Class Of Antimalarials Research Articles

Recent Advances in the Treatment of Malaria.

Malaria is still one of the major global health challenges affecting millions annually, particularly in non-Mediterranean Africa and Southeast Asia. Over the past two decades, substantial progress has been made in reducing malaria-related morbidity and mortality, primarily due to advancements in antimalarial therapeutics. This review provides a comprehensive overview of recent developments in malaria treatment, focusing on the evolution of drug therapies, mechanisms of action, and emerging resistance patterns. The cornerstone of current treatment strategies is artemisinin-based combination therapies (ACTs), which have proven highly effective against P. falciparum and P. vivax, the most prevalent malaria-causing parasites. However, the onset of artemisinin resistance, particularly in Southeast Asian countries, poses a significant threat to these gains. Additionally, other antimalarial classes, including quinine derivatives, 8-aminoquinolines, and antifolate drugs, are examined for their efficacy, resistance mechanisms, and future potential. This review also discusses the challenges associated with drug resistance, the genetic underpinnings of resistance in malaria parasites, and the implications for future treatment protocols. Furthermore, the review examines combinational therapies, such as triple artemisinin combination therapies (TACTs), and vaccines that are approved or in development to circumvent resistance issues. The need for continuous surveillance, innovative therapeutic strategies, and advances in novel antimalarial therapeutic agents is emphasized to sustain and further progress in the control of malaria and its eventual eradication.

Anti-tumor mechanism of artesunate.

Artesunate (ART) is a classic antimalarial drug with high efficiency, low toxicity and tolerance. It has been shown to be safe and has good anti-tumor effect. Existing clinical studies have shown that the anti-tumor mechanisms of ART mainly include inducing apoptosis and autophagy of tumor cells, affecting tumor microenvironment, regulating immune response, overcoming drug resistance, as well as inhibiting tumor cell proliferation, migration, invasion, and angiogenesis. ART has been proven to fight against lung cancer, hepatocarcinoma, lymphoma, multiple myeloma, leukemia, colorectal cancer, ovarian cancer, cervical cancer, malignant melanoma, oral squamous cell carcinoma, bladder cancer, prostate cancer and other neoplasms. In this review, we highlight the effects of ART on various tumors with an emphasis on its anti-tumor mechanism, which is helpful to propose the potential research directions of ART and expand its clinical application.

Abstract We056: Hydroxychloroquine cures autoimmune myocarditis by inhibiting innate immune via the CXCL16-CXCR6 axis between macrophages and T cells

Background: Myocarditis is a live-threatening inflammatory disease of the heart and is lack of effective treatment measures. Hydroxychloroquine (HCQ), a classic antimalarial drug, has been widely used in the treatment of rheumatic diseases. This study investigated whether HCQ can treat chronic autoimmune myocarditis. Methods and Results: Murine autoimmune myocarditis was induced, and therapeutic effects of oral HCQ on acute and chronic myocarditis were evaluated using echocardiography, cardiac catheterization, and analysis of inflammatory scores in cardiac tissue. Results showed that HCQ treatment significantly improved cardiac function, inhibited ventricle enlargement and reduced cardiac inflammation. Single-cell transcriptomic analysis in the heart showed that HCQ treatment significantly reduced infiltration of macrophage, neutrophiles and T-cells, inhibited inflammatory pathway, especially the secretion of CXCL16 from macrophages, thereby reducing the chemotaxis of T cells, especially NKT cells and Th17 cells. Finally, both in vitro and in vivo experiments confirm the inhibitory effect of HCQ on CXCL16-CXCR6 axis between macrophages and T cells. Additionally, treatment with anti-CXCL16 antibody can also improve cardiac function and attenuate cardiac fibrosis in myocarditis. Conclusions: HCQ treatments clinically cure mice with autoimmune myocarditis through inhibiting innate immune and infiltration of macrophages majorly via CXCL16-CXCR6 axis.

Metformin in COVID-19: a magical role beyond the hyperglycemia

Coronavirus disease-2019 (COVID-19) has emerged as an aggressive viral infection in the last few years. Initially reported in the Wuhan area of the People’s Republic of China, it soon emerged across the globe. Researchers confront a worrying situation to rapidly develop effective strategies to combat this novel infection and its long-term aftereffects. To date, there have been myriad reports ranging from the repurposing of the classical antimalarial drug hydroxychloroquine to several other antiviral and anti-bacterial agents like remdesivir, favipiravir, and most recently azithromycin, which has entered clinical use in many countries for combating COVID-19 infections. Several studies have highlighted the nexus between COVID-19-associated morbidity and diabetes in a wide-ranging class of subjects ranging from pediatric cases to adults and patients with other co-morbidities. Metformin is a mainstay in the treatment of type 2 diabetes (T2D). It is safe, inexpensive, and effective and does more than merely control blood sugar levels. Important metabolites that encourage blood clotting and inflammation are also suppressed by metformin. Pro-inflammatory molecules are linked to obesity and T2D. Both are major risk factors for aggravated COVID-19. These characteristics gave rise to a hypothesis that metformin may find use as an efficacious treatment for COVID-19 especially if it decreases the inflammatory molecules that fuel the COVID-19 virus-induced effects. In this review, we attempt to elucidate the role of classical anti-diabetic medicine metformin in the treatment of COVID-19 infections by highlighting the pharmacological role of this drug during elevated glucose levels and insulin resistance. We examine how COVID-19 has correlations to diabetic physiology and thereby the possibility of repurposing metformin for COVID-19 treatment.

