Antimalarial Research Articles

Tetrahydropyridine appended 8-aminoquinoline derivatives: Design, synthesis, in silico, and in vitro antimalarial studies

Antimalarial drug resistance is a major obstacle in the ongoing quest against malaria. The disease affects half of the world’s population. The majority of them are toddlers and pregnant women. Needed a potent compound to act on drug-resistant Pf at appropriate concentrations without endangering the host. Envisaged solving this issue through rational drug design by creating a novel hybrid drug possessing two pharmacophores that can act on two marvellous and independent aims within the cell. Synthesized a new series of substituted 4-phenyl-1,2,3,6-tetrahydropyridine (THP) 8-Aminoquinoline-based hybrid analogs which have been integrated with quinoline, chloroquine, pamaquine, and primaquine, which exhibited antimalarial activity against Pf. Out of thirteen 4-phenyl-1,2,3,6-THP appended 8-Aminoquinoline derivatives, the compounds 1j, 1e, 1b, and 1l have exhibited good antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-9) strain with the minimum inhibitory concentration. Compound 1b was the most effective and showed consistently good potency against the drug-resistant (RKL-9) strain, although all other arrays showed good antimalarial efficacy. Additional docking and molecular dynamics studies were carried out at several targeting sites to quantify the structural parameters necessary for the activity.

Computational and Experimental IM-MS Determination of the Protonated Structures of Antimalarial Drugs.

A combination of ion mobility-mass spectrometry (IM-MS) measurements and computational methods were used to study structural and physicochemical properties of a range of quinoline-based drugs: amodiaquine (AQ), cinchonine (CIN), chloroquine (CQ), mefloquine (MQ), pamaquine (PQ), primaquine (PR), quinacrine (QR), quinine (QN), and sitamaquine (SQ). In experimental studies, ionization of these compounds using atmospheric pressure chemical ionization (APCI) yields monoprotonated species in the gas phase while electrospray ionization (ESI) also produces diprotonated forms of AQ, CQ, and QR and also for PQ, SQ, and QN in the presence of formic acid as an additive. Comparison of the trajectory-method-calculated and experimental IM-derived collisional cross sections (CCSN2) were used to assign both the protonation sites and conformer geometry of all drugs considered with biases of 0.7-2.8% between calculated and experimental values. It was found that, in solution, AQ and QR are protonated at the ring nitrogen of the quinoline group, whereas the other drugs are protonated at the amine group of the alkyl chain. Finally, the conformers of [M + H]+ and [M + 2H]2+ assigned according to the lowest energies and CCSN2 calculations were used to calculate the pKa values of the antimalarial drugs and the relative abundance of these ions at different pH values that provided validation of the computational and experimental IM-MS results.

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.

Ex vivo susceptibility to antimalarial drugs and polymorphisms in drug resistance genes of African Plasmodium falciparum, 2016-2023: a genotype-phenotype association study.

Given the altered responses to both artemisinins and lumefantrine in Eastern Africa, monitoring antimalarial drug resistance in all African countries is paramount. We measured the susceptibility to six antimalarials using ex vivo growth inhibition assays (IC50) for a total of 805 Plasmodium falciparum isolates obtained from travelers returning to France (2016-2023), mainly from West and Central Africa. Isolates were sequenced using molecular inversion probes (MIPs) targeting fourteen drug resistance genes across the parasite genome. Ex vivo susceptibility to several drugs has significantly decreased in 2019-2023 versus 2016-2018 parasite samples: lumefantrine (median IC50: 23·0 nM [IQR: 14·4-35·1] in 2019-2023 versus 13·9 nM [8·42-21·7] in 2016-2018, p<0·0001), monodesethylamodiaquine (35·4 [21·2-51·1] versus 20·3 nM [15·4-33·1], p<0·0001), and marginally piperaquine (20·5 [16·5-26·2] versus 18.0 [14·2-22·4] nM, p<0·0001). Only four isolates carried a validated pfkelch13 mutation. Multiple mutations in pfcrt and one in pfmdr1 (N86Y) were significantly associated with altered susceptibility to multiple drugs. The susceptibility to lumefantrine was altered by pfcrt and pfmdr1 mutations in an additive manner, with the wild-type haplotype (pfcrt K76-pfmdr1 N86) exhibiting the least susceptibility. Our study on P. falciparum isolates from West and Central Africa indicates a low prevalence of molecular markers of artemisinin resistance but a significant decrease in susceptibility to the partner drugs that have been the most widely used since a decade -lumefantrine and amodiaquine. These phenotypic changes likely mark parasite adaptation to sustained drug pressure and call for intensifying the monitoring of antimalarial drug resistance in Africa. This work was supported by the French Ministry of Health (grant to the French National Malaria Reference Center) and by the Agence Nationale de la Recherche (ANR-17-CE15-0013-03 to JC). JAB was supported by NIH R01AI139520. JR postdoctoral fellowship was funded by Institut de Recherche pour le Développement.

