Antimalarial analysis of pharmaceutical formulations and biological samples by capillary electrophoresis: the state of the art and applications.

Malaria is a serious public health problem, being an endemic disease in 84 countries, mainly in Africa. This review explores the application of capillary electrophoresis (CE) techniques for analyzing antimalarial drugs, highlighting methods from 2000 to 2023 for the analysis of pharmaceutical formulations and human biological samples. The versatility, selectivity, high efficiency, cost-effectiveness, and high analytical frequency of CE techniques have become attractive choices for pharmaceutical analysis, focusing on quality control and impurity analysis applications. The evolution of achiral and chiral electromigration methods has been described based on the features of each mode of separation: capillary zone electrophoresis (CZE), micellar electrokinetic chromatography, microemulsion electrokinetic chromatography, and capillary electrochromatography. As expected, CZE is reported in most articles owing to its compatibility with drug properties and separation mode. However, it is necessary to perform other separation modes for a few drugs that are present in neutral form. After exhaustive research using different databases and statistical analyses, 27 articles using CE techniques for antimalarial drug analysis were found and are mentioned in this review.

Lycopene supplementation promoted increased survival and decreased parasitemia in mice with severe malaria: comparison with N-acetylcysteine.

Oxidative stress is involved in the pathogenesis of malaria, causing anemia, respiratory complications, and cerebral malaria. To mitigate oxidative stress, we investigated the effect of nutritional supplementation whit lycopene (LYC) on the evolution of parasitemia and survival rate in mice infected with Plasmodium berghei ANKA (Pb), comparing to the effects promoted by N-acetylcysteine (NAC). Therefore, 175 mice were randomly distributed into 4 groups; Sham: untreated and uninfected animals; Pb: animals infected with Pb; LYC+Pb: animals treated with LYC and infected with Pb; NAC+Pb: animals treated with NAC and infected with Pb. The animals were followed for 12 days after infection, and survival and parasitemia rates were evaluated. There was a 40.1% increase in parasitemia in the animals of the Pb group on the 12th day, and a survival rate of 45%. LYC supplementation slowed the development of parasitemia to 19% and promoted a significative increase in the survival rate of 80% on the 12th day after infection, compared to the Pb group, effects superior to those promoted by NAC, providing strong evidence of the beneficial effect of LYC on in vivo malaria and stressing the importance of antioxidant supplementation in the treatment of this disease.

The human malaria-Aotus monkey model: a historical perspective in antimalarial chemotherapy research at the Gorgas Memorial Laboratory-Panama.

The human malaria-Aotus monkey model has served the malaria research community since its inception in 1966 at the Gorgas Memorial Laboratory (GML) in Panama. Spanning over five decades, this model has been instrumental in evaluating the in vivo efficacy and pharmacokinetics of a wide array of candidate antimalarial drugs, whether used singly or in combination. The animal model could be infected with drug-resistant and susceptible Plasmodium falciparum and Plasmodium vivax strains that follow a characteristic and reproducible course of infection, remarkably like human untreated and treated infections. Over the years, the model has enabled the evaluation of several synthetic and semisynthetic endoperoxides, for instance, artelinic acid, artesunate, artemether, arteether, and artemisone. These compounds have been evaluated alone and in combination with long-acting partner drugs, commonly referred to as artemisinin-based combination therapies, which are recommended as first-line treatment against uncomplicated malaria. Further, the model has also supported the evaluation of the primaquine analog tafenoquine against blood stages of P. vivax, contributing to its progression to clinical trials and eventual approval. Besides, the P. falciparum/Aotus model at GML has also played a pivotal role in exploring the biology, immunology, and pathogenesis of malaria and in the characterization of drug-resistant P. falciparum and P. vivax strains. This minireview offers a historical overview of the most significant contributions made by the Panamanian owl monkey (Aotus lemurinus lemurinus) to malaria chemotherapy research.

Delayed gametocyte clearance in Plasmodium vivax malaria is associated with polymorphisms in the cytochrome P450 reductase (CPR).

Primaquine (PQ) is the main drug used to eliminate dormant liver stages and prevent relapses in Plasmodium vivax malaria. It also has an effect on the gametocytes of Plasmodium falciparum; however, it is unclear to what extent PQ affects P. vivax gametocytes. PQ metabolism involves multiple enzymes, including the highly polymorphic CYP2D6 and the cytochrome P450 reductase (CPR). Since genetic variability can impact drug metabolism, we conducted an evaluation of the effect of CYP2D6 and CPR variants on PQ gametocytocidal activity in 100 subjects with P. vivax malaria. To determine gametocyte density, we measured the levels of pvs25 transcripts in samples taken before treatment (D0) and 72 hours after treatment (D3). Generalized estimating equations (GEEs) were used to examine the effects of enzyme variants on gametocyte densities, adjusting for potential confounding factors. Linear regression models were adjusted to explore the predictors of PQ blood levels measured on D3. Individuals with the CPR mutation showed a smaller decrease in gametocyte transcript levels on D3 compared to those without the mutation (P = 0.02, by GEE). Consistent with this, higher PQ blood levels on D3 were associated with a lower reduction in pvs25 transcripts. Based on our findings, the CPR variant plays a role in the persistence of gametocyte density in P. vivax malaria. Conceptually, our work points to pharmacogenetics as a non-negligible factor to define potential host reservoirs with the propensity to contribute to transmission in the first days of CQ-PQ treatment, particularly in settings and seasons of high Anopheles human-biting rates.

Artesunate-mefloquine therapy for uncomplicated Plasmodium falciparum malaria: an updated systematic review and meta-analysis of efficacy and safety.

To provide a continuous update on the safety and efficacy of artesunate-mefloquine (ASMQ) compared with other artemisinin combination therapy (ACT) schemes used in the treatment of uncomplicated malaria caused by Plasmodium falciparum, this study updated and expanded the results of the systematic literature review published in 2016. Only randomised controlled clinical trials published from 1 January 2001 to 12 June 2023 from five databases were included in this study. The results related to efficacy, expressed through RR, were summarized in meta-analyses, performed according to the compared ACTs and with the intention-to-treat and per-protocol analyses. The results related to safety were synthesized in a descriptive manner. Thirty-two studies were included, of which 24 had been analysed in the 2016 review and eight new ones were added. Although the methodological quality of most studies was considered moderate, the body of evidence gathered indicates that ASMQ continues to be safe and effective for the treatment of uncomplicated infections caused by P. falciparum compared with other ACTs. However, the inclusion of two new studies, which identified failure rates exceeding 10%, suggests a possible reduction in the efficacy of ASMQ in the analysed locations. The incidence of serious adverse effects, such as seizure, encephalopathy and cardiac arrhythmia, was infrequent in both the ASMQ group and the comparison groups. After including new evidence, ASMQ is still recommended as a first-line treatment of uncomplicated malaria caused by P. falciparum, although local aspects need to be considered.

Exploring the Potential of Natural Products as Antiparasitic Agents for Neglected Tropical Diseases.

Recent developments in the use of natural product-based molecules as antiparasitic agents for Malaria, leishmaniasis (LE), Chagas disease (CD), and Human African trypanosomiasis (HAT) are reviewed. The role of diverse plants in developing bioactive species is discussed in addition to analyzing the structural diversity of natural products as active agents and the diverse biological applications in CD, HAT, LE, and Malaria. This review focuses on medicinal chemistry, emphasizing the structural characteristics of natural molecules as bioactive agents against parasitic infections caused by Leishmania, Trypanosoma, and Plasmodium parasites.

In Vitro and in Vivo Antimalarial Activity, Cytotoxicity and Phytochemical HRMS2 Profile of Plants from the Western Pará State, Brazilian Amazonia.

