Ex vivo drug susceptibility and resistance mediating genetic polymorphisms of Plasmodium falciparum in Bobo-Dioulasso, Burkina Faso.

Malaria remains a leading cause of morbidity and mortality in Burkina Faso, which utilizes artemether-lumefantrine as the principal therapy to treat uncomplicated malaria and seasonal malaria chemoprevention with monthly sulfadoxine-pyrimethamine plus amodiaquine in children during the transmission season. Monitoring the activities of available antimalarial drugs is a high priority. We assessed the ex vivo susceptibility of Plasmodium falciparum to 11 drugs in isolates from patients presenting with uncomplicated malaria in Bobo-Dioulasso in 2021 and 2022. IC50 values were derived using a standard 72 h growth inhibition assay. Parasite DNA was sequenced to characterize known drug resistance-mediating polymorphisms. Isolates were generally susceptible, with IC50 values in the low-nM range, to chloroquine (median IC5010 nM, IQR 7.9-24), monodesethylamodiaquine (22, 14-46) piperaquine (6.1, 3.6-9.2), pyronaridine (3.0, 1.3-5.5), quinine (50, 30-75), mefloquine (7.1, 3.7-10), lumefantrine (7.1, 4.5-12), dihydroartemisinin (3.7, 2.2-5.5), and atovaquone (0.2, 0.1-0.3) and mostly resistant to cycloguanil (850, 543-1,290) and pyrimethamine (33,200, 18,400-54,200), although a small number of outliers were seen. Considering genetic markers of resistance to aminoquinolines, most samples had wild-type PfCRT K76T (87%) and PfMDR1 N86Y (95%) sequences. For markers of resistance to antifolates, established PfDHFR and PfDHPS mutations were highly prevalent, the PfDHPS A613S mutation was seen in 19% of samples, and key markers of high-level resistance (PfDHFR I164L; PfDHPS K540E) were absent or rare (A581G). Mutations in the PfK13 propeller domain known to mediate artemisinin partial resistance were not detected. Overall, our results suggest excellent susceptibilities to drugs now used to treat malaria and moderate, but stable, resistance to antifolates used to prevent malaria.

Ex vivo susceptibilities to ganaplacide and diversity in potential resistance mediators in Ugandan Plasmodium falciparum isolates.

Novel antimalarials are urgently needed to combat rising resistance to available drugs. The imidazolopiperazine ganaplacide is a promising drug candidate, but decreased susceptibility of laboratory strains has been linked to polymorphisms in the Plasmodium falciparum cyclic amine resistance locus (PfCARL), acetyl-CoA transporter (PfACT), and UDP-galactose transporter (PfUGT). To characterize parasites causing disease in Africa, we assessed ex vivo drug susceptibilities to ganaplacide in 750 P. falciparum isolates collected in Uganda from 2017 to 2023. Drug susceptibilities were assessed using a 72-hour SYBR Green growth inhibition assay. The median IC50 for ganaplacide was 13.8 nM, but some isolates had up to 31-fold higher IC50s (31/750 with IC50 > 100 nM). To assess genotype-phenotype associations, we sequenced genes potentially mediating altered ganaplacide susceptibility in the isolates using molecular inversion probe and dideoxy sequencing methods. PfCARL was highly polymorphic, with eight mutations present in >5% of isolates. None of these eight mutations had previously been selected in laboratory strains with in vitro drug pressure and none were found to be significantly associated with decreased ganaplacide susceptibility. Mutations in PfACT and PfUGT were found in ≤5% of isolates, except for two frequent (>20%) mutations in PfACT; one mutation in PfACT (I140V) was associated with a modest decrease in susceptibility. Overall, Ugandan P. falciparum isolates were mostly highly susceptible to ganaplacide. Known resistance mediators were polymorphic, but mutations previously selected with in vitro drug pressure were not seen, and mutations identified in the Ugandan isolates were generally not associated with decreased ganaplacide susceptibility.

Exploring the unexplored chemical space: Rational identification of new Tafenoquine analogs with antimalarial properties.

Patents tend to define a huge chemical space described by the combinatorial nature of Markush structures. However, the optimization of new principal active ingredient is frequently driven by a simple Free Wilson approach. This procedure leads to a highly focused study on the chemical space near a hit compound leaving many unexplored regions that may present highly biological active reservoirs. This study aims to demonstrate that this unveiled chemical space can hide compounds with interesting potential biological activity that would be worth pursuing. This underlines the value and necessity of broadening an approach beyond conventional strategies. Hence, we advocate for an alternative methodology that may be more efficient in the early drug discovery stages. We have selected the case of Tafenoquine, a single-dose treatment for the radical cure of P. vivax malaria approved by the FDA in 2018, as an example to illustrate the process. Through the deep exploration of the Tafenoquine chemical space, seven compounds with potential antimalarial activity have been rationally identified and synthesized. This small set is representative of the chemical diversity unexplored by the 58 analogs reported to date. After biological assessment, results evidence that our approach for rational design has proven to be a very efficient exploratory methodology suitable for the early drug discovery stages.

Antimalarial Drugs at the Intersection of SARS-CoV-2 and Rheumatic Diseases: What Are the Potential Opportunities?

Background and Objectives: The coronavirus disease of 2019 (COVID-19) pandemic has posed a serious threat to humanity and is considered a global health emergency. Antimalarial drugs (ADs) have been used in the treatment of immuno-inflammatory arthritis (IIA) and coronavirus infection (COVID-19). The aim of this review is to analyze the current knowledge about the immunomodulatory and antiviral mechanisms of action, characteristics of use, and side effects of antimalarial drugs. Material and Methods: A literature search was carried out using PubMed, MEDLINE, SCOPUS, and Google Scholar databases. The inclusion criteria were the results of randomized and cohort studies, meta-analyses, systematic reviews, and original full-text manuscripts in the English language containing statistically confirmed conclusions. The exclusion criteria were summary reports, newspaper articles, and personal messages. Qualitative methods were used for theoretical knowledge on antimalarial drug usage in AIRDs and SARS-CoV-2 such as a summarization of the literature and a comparison of the treatment methods. Results: The ADs were considered a "candidate" for the therapy of a new coronavirus infection due to mechanisms of antiviral activity, such as interactions with endocytic pathways, the prevention of glycosylation of the ACE2 receptors, blocking sialic acid receptors, and reducing the manifestations of cytokine storms. The majority of clinical trials suggest no role of antimalarial drugs in COVID-19 treatment or prevention. These circumstances do not allow for their use in the treatment and prevention of COVID-19. Conclusions: The mechanisms of hydroxychloroquine are related to potential cardiotoxic manifestations and demonstrate potential adverse effects when used for COVID-19. Furthermore, the need for high doses in the treatment of viral infections increases the likelihood of gastrointestinal side effects, the prolongation of QT, and retinopathy. Large randomized clinical trials (RCTs) have refuted the fact that there is a positive effect on the course and results of COVID-19.

Activity of Ivermectin and Its Metabolites against Asexual Blood Stage Plasmodium falciparum and Its Interactions with Antimalarial Drugs.

Ivermectin is an endectocide used widely to treat a variety of internal and external parasites. Field trials of ivermectin mass drug administration for malaria transmission control have demonstrated a reduction of Anopheles mosquito survival and human malaria incidence. Ivermectin will mostly be deployed together with artemisinin-based combination therapies (ACT), the first-line treatment of falciparum malaria. It has not been well established if ivermectin has activity against asexual stage Plasmodium falciparum or if it interacts with the parasiticidal activity of other antimalarial drugs. This study evaluated antimalarial activity of ivermectin and its metabolites in artemisinin-sensitive and artemisinin-resistant P. falciparum isolates and assessed in vitro drug-drug interaction with artemisinins and its partner drugs. The concentration of ivermectin causing half of the maximum inhibitory activity (IC50) on parasite survival was 0.81 µM with no significant difference between artemisinin-sensitive and artemisinin-resistant isolates (P = 0.574). The ivermectin metabolites were 2-fold to 4-fold less active than the ivermectin parent compound (P < 0.001). Potential pharmacodynamic drug-drug interactions of ivermectin with artemisinins, ACT-partner drugs, and atovaquone were studied in vitro using mixture assays providing isobolograms and derived fractional inhibitory concentrations. There were no synergistic or antagonistic pharmacodynamic interactions when combining ivermectin and antimalarial drugs. In conclusion, ivermectin does not have clinically relevant activity against the asexual blood stages of P. falciparum. It also does not affect the in vitro antimalarial activity of artemisinins or ACT-partner drugs against asexual blood stages of P. falciparum.

Cladosporin, A Highly Potent Antimalaria Drug?