Ex vivo susceptibility to antimalarial drugs and polymorphisms in drug resistance genes of African Plasmodium falciparum, 2016-2023: a genotype-phenotype association study.

Background: Given the altered responses to both artemisinins and lumefantrine in Eastern Africa, monitoring antimalarial drug resistance in all African countries is paramount. Methods: We measured the susceptibility to six antimalarials using ex vivo growth inhibition assays (IC 50 ) for a total of 805 Plasmodium falciparum isolates obtained from travelers returning to France (2016-2023), mainly from West and Central Africa. Isolates were sequenced using molecular inversion probes (MIPs) targeting fourteen drug resistance genes across the parasite genome. Findings: Ex vivo susceptibility to several drugs has significantly decreased in 2019-2023 versus 2016-2018 parasite samples: lumefantrine (median IC 50 : 23·0 nM [IQR: 14·4-35·1] in 2019-2023 versus 13·9 nM [8·42-21·7] in 2016-2018, p<0·0001), monodesethylamodiaquine (35·4 [21·2-51·1] versus 20·3 nM [15·4-33·1], p<0·0001), and marginally piperaquine (20·5 [16·5-26·2] versus 18.0 [14·2-22·4] nM, p<0·0001). Only four isolates carried a validated pfkelch13 mutation. Multiple mutations in pfcrt and one in pfmdr1 (N86Y) were significantly associated with altered susceptibility to multiple drugs. The susceptibility to lumefantrine was altered by pfcrt and pfmdr1 mutations in an additive manner, with the wild-type haplotype ( pfcrt K76- pfmdr1 N86) exhibiting the least susceptibility. Interpretation: Our study on P. falciparum isolates from West and Central Africa indicates a low prevalence of molecular markers of artemisinin resistance but a significant decrease in susceptibility to the partner drugs that have been the most widely used since a decade -lumefantrine and amodiaquine. These phenotypic changes likely mark parasite adaptation to sustained drug pressure and call for intensifying the monitoring of antimalarial drug resistance in Africa.

Preparation and In-Vitro Characterization of Solid Lipid Nanoparticles Containing Artemisinin and Curcumin.

Malaria remains a formidable public health obstacle across Africa, Southeast Asia, and portions of South America, exacerbated by resistance to antimalarial medications, such as artemisinin-based combinations. The combination of curcumin and artemisinin shows promise due to its potential for dose reduction, reduced toxicity, synergistic effects, and suitability for drug delivery improvement. This research aims to enhance the solubility and dissolution rates of curcumin and artemisinin by employing Solid Lipid Nanoparticles (SLNs). Oral delivery of both drugs faces challenges due to their poor water solubility, inefficient absorption, and rapid metabolism and elimination. The study focuses on formulating and optimizing Solid Lipid Nanoparticles (SLNs) encapsulating artemisinin (ART) and curcumin (CUR). SLNs were developed using the hot homogenization method, incorporating ultrasonication. Drug-excipient compatibility was evaluated using Differential Scanning Calorimetry (DSC). Lipid and surfactant screening was performed to select suitable components. A 3² full factorial design was utilized to investigate the influence of lipid and surfactant concentrations on key parameters, such as entrapment efficiency (%EE) and cumulative drug release (%CDR). Additionally, evaluations of % entrapment efficiency, drug loading, particle size, zeta potential, and in-vitro drug release were conducted. Successful development of artemisinin and curcumin SLNs was achieved using a full factorial design, demonstrating controlled drug release and high entrapment efficiency. The optimized nanoparticles exhibited a size of 114.7nm, uniformity (PDI: 0.261), and a zeta potential of -9.24 mV. Artemisinin and curcumin showed %EE values of 79.1% and 74.5%, respectively, with cumulative drug release of 85.1% and 80.9%, respectively. The full factorial design indicated that increased lipid concentration improved %EE, while higher surfactant concentration enhanced drug release and %EE. Stability studies of the optimized batch revealed no alterations in physical or chemical characteristics. The study successfully developed Solid Lipid Nanoparticles (SLNs) for artemisinin and curcumin, achieving controlled drug release, high entrapment efficiency, and desired particle size and uniformity. This advancement holds promise for enhancing drug delivery of herbal formulations.