Ethnopharmacology and botanical taxonomy are valid criteria used to selecting plants for antimalarial bioprospection purposes. Based on these two criteria, ethanol extracts of 11 plants from Santarém City vicinities, Western Pará State, Brazilian Amazonia, had their in vitro antiplasmodial activity against chloroquine-resistant Plasmodium falciparum (W2 clone) assessed by the PfLDH method, whereas their cytotoxicity to HepG2-A16 cells was assessed through MTT assay. Acmella oleracea, Siparuna krukovii and Trema micrantha extracts disclosed the highest rate of parasite growth inhibition (90 %) in screening tests. In vivo antimalarial assays were conducted with these extracts against Plasmodium berghei (NK 65 strain) infected mice. Inhibition rate of parasite multiplication ranged from 41.4 % to 60.9 % at the lowest extract dose (25 mg/kg). HPLC-ESI-HRMS2 analyses allowed the putative identification of alkylamides, fatty acids, flavonoid glycosides and alkaloids in ethanol extracts deriving from these three plant species. Results pointed towards A. oleracea flowers ethanol extract as the most promising potential candidate to preclinical studies aiming the development of antimalarial phytomedicine.

Brazilian plants with antimalarial activity: A review of the period from 2011 to 2022.

ETHNOPHARMACOLOGICAL RELEVANCE: Malaria continues to be a serious global public health problem in subtropical and tropical countries of the world. The main drugs used in the treatment of human malaria, quinine and artemisinin, are isolates of medicinal plants, making the use of plants a widespread practice in countries where malaria is endemic. Over the years, due to the increased resistance of the parasite to chloroquine and artemisinin in certain regions, new strategies for combating malaria have been employed, including research with medicinal plants. AIM: This review focuses on the scientific production regarding medicinal plants from Brazil whose antimalarial activity was evaluated during the period from 2011 to 2022. 2. METHODOLOGY: For this review, four electronic databases were selected for research: Pubmed, ScienceDirect, Scielo and Periódicos CAPES. Searches were made for full texts published in the form of scientific articles written in Portuguese or English and in a digital format. In addition, prospects for new treatments as well as future research that encourages the search for natural products and antimalarial derivatives are also presented. RESULTS: A total of 61 publications were encountered, which cited 36 botanical families and 92 species using different Plasmodium strains in in vitro and in vivo assays. The botanical families with the most expressive number of species found were Rubiaceae, Apocynaceae, Fabaceae and Asteraceae (14, 14, 9 and 6 species, respectively), and the most frequently cited species were of the genera Psychotria L. (8) and Aspidosperma Mart. (12), which belong to the families Rubiaceae and Apocynaceae. Altogether, 75 compounds were identified or isolated from 28 different species, 31 of which are alkaloids. In addition, the extracts of the analyzed species, including the isolated compounds, showed a significant reduction of parasitemia in P. falciparum and P. berghei, especially in the clones W2 CQ-R (in vitro) and ANKA (in vivo), respectively. The Brazilian regions with the highest number of species analyzed were those of the north, especially the states of Pará and Amazonas, and the southeast, especially the state of Minas Gerais. CONCLUSION: Although many plant species with antimalarial potential have been identified in Brazil, studies of new antimalarial molecules are slow and have not evolved to the production of a phytotherapeutic medicine. Given this, investigations of plants of traditional use and biotechnological approaches are necessary for the discovery of natural antimalarial products that contribute to the treatment of the disease in the country and in other endemic regions.

In silico prediction and in vitro assessment of novel heterocyclics with antimalarial activity.

The development of new antimalarials is paramount to keep the goals on reduction of malaria cases in endemic regions. The search for quality hits has been challenging as many inhibitory molecules may not progress to the next development stage. The aim of this work was to screen an in-house library of heterocyclic compounds (HCUV) for antimalarial activity combining computational predictions and phenotypic techniques to find quality hits. The physicochemical determinants, pharmacokinetic properties (ADME), and drug-likeness of HCUV were evaluated in silico, and compounds were selected for structure-based virtual screening and in vitro analysis. Seven Plasmodium target proteins were selected from the DrugBank Database, and ligands and receptors were processed using UCSF Chimera and Open Babel before being subjected to docking using Autodock Vina and Autodock 4. Growth inhibition of P. falciparum (3D7) cultures was tested by SYBR Green assays, and toxicity was assessed using hemolytic activity tests and the Galleria mellonella in vivo model. From a total of 792 compounds, 341 with good ADME properties, drug-likeness, and no interference structures were subjected to in vitro analysis. Eight compounds showed IC50 ranging from 0.175 to 0.990 µM, and active compounds included pyridyl-diaminopyrimido-diazepines, pyridyl-N-acetyl- and pyridyl-N-phenyl-pyrazoline derivatives. The most potent compound (UV802, IC50 0.178 µM) showed no toxicophoric and was predicted to interact with P. falciparum 1-cysperoxidredoxin (PfPrx1). For the remaining 7 hits (IC50 < 1 µM), 3 showed in silico binding to PfPrx1, one was predicted to bind the haloacid dehalogenase-like hydrolase and plasmepsin II, and one interacted with the plasmodial heat shock protein 90.

Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activity.

Drug resistance to commercially available antimalarials is a major obstacle in malaria control and elimination, creating the need to find new antiparasitic compounds with novel mechanisms of action. The success of kinase inhibitors for oncological treatments has paved the way for the exploitation of protein kinases as drug targets in various diseases, including malaria. Casein kinases are ubiquitous serine/threonine kinases involved in a wide range of cellular processes such as mitotic checkpoint signaling, DNA damage response, and circadian rhythm. In Plasmodium, it is suggested that these protein kinases are essential for both asexual and sexual blood-stage parasites, reinforcing their potential as targets for multi-stage antimalarials. To identify new putative PfCK2α inhibitors, we utilized an in silico chemogenomic strategy involving virtual screening with docking simulations and quantitative structure-activity relationship predictions. Our investigation resulted in the discovery of a new quinazoline molecule (542), which exhibited potent activity against asexual blood stages and a high selectivity index (>100). Subsequently, we conducted chemical-genetic interaction analysis on yeasts with mutations in casein kinases. Our chemical-genetic interaction results are consistent with the hypothesis that 542 inhibits yeast Cka1, which has a hinge region with high similarity to PfCK2α. This finding is in agreement with our in silico results suggesting that 542 inhibits PfCK2α via hinge region interaction.

[Extracorporeal support treatment in severe malaria]. / Tratamiento con sostén extracorpóreo en malaria grave.

Malaria is a wide-spread disease in tropical areas. The severe form is characterized by organic involvement and/or hyperparasitaemia. Criteria for early monitoring in intensive care rooms are defined; without a timely and early treatment, severe malaria has a 100% mortality. Although the literature in these cases is not extensive, extracorporeal therapy used sequentially for hepatic and renal detoxification is a useful and safe tool that can be used in intensive care. We describe the case of a 36-year-old man with a diagnosis of severe malaria according to WHO criteria. He began treatment with intravenous artesunate and due to a torpid evolution, a sudden increase in bilirubinemia with encephalopathy, parameters of acute kidney injury and acute pulmonary edema, undergoes extracorporeal sequential treatment, coupled with plasma filtration adsorption, high-exchange plasmapheresis, and continuous hemodiafiltration with favorable evolution. This case shows that extracorporeal support in trained hands and in a timely manner is effective when organ failure evolves rapidly to achieve stability and provide necessary time for definitive treatment, in this case rapid action antimalarials until parasitemia becomes negative.

La malaria es una enfermedad con amplia distribución en áreas tropicales. En su forma grave se caracteriza por afección orgánica y/o hiperparasitemia. Se definen los criterios para el monitoreo temprano en las salas de terapia intensiva, debido a que sin tratamiento oportuno y precoz la malaria grave tiene una mortalidad de 100%. Si bien no es amplia la literatura en este aspecto la terapia extracorpórea en forma secuencial para detoxificación hepática y renal es una herramienta útil y segura que puede ser utilizada en terapia intensiva. Se describe un caso de un varón de 36 años con diagnóstico de malaria grave según criterio de la Organización Mundial de la Salud (OMS) que comenzó con tratamiento con artesunato endovenoso y por evolución tórpida, ascenso brusco de bilirrubinemia con encefalopatía, parámetros de lesión renal aguda y edema agudo de pulmón, realiza tratamiento extracorpóreo secuencial, plasma filtración acoplada a adsorción, plasmaféresis de alto intercambio y hemodiafiltración continua con evolución favorable. En conclusión, el caso presentado nos demuestra que el rol del sostén extracorpóreo en manos entrenadas y en forma oportuna es crucial cuando el fallo de órganos evoluciona rápidamente para lograr dar estabilidad y otorgar el tiempo necesario para la acción del tratamiento definitivo en este caso, los antimaláricos de acción rápida hasta negativización de la parasitemia.

In Silico Studies of Four Compounds of Cecropia obtusifolia against Malaria Parasite.

Malaria is a disease that affects many people in the world. In Mexico, malaria remains an active disease in certain regions, particularly in the states of Chiapas and Chihuahua. While antimalarial effects have been attributed to some species of Cecropia in various countries, no such studies have been conducted in Mexico. Therefore, the objective of this study was to evaluate the in silico antimalarial activity of some active compounds identified according to the literature in the species of Cecropia obtusifolia, belonging to the Cecropiaceae family, such as ursolic acid, α-amyrin, chrysin, and isoorientin. These compounds were evaluated with specific molecular docking and molecular dynamics (MD) studies using three different malarial targets with the PDB codes 1CET, 2BL9, and 4ZL4 as well as the prediction of their pharmacokinetic (Pk) properties. Docking analysis revealed the following best binding energies (kcal/mol): isoorientin-1CET (-9.1), isoorientin-2BL9 (-8.8), and chrysin-4ZL4 (-9.6). MD simulation validated the stability of the complexes. Pharmacokinetics analysis suggested that the compounds would generally perform well if administered. Therefore, these results suggest that these compounds may be used as potential drugs for the treatment of malaria.

Antimalarial Agents Derived from Metal-Amodiaquine Complexes with Activity in Multiple Stages of the Plasmodium Life Cycle.

Malaria is the one of the deadliest infectious diseases worldwide. Chemically, quinolines are excellent ligands for metal coordination and are deployed as drugs for malaria treatment. There is a growing body of evidence indicating that metal complexes can be conjugated with antimalarial quinolines to be used as chemical tools to overcome the disadvantages of quinolines, improving their bioactive speciation, cellular distribution, and subsequently broadening the spectrum of activity to multiple stages of the complex Plasmodium life cycle. In this study, four novel complexes of ruthenium(II)- and gold(I)-containing amodiaquine (AQ) were synthesized, and a careful chemical characterization revealed the precise coordination site of AQ to the metals. Their speciation in solution was investigated, demonstrating the stability of the quinoline-metal bond. RuII - and AuI -AQ complexes were demonstrated to be potent and efficacious in inhibiting parasite growth in multiple stages of the Plasmodium life cycle as assayed in vitro and in vivo. These properties could be attributed to the ability of the metal-AQ complexes to reproduce the suppression of heme detoxification induced by AQ, while also inhibiting other processes in the parasite life cycle; this can be attributed to the action of the metallic species. Altogether, these findings indicate that metal coordination with antimalarial quinolines is a potential chemical tool for drug design and discovery in malaria and other infectious diseases susceptible to quinoline treatment.

Transmission-blocking activity of antimalarials for Plasmodium vivax malaria in Anopheles darlingi.