Cladosporin, a unique natural product from the fungus Cladosporium cladosporioides, exhibits nanomolar inhibitory activity against Plasmodium falciparum by targeting its cytosolic lysyl-tRNA synthetase (PfKRS) to inhibit protein biosynthesis. Due to its exquisite selectivity towards pathogenic parasites, cladosporin has become a very promising lead compound for developing antiparasitic drugs to treat drug-resistant malaria and cryptosporidiosis infections. Here we review the recent research progress of cladosporin covering aspects of the chemical synthesis, biosynthesis, bioactivity, cellular target and structure-activity relationship.

The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures.

BACKGROUND: By 2016, signs of emergence of Plasmodium falciparum resistance to artemisinin and partner drugs were detected in the Greater Mekong Subregion. Recently, the independent evolution of artemisinin resistance has also been reported in Africa and South America. This alarming scenario calls for the urgent development of new antimalarials with novel modes of action. We investigated the interference with protein aggregation, which is potentially toxic for the cell and occurs abundantly in all Plasmodium stages, as a hitherto unexplored drug target in the pathogen. RESULTS: Attempts to exacerbate the P. falciparum proteome's propensity to aggregation by delivering endogenous aggregative peptides to in vitro cultures of this parasite did not significantly affect their growth. In contrast, protein aggregation inhibitors clearly reduced the pathogen's viability. One such compound, the bis(styrylpyridinium) salt YAT2150, exhibited potent antiplasmodial activity with an in vitro IC50 of 90 nM for chloroquine- and artemisinin-resistant lines, arresting asexual blood parasites at the trophozoite stage, as well as interfering with the development of both sexual and hepatic forms of Plasmodium. At its IC50, this compound is a powerful inhibitor of the aggregation of the model amyloid ß peptide fragment 1-40, and it reduces the amount of aggregated proteins in P. falciparum cultures, suggesting that the underlying antimalarial mechanism consists in a generalized impairment of proteostasis in the pathogen. YAT2150 has an easy, rapid, and inexpensive synthesis, and because it fluoresces when it accumulates in its main localization in the Plasmodium cytosol, it is a theranostic agent. CONCLUSIONS: Inhibiting protein aggregation in Plasmodium significantly reduces the parasite's viability in vitro. Since YAT2150 belongs to a novel structural class of antiplasmodials with a mode of action that potentially targets multiple gene products, rapid evolution of resistance to this drug is unlikely to occur, making it a promising compound for the post-artemisinin era.

The Problem of Antimalarial-Drug Abuse by the Inhabitants of Ghana.

Introduction: Malaria is still a huge social and economic health problem in the world. It especially affects the developing countries of Africa. A particular problem is the misuse and abuse of over-the-counter antimalarials. This problem could lead to the emergence of drug-resistant strains and the subsequent elimination of more antimalarials from the list of effective antimalarials in Ghana. Methods: During the implementation of the study, an original questionnaire was used to collect data among Ghanaians on their knowledge of malaria, attitude towards antimalarials and their use of antimalarials. Results: The proportion in the analyzed subgroups was compared using the chi-square test. The analysis was conducted using TIBCO Software Inc., Krakow, Poland (2017) and Statistica (data analysis software system), version 13. In total, 86.29% of respondents knew the symptoms of malaria (p = 0.02) and 57.2% knew the cause of malaria (p < 0.001). Respondents with higher education were significantly more likely to know the symptoms of malaria (96%) p < 0.001. In the study group, only 74.59% of the respondents consulted medical personnel before taking the antimalarial drug (p = 0.51) and only 14.2% of the remaining respondents performed a rapid diagnostic test for malaria. Conclusions: The awareness of Accra and Yendi native inhabitants about the causes and symptoms of malaria and alternative ways of prevention is quite high. People's education very significantly influences the way Accra residents deal with suspected malaria. Widespread public education and awareness and accessibility to places where antimalarial drugs are sold play a very important role in the proper use of antimalarial drugs.

Novel Strategies for Cancer Combat: Drug Combination Using Repurposed Drugs Induces Synergistic Growth Inhibition of MCF-7 Breast and HT-29 Colon Cancer Cells.

Our group developed a new model of drug combination consisting of the use of antineoplastic drugs and different repurposed drugs, having demonstrated that antimalarial and central nervous system (CNS) drugs have a promising anticancer profile as standalone agents, as well as in combined regimens. Here, we evaluated the anticancer profiles of two different CNS drugs (edaravone and quetiapine), both alone and in combination with antineoplastic agents for breast and colon cancer, to explore whether these repurposed drugs could synergistically enhance the anticancer potential of chemotherapeutic drugs. We also developed a new model of combination using two repurposed drugs, to explore whether this model of combination could also be suitable for application in breast and colon cancer therapy. MCF-7 and HT-29 cancer cells were incubated for 48 h with each individual drug (0.01-100 µM) to determine their IC50. Cells were then treated with the IC50 value for doxorubicin or paclitaxel (MCF-7) or 5-fluorouracil (HT-29) and combined with increasing concentrations of edaravone or quetiapine for 48 h. Both cell lines were also treated with a combination of two antimalarial drugs (mefloquine and pyronaridine) or two CNS drugs (fluphenazine and sertraline) for 48 h. We found that the use of quetiapine in combined therapies seems to synergistically enhance the anticancer activity of doxorubicin for the management of breast cancer. Both CNS drugs significantly improved the cytotoxic potential of 5-fluorouracil in HT-29 cells, with quetiapine synergistically interacting with the antineoplastic drug in this drug combination. Regarding the combination of repurposed drugs, only found one synergic combination regimen (sertraline IC50 plus variable concentrations of fluphenazine) with anticancer potential against HT-29 colon cancer cells was found. Taken together, these results suggest that quetiapine and edaravone can be used as adjuvant agents in chemotherapy for colon cancer. It was also found that the combination of repurposed drugs, specifically the CNS drugs sertraline and fluphenazine, may have an interesting profile for application in colon cancer novel therapies.

Spirofused Tetrahydroisoquinoline-Oxindole Hybrids (Spiroquindolones) as Potential Multitarget Antimalarial Agents: Preliminary Hit Optimization and Efficacy Evaluation in Mice.

Previous studies suggest that 3',5'-dihydro-2'H-spiro[indoline-3,1'-isoquinolin]-2-ones (DSIIQs [spiroquindolones]) are multitarget antiplasmodial agents that combine the actions of spiroindolone and naphthylisoquinoline antimalarial agents. In this study, 12 analogues of compound (±)-5 (moxiquindole), the prototypical spiroquindolone, were synthesized and tested for antiplasmodial activity. Compound (±)-11 (a mixture of compounds 11a and 11b), the most potent analogue, displayed low-nanomolar activity against P. falciparum chloroquine-sensitive 3D7 strain (50% inhibitory concentration [IC50] for 3D7 = 21 ± 02 nM) and was active against all major erythrocytic stages of the parasite life cycle (ring, trophozoite, and schizont); it also inhibited hemoglobin metabolism and caused extensive vacuolation in parasites. In drug-resistant parasites, compound (±)-11 exhibited potent activity (IC50 for Dd2 = 58.34 ± 2.04 nM) against the P. falciparum multidrug-resistant Dd2 strain, and both compounds (±)-5 and (±)-11 displayed significant cross-resistance against the P. falciparum ATP4 mutant parasite Dd2 SJ733 but not against the Dd2 KAE609 strain. In mice, both compounds (±)-5 and (±)-11 displayed dose-dependent reduction of parasitemia with suppressive 50% effective dose (ED50) values of 0.44 and 0.11 mg/kg of body weight, respectively. The compounds were also found to be curative in vivo and are thus worthy of further investigation.

Simultaneous and enantiospecific quantification of primaquine and carboxyprimaquine in human plasma using liquid chromatography-tandem mass spectrometry.

BACKGROUND: The enantiomers of the 8-aminoquinoline anti-malarial primaquine have different pharmacological properties. Development of an analytical method for simultaneous quantification of the enantiomers of primaquine and its metabolite, carboxyprimaquine, will support clinical pharmacometric assessments. METHODS: A simple and sensitive method consisting of liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was developed for simultaneous and enantiospecific determination of primaquine and its metabolite, carboxyprimaquine, in human plasma. Stable isotopes were used as internal standards to compensate for potential interference and matrix effects. Plasma samples (100 µL) were precipitated with 1% formic acid in acetonitrile followed by phospholipid removal solid phase extraction. Primaquine and carboxyprimaquine enantiomers were separated on a Chiralcel OD-3R (150 mm × 4.6 mm; I.D. 3 µm) column using a LC gradient mode. For separation of racemic primaquine and carboxyprimaquine, the LC method was modified and validated using a reverse phase column (Hypersil Gold 100 mm × 4.6 mm; I.D. 3 µm) and a mobile phase composed of 10 mM ammonium acetate buffer, pH 3.5 and acetonitrile in the isocratic mode. Method validation was performed according to regulatory guidelines. RESULTS: The calibration range was set to 0.571-260 ng/mL and 2.44-2,500 ng/mL for primaquine and carboxyprimaquine enantiomers, respectively, resulting in a correlation coefficient (r2) ≥ 0.0998 for all calibration curves. The intra- and inter-day assay precisions were < 10% and the accuracy was between 94.7 to 103% for all enantiomers of primaquine and carboxyprimaquine. The enantiospecific method was also modified and validated to quantify racemic primaquine and carboxyprimaquine, reducing the total run time from 30 to 8 min. The inter-, intra-day assay precision of the racemic quantification method was < 15%. The absolute recoveries of primaquine and carboxyprimaquine were between 70 and 80%. Stability was demonstrated for up to 2 years in - 80 °C. Both the enantiomeric and racemic LC-MS/MS methods were successfully implemented in pharmacokinetic studies in healthy volunteers. CONCLUSIONS: Simple, sensitive and accurate LC-MS/MS methods for the quantification of enantiomeric and racemic primaquine and carboxyprimaquine in human plasma were validated successfully and implemented in clinical routine drug analysis.

Re-orienting anti-malarial drug development to better serve pregnant women.

Malaria is one of the most serious infectious diseases affecting predominantly low- and middle-income countries, where pregnant women are among the populations at risk. There are limited options to prevent or treat malaria in pregnancy, particularly in the first trimester, and existing ones may not work optimally in areas where the threat of drug resistance is rising. As malaria elimination is a key goal of the global health community, the inclusion of pregnant women in the adult population to protect from malaria will be key to achieving success. New, safe, and effective options are needed but it can take decades of evidence-gathering before a medicine is recommended for use in pregnancy. This is because pregnant women are typically not included in pre-registration clinical trials due to fear of causing harm. Data to support dosing and safety in pregnancy are subsequently collected in post-licensure studies. There have been growing calls in recent years that this practice needs to change, amplified by the COVID-19 pandemic and increasing public awareness that newly developed medicines generally cannot be administered to pregnant women from the onset. The development of new anti-malarials should ensure that data informing their use in pregnancy and breastfeeding are available earlier. To achieve this, a mindset change and a different approach to medications for pregnant women are needed. Changes in non-clinical, translational, and clinical approaches in the drug development pathway, in line with recent recommendations from the regulatory bodies are proposed in this Comment. The new approach applies to any malaria-endemic region, regardless of the type of Plasmodium responsible for malaria cases. By incorporating intentional and systematic data collection from pre-registration stages of development through post-licensure, it will be possible to inform on the benefit/risk balance of a new anti-malarial earlier and help ensure that the needs of pregnant individuals are addressed in a more timely and equitable manner in the future.

Advances and roadblocks in the treatment of malaria.

The deployment of artesunate for severe malaria and the artemisinin combination therapies (ACTs) for uncomplicated malaria has been a major advance in antimalarial therapeutics. These drugs have reduced treated mortality, accelerated recovery and reduced treatment failure rates and transmission from the treated infection. Artemisinin derivatives remain highly effective against falciparum malaria in most malaria endemic areas, but significant resistance has emerged in the Greater Mekong subregion of Southeast Asia. Resistance to artemisinins was followed by resistance to the ACT partner drugs, and fit multidrug resistant parasite lineages have now spread widely across the region. ACTs remain highly effective against P. vivax and the other malaria species. Recent studies have shown that radical curative regimens of primaquine (to prevent relapse) can be shortened to 7 days, and that the newly introduced single dose tafenoquine is an alternative, although the currently recommended dose is insufficient in Southeast Asia and Oceania. Targeted malaria elimination using focal mass treatments with dihydroartemisinin-piperaquine have proved safe and effective malaria elimination accelerators, but progress overall towards malaria elimination is slow. Indeed since 2015 overall malaria case numbers globally have risen. As new drugs will not become widely available in the near future, active measures to preserve the current antimalarials should be given the highest priority.

A Concise Total Synthesis of Dehydroantofine and Its Antimalarial Activity against Chloroquine-Resistant Plasmodium falciparum.

The total synthesis of dehydroantofine was achieved by employing a novel, regioselective, azahetero Diels-Alder reaction of easily accessible 3,5-dichloro-2H-1,4-oxazin-2-one with 14 a as a key step. Furthermore, it is demonstrated that dehydroantofine is a promising candidate as a new antimalarial agent in a biological assay with chloroquine-resistant Plasmodium falciparum.

Programmed Multiple C-H Bond Functionalization of the Privileged 4-hydroxyquinoline Template.

The introduction of substituents on bare heterocyclic scaffolds can selectively be achieved by directed C-H functionalization. However, such methods have only occasionally been used, in an iterative manner, to decorate various positions of a medicinal scaffold to build chemical libraries. We herein report the multiple, site selective, metal-catalyzed C-H functionalization of a "programmed" 4-hydroxyquinoline. This medicinally privileged template indeed possesses multiple reactive sites for diversity-oriented functionalization, of which four were targeted. The C-2 and C-8 decorations were directed by an N-oxide, before taking benefit of an O-carbamoyl protection at C-4 to perform a Fries rearrangement and install a carboxamide at C-3. This also released the carbonyl group of 4-quinolones, the ultimate directing group to functionalize position 5. Our study highlights the power of multiple C-H functionalization to generate diversity in a biologically relevant library, after showing its strong antimalarial potential.

Xylopic acid-amodiaquine and xylopic acid-artesunate combinations are effective in managing malaria in Plasmodium berghei-infected mice.

BACKGROUND: Evidence of Plasmodium resistance to some of the current anti-malarial agents makes it imperative to search for newer and effective drugs to combat malaria. Therefore, this study evaluated whether the co-administrations of xylopic acid-amodiaquine and xylopic acid-artesunate combinations will produce a synergistic anti-malarial effect. METHODS: Antiplasmodial effect of xylopic acid (XA: 3, 10, 30, 100, 150 mg kg-1), artesunate (ART: 1, 2, 4, 8, 16 mg kg-1), and amodiaquine (AQ: 1.25, 2.5, 5, 10, 20 mg kg-1) were evaluated in Plasmodium berghei (strain ANKA)-infected mice to determine respective ED50s. Artemether/lumefantrine was used as the positive control. XA/ART and XA/AQ were subsequently administered in a fixed-dose combination of their ED50s (1:1) and the combination fractions of their ED50s (1/2, 1/4, 1/8, 1/16, and 1/32) to determine the experimental ED50s (Zexp). An isobologram was constructed to determine the nature of the interaction between XA/ART, and XA/AQ combinations by comparing Zexp with the theoretical ED50 (Zadd). Bodyweight and 30-day survival post-treatment were additionally recorded. RESULTS: ED50s for XA, ART, and AQ were 9.0 ± 3.2, 1.61 ± 0.6, and 3.1 ± 0.8 mg kg-1, respectively. The Zadd, Zexp, and interaction index for XA/ART co-administration was 5.3 ± 2.61, 1.98 ± 0.25, and 0.37, respectively while that of XA/AQ were 6.05 ± 2.0, 1.69 ± 0.42, and 0.28, respectively. The Zexp for both combination therapies lay significantly (p < 0.001) below the additive isoboles showing XA acts synergistically with both ART and AQ in clearing the parasites. High doses of XA/ART combination significantly (p < 0.05) increased the survival days of infected mice with a mean hazard ratio of 0.40 while all the XA/AQ combination doses showed a significant (p < 0.05) increase in the survival days of infected mice with a mean hazard ratio of 0.27 similar to AL. Both XA/ART and XA/AQ combined treatments significantly (p < 0.05) reduced weight loss. CONCLUSION: Xylopic acid co-administration with either artesunate or amodiaquine produces a synergistic anti-plasmodial effect in mice infected with P. berghei.

Identification of Plasmodium falciparum heat shock 90 inhibitors via molecular docking.

A virtual screen was performed to identify anti-malarial compounds targeting Plasmodium falciparum heat shock 90 protein by applying a series of drug-like and commercial availability filters to compounds in the ZINC database, resulting in a virtual library of more than 13 million candidates. The goal of the virtual screen was to identify novel compounds which could serve as a starting point for the development of antimalarials with a mode of action different from anything currently used in the clinic. The screen targeted the ATP binding pocket of the highly conserved Plasmodium heat shock 90 protein, as this protein is critical to the survival of the parasite and has several significant structural differences from the human homolog. The top twelve compounds from the virtual screen were tested in vitro, with all twelve showing no antiproliferative activity against the human fibroblast cell line and three compounds exhibiting single digit or better micromolar antiproliferative activity against the chloroquine-sensitive P. falciparum 3D7 strain.