Innovative Multistage ML-QSAR Models for Malaria: From Data to Discovery.

Malaria presents a significant challenge to global public health, with around 247 million cases estimated to occur annually worldwide. The growing resistance of Plasmodium parasites to existing therapies underscores the urgent need for new and innovative antimalarial drugs. This study leveraged artificial intelligence (AI) to tackle this complex challenge. We developed multistage Machine Learning Quantitative Structure-Activity Relationship (ML-QSAR) models to effectively analyze large datasets and predict the efficacy of chemical compounds against multiple life cycle stages of Plasmodium parasites. We then selected 16 compounds for experimental evaluation, six of which showed at least dual-stage inhibitory activity and one inhibited all life cycle stages tested. Moreover, explainable AI (XAI) analysis provided insights into critical molecular features influencing model predictions, thereby enhancing our understanding of compound interactions. This study not only empowers the development of advanced predictive AI models but also accelerates the identification and optimization of potential antiplasmodial compounds.

Prescription of Anti-Malarial Drugs to Patients with Negative Malarial Rapid Diagnostic Test (mRDT) Result by Health Care Workers in Kano, Nigeria

Prescription of Anti-Malarial Drugs to Patients with Negative Malarial Rapid Diagnostic Test (mRDT) Result by Health Care Workers in Kano, Nigeria

Near-Term Quantum Classification Algorithms Applied to Antimalarial Drug Discovery.

Computational approaches are widely applied in drug discovery to explore properties related to bioactivity, physiochemistry, and toxicology. Over at least the last 20 years, the exploitation of machine learning on molecular data sets has been used to understand the structure-activity relationships that exist between biomolecules and druggable targets. More recently, these methods have also seen application for phenotypic screening data for neglected diseases such as tuberculosis and malaria. Herein, we apply machine learning to build quantum Quantitative Structure Activity Relationship models from antimalarial data sets. There is a continual need for new antimalarials to address drug resistance, and the readily available in vitro data sets could be utilized with newer machine learning approaches as these develop. Furthermore, quantum machine learning is a relatively new method that uses a quantum computer to perform the calculations. First, we present a classical-quantum hybrid computational approach by building a Latent Bernoulli Autoencoder machine learning model for compressing bit-vector descriptors to a size that can be adapted to quantum computers for classification tasks with limited loss of embedded information. Second, we apply our method for feature map compression to quantum classification algorithms, including a completely novel machine learning algorithm with no analogy in classical computers: the Quantum Fourier Transform Classifier. We apply both these approaches to build quantum machine learning models for small-molecule antimalarials with quantum simulation software and then benchmark these quantum models against classical machine learning approaches. While there are many challenges currently facing the development of reliable quantum computers, our results demonstrate that there is potential for the use of this technology in the field of drug discovery.

Exploration of Synthetic Potential of 2‐Chloro‐Quinoline‐3‐Carbaldehyde

Quinoline is one of the most important simple nitrogen heterocycles, being widespread in nature and present in a broad variety of pharmacologically active compounds. Specifically, quinoline is renowned antimalarial agents from several past decades and showed strong potential in this field. 3‐Formyl‐quinoline is a versatile precursor which transformed through the several easy methods into a wide range of biologically valuable scaffolds. The exploration of 3‐formyl‐quinoline gained much more attention to medicinal chemists in the field of drug discovery to design and synthesize new fused/tethered quinolines as potent therapeutical agents. The aim of this review, which covers the period from 2011 to 2023, is to update the role of formyl functionality of quinolines showing the extraordinary ability to play role in organic synthesis.

In vitro, in vivo and in silico antiplasmodial profiling of the aqueous extract of Hibiscus asper HOOK F. Leaf (Malvaceae)

Ethnopharmacological relevancePlasmodium resistance to antimalarial drugs raises the urgent need to seek for alternative treatments. Aqueous extract of Hibiscus asper leaves is currently used in malaria management but remains less documented.Aim of the study: The study aims to evaluate antimalarial effects of the aqueous extract of Hibiscus asper. UHPLC/MS, was used to identify some likely compounds present in the plant that were thereafter docked to some malaria parasite proteins. Study designIn vitro anti-plasmodium and antioxidant, UHPLC/Ms analysis, in vivo antimalarial of the plant extract, and in silico molecular docking prediction of some identified compounds were performed to investigate the pharmacological effects of H. asper. Material and methodsThe in vitro antiplasmodial activity of the extract was carried out on Plasmodium falciparum strains using SYBR-green dye; then, the curative antimalarial activity was conducted on Plasmodium berghei NK65-infected male Wistar rats. The UHPLC/MS analysis was used to identify plant compounds, followed by interactions (docking affinity) between some compounds and parasitic enzymes such as P. falciparum purine nucleoside phosphorylase (2BSX) and 6-phosphogluconate dehydrogenase (6FQY) to explore potential mechanisms of action at the molecular level. ResultsNo hemolysis effect of the extract was observed at concentrations up to 100 mg/mL. In vitro test of the aqueous leaves extract of H. asper showed inhibitory activity against P. falciparum Dd2 and 3D7 strains with IC50 values of 19.75 and 21.97 μg/mL, respectively. The curative antimalarial test of the H. asper extract in infected rats exhibited significant inhibition of the parasite growth (p < 0.001) with inhibition percentage of 95.11%, 97.68% and 95.59% at all the doses (50, 100 and 200 mg/kg) respectively. The extract corrected major physiological alterations such as liver and kidney impairments, oxidative stress and architectural disorganization in liver, spleen and kidneys tissues. The UHPLC/MS analysis identified 7 compounds, namely chlorogenic acid, azulene, quercetin, rhodine, 1-ethyl-2,4-dimethyl benzene and phthalan. Out of seven compounds identified in the extract quercetin and phthalan showed higher in silico inhibitory activity against P. falciparum purine nucleoside phosphorylase and Plasmodium falciparum 6-phosphosgluconate dehydrogenase parasite enzymes. ConclusionThese findings indicate that H. asper could be a promising complementary medicine to manage malaria. Meanwhile, the affinity of annoted compounds with these enzymes should be further confirmed.

Exploring novel camphor-derived heterocycles for antimalarial activity: Design, virtual screening, DFT, and molecular docking investigations

Nowadays, camphor-based heterocycles have attained the greater focus of the scientific community due to their specific and target-oriented medicinal properties. Based on the literature, it has been observed that the novel camphor-based heterocycles may act as prominent scaffolds to cure one of the potential diseases called malaria, which was caused by Plasmodium falciparum. In this regard, some novel camphor-based heterocycles have been designed to test their efficacy towards their antimalarial activity. First, using Spartan-14 software, Density Functional Theory investigations were conducted on the suggested heterocycles to ascertain their geometry and their associated chemical properties. All optimized camphor-based heterocycles have been docked against the proteins (PDB: 1LF3 & 3BPF) with Discovery Studio software and Autodock Vina and has been observed that the binding energies of the compounds CBH 1–15 with both the proteins have shown better results which are in the range of −6.0 to −8.6 kcal/mol. Based on docking examinations, the compounds with 1lF3 protein in CBH-10, CBH-11, and CBH-1/CBH-6 had the highest binding energies of −8.6, −8.3, and −8.2; for the compounds in CBH-11, CBH-10, and CBH-1/CBH-3 /CBH-6 CBH-13, the highest binding energies were −7.8, −7.7, and −7.6. In addition, the ADMET properties of all the compounds have been determined and observed that these compounds might be used as potential antimalarial agents.

Drugs resistance and new strategies of prevention against Malaria: An ongoing battle.

From ancient times until 21st century, Malaria has remained a fatal disease. It causes death in many poor and developing countries. Excluding vector control, Antimalarial drugs are the most reliable and effective weapon to tackle this severe disease. The emergence of antimalarial drug resistance in Plasmodium spp. becomes a barrier in Malaria elimination program as there has been no effective antimalarial vaccine till today. Apart from artemisinin, most of the antimalarial drugs have become resistant against malaria at present. Although, reduced efficacy of artemisinin-based combination therapy (ACT) has also been reported from southeast regions of Asia. Mutation of some genes within the parasite play a vital role in this drug resistance. Therefore, malaria is still a prime threat to human death and an unsolved problem. Newly emerging approaches like, vaccine development, plants based antimalarial drugs, nanoparticles, next generation antimalarial drugs should be taken & supported. In addition to that, public awareness is much needed for understanding the fatality of the disease and for encouraging self-protection and early treatment.

Antimalarial efficacy test of the aqueous crude leaf extract of Coriandrum sativum Linn.: an in vivo multiple model experimental study in mice infected with Plasmodium berghei

BackgroundMalaria continues to wreak havoc on the well-being of the community. Resistant parasites are jeopardizing the treatment. This is a wake-up call for better medications. Folk plants are the key starting point for antimalarial drug discovery. After crushing and mixing the leaves of Coriandrum sativum with water, one cup of tea is drunk daily for a duration of three to five days as a remedy for malaria by local folks in Ethiopia. Additionally, in vitro experiments conducted on the plant leaf extract elsewhere have also demonstrated the plant’s malaria parasite inhibitory effect. There has been no pharmacologic research to assert this endowment in animals, though. This experiment was aimed at evaluating the antimalarial efficacy of C. sativum in Plasmodium berghei infected mice.MethodsThe plant's leaf was extracted using maceration with distilled water. The extract was examined for potential acute toxicity. An evaluation of secondary phytoconstituents was done. Standard antimalarial screening models (prophylactic, chemosuppressive, curative tests) were utilized to assess the antiplasmodial effect. In each test, thirty mice were organized into groups of five. To the three categories, the test substance was given at doses of 100, 200 and 400 mg/kg/day before or after the commencement of P. berghei infection. Positive and negative control mice were provided Chloroquine and distilled water, respectively. Rectal temperature, parasitemia, body weight, survival time and packed cell volume were ultimately assessed. Analysis of the data was performed using Statistical Package for Social Sciences.ResultsNo toxicity was manifested in mice. The extract demonstrated a significant inhibition of parasitemia (p < 0.05) in all the models. The inhibition of parasite load was highest with the upper dose in the suppressive test (82.74%) followed by the curative procedure (78.49%). Likewise, inhibition of hypothermia, weight loss hampering, improved survival and protection against hemolysis were elicited by the extract.ConclusionsThe results of our experimental study revealed that the aqueous crude leaf extract of C. sativum exhibits significant antimalarial efficacy in multiple in vivo models involving mice infected with P. berghei. Given this promising therapeutic attribute, in depth investigation on the plant is recommended.

Association study of Plasmodium falciparum Acetyl-CoA Synthetase Mutations S868G and V949I with antimalarial drugs.

Plasmodium falciparum acetyl-CoA synthetase (PfACAS) protein is an important source of acetyl-CoA. We detected the mutations S868G and V949I in PfACAS by whole-genome sequencing analysis in some recrudescent parasites after antimalarial treatment with artesunate and dihydroartemisinin-piperaquine, suggesting that they may confer drug resistance. Using CRISPR/Cas9 technology, we engineered parasite lines carrying the PfACAS S868G and V949I mutations in two genetic backgrounds and evaluated their susceptibility to antimalarial drugs in vitro. The results demonstrated that PfACAS S868G and V949I mutations alone or in combination were not enough to provide resistance to antimalarial drugs.

Extracts from Artemisia annua Alleviates Myocardial Remodeling through TGF-β1/Smad2/3 Pathway and NLRP3 Inflammasome

Artemisinin and its derivatives, the well-known anti-malarial drugs extracted from traditional Chinese medicine, Artemisia annua, have been implicated in treating fibrotic diseases. However, whether artemisinin affects cardiac fibrosis in the pathogenesis of heart failure is still unknown. This study aimed to evaluate the possible effects of artemisinin on cardiac function and myocardial fibrosis in the heart failure model and to explore the underlying mechanisms. Isoproterenol was injected subcutaneously for induction of the cardiac fibrosis model. Proteomic analysis was performed after 4 four weeks of artemisinin treatment. Echocardiography was used to evaluate cardiac function and structure. Hematoxylin and eosin (H&E) staining, as well as Masson trichrome staining, were performed for histopathology. The α-SMA, collagen I, and III expression in the myocardium was detected by immunohistochemical staining. The ratio of heart weight to body weight (HW/BW, mg/kg) and the ratio of heart weight to tibia length (HW/TL, mg/mm) were calculated as indicators for cardiac remodeling. Brain natriuretic peptide (BNP) levels were quantified in rat plasma using enzymelinked immunosorbent assay (ELISA). In contrast, the protein levels of TGF-β1, p-Smad2/3, and Smad2/3 were assessed in the myocardium and fibroblasts via western blot analysis. RT-qPCR was performed to analysis the expression of Col-I, Col-III, α-SMA, NLRP3, Caspase-1, IL-1β, and IL-18. Proteomic analysis identified 227 differentially expressed proteins (DEPs), including 119 upregulated and 108 downregulated proteins. These proteins were identified as the core proteins targeted by artemisinin for improving myocardial remodeling. GO annotation of the DEPs indicated that the DEPs were mainly associated with biological processes such as inflammation regulation. In the in vivo study of an isoproterenol-induced rat cardiac remodeling model, we found that artemisinin administration significantly ameliorated cardiac dysfunction and reduced collagen production by suppressing TGFβ-1/Smads signaling and inhibiting NLRP3 inflammasome activation. As manifested by downregulating the expression of α-SMA, Col-I, and Col-III, NLRP3, IL-1β, IL-18, Caspase-1 mRNA, and TGF-β1, p-SMAD 2/3 protein in the myocardium. Similar beneficial effects of artemisinin were consistently observed in TGF-β1 treated primary cardiac fibroblasts. Extracts from Artemisia annua relieves myocardial remodeling through TGF-β1/Smad2/3 pathway and NLRP3 inflammasome

Discovery of an anti-malarial compound, burnettiene A, with a multidrug-sensitive Saccharomyces cerevisiae screening system based on mitochondrial function inhibitory activity.

In this paper, we describe our discovery of burnettiene A (1) as an anti-malarial compound from the culture broth of Lecanicillium primulinum (Current name: Flavocillium primulinum) FKI-6715 strain utilizing our original multidrug-sensitive yeast system. This polyene-decalin polyketide natural product was originally isolated as an anti-fungal active compound from Aspergillus burnettii. However, the anti-fungal activity of 1 has been revealed in only one fungal species for and the mechanism of action of 1 remains unknown. After the validation of mitochondrial function inhibitory of 1, we envisioned a new anti-malarial drug discovery platform based on mitochondrial function inhibitory activity. We evaluated anti-malarial activity and 1 showed anti-malarial activity against Plasmodium falciparum FCR3 (chloroquine sensitive) and K1 strain (chloroquine resistant). Our study revealed the utility of our original screening system based on a multidrug-sensitive yeast and mitochondrial function inhibitory activity for the discovery of new anti-malarial drug candidates.

Discovery of antimalarial drugs from secondary metabolites in actinomycetes culture library

BackgroundNatural products play a key role as potential sources of biologically active substances for the discovery of new drugs. This study aimed to identify secondary metabolites from actinomycete library extracts that are potent against the asexual stages of Plasmodiumfalciparum (P.falciparum).MethodsSecondary metabolites from actinomycete library extracts were isolated from culture supernatants by ethyl acetate extraction. Comprehensive screening was performed to identify novel antimalarial compounds from the actinomycete library extracts (n = 28). The antimalarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) lines of P.falciparum. The cytotoxicity was then evaluated in primary adult mouse brain (AMB) cells.ResultsOut of the 28 actinomycete extracts, 17 showed parasite growth inhibition > 50% at a concentration of 50 µg/mL, nine were identified with an IC50 value < 10 µg/mL, and seven suppressed the parasite significantly with an IC50 value < 5 µg/mL. The extracts from Streptomycesaureus strains HUT6003 (Extract ID number: 2), S.antibioticus HUT6035 (8), and Streptomyces sp. strains GK3 (26) and GK7 (27), were found to have the most potent antimalarial activity with IC50 values of 0.39, 0.09, 0.97, and 0.36 µg/mL (against 3D7), and 0.26, 0.22, 0.72, and 0.21 µg/mL (against Dd2), respectively. Among them, Streptomycesantibioticus strain HUT6035 (8) showed the highest antimalarial activity with an IC50 value of 0.09 µg/mL against 3D7 and 0.22 µg/mL against Dd2, and a selective index (SI) of 188 and 73.7, respectively.ConclusionSecondary metabolites obtained from the actinomycete extracts showed promising antimalarial activity in vitro against 3D7 and Dd2 cell lines of P.falciparum with minimal toxicity. Therefore, secondary metabolites obtained from actinomycete extracts represent an excellent starting point for the development of antimalarial drug leads.

Antimalarial activity of cecropin antimicrobial peptides derived from Anopheles mosquitoes.

The emergence of clinically drug-resistant malaria parasites requires the urgent development of new drugs. Mosquitoes are vectors of multiple pathogens and have developed resistance mechanisms against them, which often involve antimicrobial peptides (AMPs). An-cecB is an AMP of the malaria-transmitting mosquito genus Anopheles, and we herein report its antimalarial activity against Plasmodium falciparum 3D7, the artemisinin-resistant strain 803, and the chloroquine-resistant strain Dd2 in vitro. We also demonstrate its anti-parasite activity in vivo, using the rodent malaria parasite Plasmodium berghei (ANKA). We show that An-cecB displays potent antimalarial activity and that its mechanism of action may occur through direct killing of the parasite or through interaction with infected red blood cell membranes. Unfortunately, An-cecB was found to be cytotoxic to mammalian cells and had poor antimalarial activity in vivo. However, its truncated peptide An-cecB-1 retained most of its antimalarial activity and avoided its cytotoxicity in vitro. An-cecB-1 also showed better antimalarial activity in vivo. Mosquito-derived AMPs may provide new ideas for the development of antimalarial drugs against drug-resistant parasites, and An-cecB has potential use as a template for antimalarial peptides.

Synthesis, In Silico Study and Antimalarial Activity of Triazolo[1,5‐a]pyrimidine Derivatives

AbstractThe present study mainly focused on synthesizing novel triazolo[1,5‐a]pyrimidine‐6‐carboxamide derivatives using multicomponent reaction. Synthesized derivatives were duly characterized using spectroscopic methods of analysis FT‐IR and mass spectroscopy, and 1H NMR and 13C NMR confirmed the structure of compounds. Further, the potential of the synthesized compounds against Plasmodium falciparum dihydrofolate reductase (Pf‐DHFR) inhibitors was evaluated by in vitro antimalarial activity, and the results of the study showed moderate to good antimalarial profile of synthesized entities. In silico study of all the synthesized compounds was carried out using Schrödinger LLC‐2020‐3 Software to explain the binding mode and interactions between molecules and pf DHFR enzyme. To study the drug likeliness of molecules, 3D QSAR and Pharmacokinetic studies have been carried out, and the results obtained showed a good pharmacokinetics profile of two compounds, namely AMP‐24 and AMP‐28, having good IC50 values concerning standard drugs. Further, the in vitro enzyme inhibition assay results suggested that the synthesized compound interacts nicely with the enzyme and might be used as a potent antimalarial agent.