Malaria is caused by parasite of the genus Plasmodium and is still one of the most important infectious diseases in the world. Several biological characteristics of Plasmodium vivax contribute to the resilience of this species, including early gametocyte production, both of which lead to efficient malaria transmission to mosquitoes. This study evaluated the impact of currently used drugs on the transmission of P. vivax. Participants received one of the following treatments for malaria: i) chloroquine [10 mg/kg on day 1 and 7.5 mg/kg on day 2 and 3] co-administered with Primaquine [0.5 mg/kg/day for 7 days]; ii) Chloroquine [10 mg/kg on day 1 and 7.5 mg/kg on day 2 and 3] co-administered with one-dose of Tafenoquine [300 mg on day 1]; and iii) Artesunate and Mefloquine [100 mg and 200 mg on day 1, 2 and 3] co-administered with Primaquine [0.5 mg/kg/day for 14 days]. Patient blood was collected before treatment and 4 h, 24 h, 48 h and 72 h after treatment. The blood was used to perform a direct membrane feeding assay (DMFA) using Anopheles darlingi mosquitoes. The results showed 100% inhibition of the mosquito infection after 4 h using ASMQ+PQ, after 24 h for the combination of CQ+PQ and 48 h using CQ+TQ. The density of gametocytes declined over time in all treatment groups, although the decline was more rapid in the ASMQ+PQ group. In conclusion, it was possible to demonstrate the transmission-blocking efficacy of the malaria vivax treatment and that ASMQ+PQ acts faster than the two other treatments.

Toxins from Animal Venoms as a Potential Source of Antimalarials: A Comprehensive Review.

Malaria is an infectious disease caused by Plasmodium spp. and it is mainly transmitted to humans by female mosquitoes of the genus Anopheles. Malaria is an important global public health problem due to its high rates of morbidity and mortality. At present, drug therapies and vector control with insecticides are respectively the most commonly used methods for the treatment and control of malaria. However, several studies have shown the resistance of Plasmodium to drugs that are recommended for the treatment of malaria. In view of this, it is necessary to carry out studies to discover new antimalarial molecules as lead compounds for the development of new medicines. In this sense, in the last few decades, animal venoms have attracted attention as a potential source for new antimalarial molecules. Therefore, the aim of this review was to summarize animal venom toxins with antimalarial activity found in the literature. From this research, 50 isolated substances, 4 venom fractions and 7 venom extracts from animals such as anurans, spiders, scorpions, snakes, and bees were identified. These toxins act as inhibitors at different key points in the biological cycle of Plasmodium and may be important in the context of the resistance of Plasmodium to currently available antimalarial drugs.

Green Synthesis of Molecules for the Treatment of Neglected Diseases.

Neglected tropical diseases (NTDs) affect mainly poor and marginalized populations of tropical and subtropical areas in 150 countries. Many of the chemical processes involved in the synthesis of active pharmaceutical ingredients (APIs) are highly polluting and inefficient, both in terms of materials and energy-consuming. In this review, we present the green protocols developed in the last 10 years to access new small molecules with potential applications in the treatment of leishmania, tuberculosis, malaria, and Chagas disease. The use of alternative and efficient energy sources, like microwaves and ultrasound, as well as reactions using green solvents and solvent-free protocols, are discussed in this review.

Acceptability, Feasibility, Drug Safety, and Effectiveness of a Pilot Mass Drug Administration with a Single Round of Sulfadoxine-Pyrimethamine Plus Primaquine and Indoor Residual Spraying in Communities with Malaria Transmission in Haiti, 2018.

For a malaria elimination strategy, Haiti's National Malaria Control Program piloted a mass drug administration (MDA) with indoor residual spraying (IRS) in 12 high-transmission areas across five communes after implementing community case management and strengthened surveillance. The MDA distributed sulfadoxine-pyrimethamine and single low-dose primaquine to eligible residents during house visits. The IRS campaign applied pirimiphos-methyl insecticide on walls of eligible houses. Pre- and post-campaign cross-sectional surveys were conducted to assess acceptability, feasibility, drug safety, and effectiveness of the combined interventions. Stated acceptability for MDA before the campaign was 99.2%; MDA coverage estimated at 10 weeks post-campaign was 89.6%. Similarly, stated acceptability of IRS at baseline was 99.9%; however, household IRS coverage was 48.9% because of the high number of ineligible houses. Effectiveness measured by Plasmodium falciparum prevalence at baseline and 10 weeks post-campaign were similar: 1.31% versus 1.43%, respectively. Prevalence of serological markers were similar at 10 weeks post-campaign compared with baseline, and increased at 6 months. No severe adverse events associated with the MDA were identified in the pilot; there were severe adverse events in a separate, subsequent campaign. Both MDA and IRS are acceptable and feasible interventions in Haiti. Although a significant impact of a single round of MDA/IRS on malaria transmission was not found using a standard pre- and post-intervention comparison, it is possible there was blunting of the peak transmission. Seasonal malaria transmission patterns, suboptimal IRS coverage, and low baseline parasitemia may have limited the effectiveness or the ability to measure effectiveness.

Investigation of Four Cases of Stevens-Johnson Syndrome among Participants in a Mass Drug Administration Campaign with Sulfadoxine-Pyrimethamine and Primaquine in Haiti, 2020.

In 2018, a mass drug administration (MDA) campaign for malaria elimination was piloted in Haiti. The pilot treated 36,338 people with sulfadoxine-pyrimethamine (SP) and primaquine; no severe adverse events were detected. In 2020, another MDA campaign using the same medications was implemented to mitigate an upsurge in malaria cases during the COVID-19 pandemic. Four cases of Stevens-Johnson syndrome (SJS) were identified among the 42,249 people who took the medications. Three of these individuals required hospitalization; all survived. In addition to SP ingestion, an investigation of potential causes for increased SJS cases identified that all four cases had human leukocyte antigens A*29 and/or B*44:03, another known risk factor for SJS. Additionally, three of the four case individuals had antibodies to SARS-CoV-2, and the fourth may have been exposed around the same time. These findings raise the possibility that recent SARS-CoV-2 infection may have contributed to the increased risk for SJS associated with SP exposure during the 2020 campaign.

Biological activity of 1,2,3-triazole-2-amino-1,4-naphthoquinone derivatives and their evaluation as therapeutic strategy for malaria control.

Malaria can be caused by several Plasmodium species and the development of an effective vaccine is challenging. Currently, the most effective tool to control the disease is the administration of specific chemotherapy; however, resistance to the frontline antimalarials is one of the major problems in malaria control and thus the development of new drugs becomes urgent. The study presented here sought to evaluate the antimalarial activities of compounds derived from 2-amino-1,4-naphthoquinones containing 1,2,3-triazole using in vivo and in vitro models. 1H-1,2,3-Triazole 2-amino-1,4-naphthoquinone derivatives were synthesized and evaluated for antimalarial activity in vitro, using P. falciparum W2 chloroquine (CQ) resistant strain and in vivo using the murine-P. berghei ANKA strain. Acute toxicity was determined as established by the OECD (2001). Cytotoxicity was evaluated against HepG2 and Vero mammalian cell lines. Transmission electron microscopy of the Plasmodium falciparum trophozoite (early and late stages) was used to evaluate the action of compounds derived at ultra-structural level. The compounds displayed low cytotoxicity CC50 > 100 µM, neither did they cause hemolysis at the tested doses and nor the signs of toxicity in the in vivo acute toxicity test. Among the five compounds tested, one showed IC50 values in submicromolar range of 0.8 µM. Compounds 7, 8 and 11 showed IC50 values < 5 µM, and selectivity index (SI) ranging from 6.8 to 343 for HepG2, and from 13.7 to 494.8 for Vero cells. Compounds 8 and 11 were partially active against P. berghei induced parasitemia in vivo. Analysis of the ultrastructural changes associated with the treatment of these two compounds, showed trophozoites with completely degraded cytoplasm, loss of membrane integrity, organelles in the decomposition stage and possible food vacuole deterioration. Our results indicated that compounds 8 and 11 may be considered hit molecules for antimalarial drug discovery platform and deserve further optimization studies.