Optimization of pyrazolopyridine 4-carboxamides with potent antimalarial activity for which resistance is associated with the P. falciparum transporter ABCI3

Emerging resistance to current antimalarials is reducing their effectiveness and therefore there is a need to develop new antimalarial therapies. Toward this goal, high throughput screens against the P. falciparum asexual parasite identified the pyrazolopyridine 4-carboxamide scaffold. Structure-activity relationship analysis of this chemotype defined that the N1-tert-butyl group and aliphatic foliage in the 3- and 6-positions were necessary for activity, while the inclusion of a 7′-aza-benzomorpholine on the 4-carboxamide motif resulted in potent anti-parasitic activity and increased aqueous solubility. A previous report that resistance to the pyrazolopyridine class is associated with the ABCI3 transporter was confirmed, with pyrazolopyridine 4-carboxamides showing an increase in potency against parasites when the ABCI3 transporter was knocked down. The low metabolic stability intrinsic to the pyrazolopyridine scaffold and the slow rate by which the compounds kill asexual parasites resulted in poor performance in a P. berghei asexual blood stage mouse model. Lowering the risk of resistance and mitigating the metabolic stability and cytochrome P450 inhibition will be challenges in the future development of the pyrazolopyrimidine antimalarial class.

Exploring the Recent Pioneering Developments of Small Molecules in Antimalarial Drug Armamentarium: A Chemistry Prospective Appraisal.

Malaria is a very destructive and lethal parasitic disease that causes significant mortality worldwide, resulting in the loss of millions of lives annually. It is an infectious disease transmitted by mosquitoes, which is caused by different species of the parasite protozoan belonging to the genus Plasmodium. The uncontrolled intake of antimalarial drugs often employed in clinical settings has resulted in the emergence of numerous strains of plasmodium that are resistant to these drugs, including multidrug-resistant strains. This resistance significantly diminishes the effectiveness of many primary drugs used in the treatment of malaria. Hence, there is an urgent need for developing unique classes of antimalarial drugs that function with distinct mechanisms of action. In this context, the design and development of hybrid compounds that combine pharmacophoric properties from different lead molecules into a single unit gives a unique perspective towards further development of malaria drugs in the next generation. In recent years, the field of medicinal chemistry has made significant efforts resulting in the discovery and synthesis of numerous small novel compounds that exhibit potent antimalarial properties, while also demonstrating reduced toxicity and desirable efficacy. In light of this, we have reviewed the progress of hybrid antimalarial agents from 2021 up to the present. This manuscript presents a comprehensive overview of the latest advancements in the medicinal chemistry pertaining to small molecules, with a specific focus on their potential as antimalarial agents. As possible antimalarial drugs that might target both the dual stage and multi-stage stages of the parasite life cycle, these small hybrid molecules have been studied. This review explores a variety of physiologically active compounds that have been described in the literature in order to lay a strong foundation for the logical design and eventual identification of antimalarial drugs based on lead frameworks.

Malaria’s molecular dance: Mechanism, therapies, and emerging insights

Malaria, caused by Plasmodium parasites and transmitted through Anopheles mosquitoes, remains a formidable global health challenge. This abstract provides an overview of the intricate molecular mechanisms underlying malaria pathogenesis, explores current therapeutic approaches, and highlights emerging insights that may shape future strategies for malaria control. The intricate dance between Plasmodium parasites and their human hosts begins with the mosquito’s bite, leading to the invasion of erythrocytes by Plasmodium species. We delve into the molecular mechanisms governing parasite entry and subsequent replication within host cells, shedding light on key factors such as erythrocyte surface receptors and parasite-encoded proteins critical to invasion and survival. While malaria treatment has relied heavily on antimalarial drugs, the emergence of drug resistance necessitates ongoing exploration of novel therapeutic strategies. This abstract reviews current antimalarial drug classes, their mechanisms of action, and the challenges posed by drug resistance. We also highlight promising drug candidates and innovative approaches in the pipeline, including the use of advanced molecular techniques and immunotherapies. Emerging insights from genomics, proteomics, and transcriptomics have deepened our understanding of Plasmodium biology and host-parasite interactions. We discuss the potential of these omics approaches in identifying new drug targets, understanding drug resistance mechanisms, and developing vaccines. Additionally, we examine the role of human genetics in influencing susceptibility to malaria and response to treatment. Vector control remains a critical component of malaria prevention. We touch upon emerging strategies, such as genetically modified mosquitoes and novel insecticides, in the context of integrated vector management programs. Finally, we emphasize the importance of a multifaceted approach to malaria control, combining advances in molecular biology, drug development, vector control, and public health interventions.

Novel quinolinepiperazinyl-aryltetrazoles targeting the blood stage of Plasmodium falciparum.

The emergence of drug resistance against the frontline antimalarials is a major challenge in the treatment of malaria. In view of emerging reports on drug-resistant strains of Plasmodium against artemisinin combination therapy, a dire need is felt for the discovery of novel compounds acting against novel targets in the parasite. In this study, we identified a novel series of quinolinepiperazinyl-aryltetrazoles (QPTs) targeting the blood stage of Plasmodium. In vitro anti-plasmodial activity screening revealed that most of the compounds showed IC50 < 10 μM against chloroquine-resistant PfINDO strain, with the most promising lead compounds 66 and 75 showing IC50 values of 2.25 and 1.79 μM, respectively. