cells. Emerging adult's ovaries showed significant changes in the ovarian sheath and lack of yolk spheres. The present investigation in accordance with our previous studies may ultimately lead to a formulation in controlling this notorious pest especially in mulberry orchards where the use of conventional chemicals is restricted.

Evaluation of 1,1-cyclopropylidene as a thioether isostere in the 4-thio-thienopyrimidine (TTP) series of antimalarials

The 4-(heteroarylthio)thieno[2,3-d]pyrimidine (TTP) series of antimalarials, represented by 1 and 17, potently inhibit proliferation of the 3D7 strain of P. falciparum (EC50 70–100 nM), but suffer from oxidative metabolism. The 1,1-cyclopropylidene isosteres 6 and 16 were designed to obviate this drawback. They were prepared by a short route that features a combined Peterson methylenation / cyclopropanation transformation of, e. g., ketone 7. Isosteres 6 and 16 possess significantly attenuated antimalarial potency relative to parents 1 and 17. This outcome can be rationalized based on the increased out-of-plane steric demands of the latter two. In support of this hypothesis, the relatively flat ketone 7 retains some of the potency of 1, even though it appears to be a comparatively inferior mimic with respect to electronics and bond lengths and angles. We also demonstrate crystallographically and computationally an apparent increase in the strength of the intramolecular sulfur hole interaction of 1 upon protonation.

Pharmacological Advances of Chloroquine and Hydroxychloroquine: From Antimalarials to Investigative Therapies in COVID-19

During the coronavirus disease 2019 (COVID-19) pandemic, numerous existing chemicals have been screened for antiviral potential against the emerging coronavirus severe acute respiratory syndrome coronavirus 2. Chloroquine and hydroxychloroquine, after exhibiting potent in vitro efficacy, have gained tremendous attention. Both therapeutics are derivatives of natural alkaloid quinine and were first synthesized to treat malaria. Thereafter, the pharmaceutical applications of the agents have expanded to many new areas. In this article, the medicinal history and pharmacological activities of chloroquine and hydroxychloroquine are summarized. Antimalarial, anti-inflammatory, antitumor, antiviral properties, and therapeutic potential in the emerging viral infection COVID-19 are discussed. Pharmacokinetics, adverse effects, and toxicities are reviewed.

English

Despite past decades of steady advances in the fight against Malaria, statistics show that the disease is still a threat to human health. Previous successes in the development of antimalarial drugs from medicinal plants have fuelled research in this area. However, antimalarial studies on fractionated extracts from such plants have progressed slowly. This study reports the antimalarial potential of fractions from Lippia kituiensis Vatke, for the first time. Column chromatography was used during fractionation. Antiplasmodial assay against chloroquine-sensitive (D6) and resistant (W2) plasmodium strains were done using hypoxanthine incorporation assay. MTT assay was used to assess the cytotoxicity of fractions against the Vero cell line. Fractions obtained exhibited varied inhibitory concentrations (IC50); with the most efficacious being, Lk-5 (19.45 &plusmn; 6.20 &mu;g/ml), Lk-3 (30.43 &plusmn; 0.68 &mu;g/ml), Lk-4 (30.82 &plusmn; 18.01 &mu;g/ml), and Lk-6 (36.53 &plusmn; 14.42 &mu;g/ml) against D6. Generally, lower activity against W2 was obtained with the most active being LK-4 (24.18&plusmn;2.50 &mu;g/ml), and Lk-5 (24.42&plusmn;5.95 &mu;g/ml), while chloroquine (positive control) exerted IC50 of 77.86&plusmn;4.09 ng/ml (W2) and 15.71&plusmn;6.49 ng/ml (D6). LK-4 was the most cytotoxic showing cytotoxic concentration (CC50), 46.26 &mu;g/ml. When tested in mice, fractions suppressed Plasmodium berghei significantly compared to the negative control with Lk-3 being most efficacious (80.01&plusmn;1). Due to substantive efficacy, GC-MS done on Lk-3 revealed 8 compounds where three have previously been ascribed to antimalarial activity and other pharmacological effects. This study adds to present knowledge of antimalarial efficacy of L. kituiensis and provides the basis for further work to be done on the isolation of compounds from its extracts. Key words: Malaria, chromatography, alkaloids, cytotoxicity, phytochemistry. &nbsp

Phytochemical screening and antioxidant activity of methanolic extracts of 53 antimalarial plants from Bagira in Eastern DR Congo

A previous study inventoried 53 plants used in traditional medicine in Bagira in Eastern Democratic Republic of Congo (DRC) in the management of malaria. During malaria disease, oxidative stress is responsible for the worsening of the patient's condition. This study aims to identify phytochemical groups and to evaluate antioxidant activity of 53 plants used in traditional medicine in Bagira to treat malaria. The phytochemical screening was carried out by conventional reactions in solution and antioxidant activity used in vitro method with 1,1-diphenyl-2- picrylhydrazyl radical (DPPH). Chemical screening has identified secondary metabolites with both antimalarial and antioxidant potential such as coumarins, steroids, saponins, tannins and terpenoids in more than 70% of plants. Antioxidant screening revealed for the first-time antioxidant activity of 18 plants, among which Dalbergia katangensis, Dialium angolense and Solanecio cydoniifolius with IC50 ≤ 1.6 µg / mL having the highest activities. This study shows that among plants used as antimalarial in Bagira several possess antioxidant power and contain many of groups presumed to be both antioxidant and antimalarial. This suggests that further studies continue to isolate compounds responsible for the proven activity.

Phytochemical constituents from Xanthium strumarium L. and evaluation of their in vitro antimalarial activities

Malaria is a major threat to global health and continues to claim lives of many people each year, especially in developing countries. Xanthium strumarium L., is used by traditional health practitioners in the management of malaria fever in North East India. Bioassay guided fractionation of X. strumarium L. extracts, led to the isolation of five compounds from the aerial part and fruit of Xanthium strumarium, namely, stigmasta-5,22-dien-3β-ol (1), xanthinosin (2), stigmasterol-3-O-β-D-glucopyranoside (3), oleic acid (4) and (E)-2, 3-dihydroxypropyl-octadec-9-enoate (5). Antimalarial potential of isolated compounds were evaluated against 3D7 strain of Plasmodium falciparum by schizont maturation inhibition assay method. The structures of isolated compounds were established by HR-MS, NMR experiments and comparison from literature data. Compounds 2 and 3 showed significant antimalarial properties against 3D7 strain of P.falciparum with IC50 value 27.25 and 7.14μM respectively. The antimalarial activities of xanthinosin (2) and stigmasterol-3-O-β-D-glucopyranoside (3) lend credence to the application of X. strumarium against malaria and thus provides new template for development of antimalarial molecules. X. strumarium has also scope for the development of antimalarial phyto-pharmaceutical with five identified compounds with P.falciparum inhibitory activity as per the drugs and cosmetics act of India (1940, amended 31st December 2016).

In Vivo Antimalarial Activity of Crude Fruit Extract of Capsicum frutescens Var. Minima (Solanaceae) against Plasmodium berghei-Infected Mice.

Background The alarming spread of parasite resistance to current antimalarial agents is threatening malaria controlling efforts. This, consequently, urged the scientific community to discover novel antimalarial drugs. Successful and most potent antimalarial drugs were obtained from medicinal plants. Capsicum frutescens is claimed to possess an antiplasmodial activity in Ethiopian and Ugandan folkloric medicine. However, there is a lack of pharmacological evidence for its antiplasmodial activity. This study, hence, was aimed at evaluating the in vivo antiplasmodial activity of C. frutescens in a mouse model. Methods The dried fruits of the plant were extracted with 80% methanol using cold maceration. A 4-day suppressive test was employed to ascertain the claimed antiplasmodial effect of the plant. Following inoculation with P. berghei, mice in treatment groups were provided with three dose levels (100, 200, and 400 mg/kg) of the extract, while 2% Tween 80 and chloroquine served as the negative and positive controls, respectively. Weight, temperature, packed cell volume, parasitemia, and survival time were then monitored. Results The acute oral toxicity study revealed that the crude extract caused no mortality and revealed no overt sign of toxicity. In the 4-day suppressive test, all dose levels of the extract were found to exhibit a significant (p < 0.05) inhibition of parasitemia compared to those of the negative control. Maximum parasite suppression (93.28%) was exerted by the highest dose (400 mg/kg/day) of extract. Also, the extract significantly (p < 0.05) prolonged survival time and prevented body weight loss and reduction in temperature and anemia compared to the vehicle-treated group. Conclusion This investigation found strong evidence that the fruit extract of C. frutescens is endowed with promising antiplasmodial activity. Hence, the plant could serve as a potential source of a newer antimalarial agent.

Alkaloid and terpenoid fractions from the leaves of Launaea taraxacifolia (Willd.) repressed the proliferation of Plasmodium berghei in mice

Medicinal plants play a major role in the treatment and prevention of malaria in many communities across the world. The aim of the study was to validate the ethno pharmacological claims of L. taraxacifolia, traditionally used to treat malaria in western part of Nigeria by evaluating its antiplasmodial efficacies. A maceration of dried leaves of L. taraxacifolia was prepared in ethanol. Alkaloid and terpenoid fractions of L. taraxacifolia were extracted using solvent-solvent extraction methods. Antiplasmodial activities of crude extract, alkaloid and terpenoid fractions of L. taraxacifolia were assessed by suppressive, curative and prophylaxis assays against chloroquine-sensitive P. berghei (NK-65) infected mice. Enzyme activities (AST, ALT, ALP and gamma-GT) were evaluated in serum of P. berghei infected mice. Radical scavenging activity of the extract was measured using DPPH, hydroxyl radical and FRAP FRPAS assays. Phytochemical analysis of the extract and fractions were done using GC system. The results of this study showed that the crude extract and fractions inhibited the proliferation of P. berghei with varying degrees. Crude extract displayed a significant (p < 0.05) chemosuppression effects at 200 and 400 mg/kg body weight. Alkaloid and terpenoid fractions were relatively potent than the crude extract at 10 mg/kg body weight. The extract and fractions of L. taraxacifolia significantly (p < 0.05) reversed the increase in activities of enzymes caused by P. berghei infection in mice. In addition, oral administration of L. taraxacifolia extract and fractions significantly normalized the concentration of urea and creatinine in the serum of treated mice. Some known alkaloids and terpenoids identified from the leaves of L. taraxacifolia are β-sitosterol 3-0-β-D-glucopyranoside, 16-carbaldehyde, 7a-Hexahydro 6H-indol-6-one, 3,4-Dimethoxyphenyl, octahydro-1-methyl and β-carboline-3-carboxylic acid. The results of this study support the ethno medical use of L. taraxacifolia leave as antimalarial remedies. Further studies on the mechanism of actions of the antiplasmodial components of L. taraxacifolia may lead to the discovery of a more potent antimalarial drug.

A Review on Antimalarial 1,2,4-Trioxane Derivatives

Malaria in recent years becomes a major health hitch globally due to the surfacing of multidrug-resistant strains of Plasmodium falciparum parasite. In recent times, artemisinin (ART)-based drugs and combination therapies become the drugs of preference for the treatment and prophylaxis of resistant P. falciparum malaria. Endoperoxide compounds natural, semi-synthetic or synthetic signifying a massive number of antimalarial agents which possess a wide structural miscellany with needed antimalarial effectiveness against resistant P. falciparum malaria. The 1,2,4-trioxane ring system deficient the lactone ring which constitutes the most significant endoperoxide structural scaffold which is believed to be the key pharmacophoric moiety and is principally responsible for the pharmacodynamic potential of endoperoxide-based antimalarials. This becomes the main reason for the research related to endoperoxide particularly 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-tetraoxane-based scaffolds gaining the noteworthy interest in recent years for developing antimalarial drugs against resistant malaria. In this paper, a comprehensive endeavour has been made to review the development of different endoperoxide antimalarial agents and structural diversity of endoperoxide molecules derived from 1,2,4-trioxane- based structural scaffolds.&#x0D; Keywords: Endoperoxide; 1,2,4-trioxane; pharmacophores; artemisinin; antimalarial.

Aminoquinolines afford resistance to cerebral malaria in susceptible mice

ObjectivesMalaria treatment is impeded by increasing resistance to conventional antimalarial drugs. Here we explored the activity of ten novel benzothiophene, thiophene and benzene aminoquinolines. MethodsIn vitro testing was performed by the lactate dehydrogenase assay in chloroquine (CQ)-sensitive Plasmodium falciparum strain 3D7 and CQ-resistant (CQR) P. falciparum strain Dd2. In vivo activity was evaluated by a modified Thompson test using C57BL/6 mice infected with Plasmodium berghei ANKA strain. ResultsNine of the ten compounds had a lower 50% inhibitory concentration (IC50) than CQ against the CQR strain Dd2. Five of these compounds that were available for in vivo evaluation were shown to be non-toxic. All five compounds administered at a dose of 160mg/kg/day for 3 days prolonged the survival of treated compared with untreated mice. Untreated control mice died by Day 7 with a mean parasitaemia of 15%. Among treated mice, a dichotomous outcome was observed, with a two-third majority of treated mice dying by Day 17 with a low mean parasitaemia of 5%, whilst one-third survived longer with a mean hyperparasitaemia of 70%; specifically, five of these mice survived a mean of 25 days, whilst two even survived past Day 31. ConclusionsThe significant antimalarial potential of this aminoquinoline series is illustrated by its excellent in vitro activity against the CQRP. falciparum strain and significant in vivo activity. Interestingly, compounds ClAQ7, ClAQ9 and ClAQ11 were able to confer resistance to cerebral malaria and afford a switch to hyperparasitaemia to mice prone to the neurological syndrome.