Chemotherapeutic and prophylactic antimalarial drugs induce cell death through mitochondrial-mediated apoptosis in murine models.

Malaria is a parasitic disease that has defied many treatment plans. This study was carried out to investigate the host mitochondrial response to malarial infection and selected antimalarial chemotherapy using murine models. The effects of artesunate (ART) and proguanil (PRG) on mitochondrial Permeability Transition (mPT), mitochondrial ATPase (mATPase), level of malondialdehyde (MDA) and activities of antioxidant enzymes; catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), Xanthine oxidase (XO), glutathione S-transferase (GST) and reduced glutathione (GSH) were estimated in Plasmodium berghei-infected mice treated with ART and PRG. Besides, apoptotic markers, such as caspases 3, 9 and DNA fragmentation were estimated. Unparasitised (NORMAL) and parasitized but untreated (PU) animals were used as controls. The mPT pore opening fold of 9 (ART), 3 (PRG), and 4 (PU) were observed relative to calcium (23) for in vivo study. In vitro, graded concentrations (20, 40, 80 and 160 µg/mL) of ART gave mPT induction folds of 1, 21, 23 and 25, respectively, relative to calcium (9) while PRG did not have effect in the absence of calcium. In vivo, ART significantly (p < 0.001) enhanced mATPase activity than PRG. The PRG and ART increased the MDA levels in vivo. Oral administration of ART and PRG altered antioxidant enzymes status, Caspases 3 and 9 were significantly activated in PRG-treated groups; there was significant increase in DNA fragmentation in PU and PRG groups compared with the normal control. The results obtained showed that malaria parasite and antimalarial drugs cause mitochondrial-mediated apoptosis.

Recent advances in targeting malaria with nanotechnology-based drug carriers.

Malaria, as one of the most common human infectious diseases, remains the greatest global health concern, since approximately 3.5 billion people around the world, especially those in subtropical areas, are at the risk of being infected by malaria. Due to the emergence and spread of drug resistance to the current antimalarials, malaria-related mortality and incidence rates have recently increased. To overcome the aforementioned obstacles, nano-vehicles based on biodegradable, natural, and non-toxic polymers have been developed. Accordingly, these systems are considered as a potential drug vehicle, which due to their unique properties such as the excellent safety profile, good biocompatibility, tunable structure, diversity, and the presence of functional groups within the polymer structure, could facilitate covalent attachment of targeting moieties and antimalarials to the polymeric nano-vehicles. In this review, we highlighted some recent developments of liposomes as unique nanoscale drug delivery vehicles and several polymeric nanovehicles, including hydrogels, dendrimers, self-assembled micelles, and polymer-drug conjugates for the effective delivery of antimalarials.

Effect of Antimalarial Drugs on the Immune Response to Intramuscular Rabies Vaccination Using a Postexposure Prophylaxis Regimen.

BACKGROUND: Chloroquine can impair the immune responses to intradermal rabies vaccination. Current guidelines recommend an extra intramuscular dose be given for postexposure prophylaxis in previously unvaccinated persons taking any antimalarial drug. METHODS: We conducted a randomized, open-label, single-site study in 103 previously unvaccinated healthy adults age ≥18 to ≤60 years old to evaluate the effects of chloroquine, atovaquone/proguanil (Malarone), and doxycycline on the antibody response to a purified chick embryo cell vaccine, given on a postexposure prophylaxis schedule. All treatment groups received antimalarials 14 days prior to and during vaccination. RESULTS: All subjects achieved accepted neutralizing antibody titers of ≥0.5 IU/mL following the second rabies vaccination dose and maintained this protection through the duration of the study. We observed a reduction in rabies antibody geometric mean titer in the chloroquine versus control groups 28 days after vaccination: 2.3 versus 6.87 IU/mL, respectively (P < .001, t test). A significant difference was not observed for those taking Malarone or doxycycline. CONCLUSIONS: We conclude that there is no reduction of rabies antibody response in subjects taking Malarone or doxycycline, but a significant reduction in those taking chloroquine; however, accepted antibody levels were achieved for all 3 antimalarials. CLINICAL TRIALS REGISTRATION: NCT02564471.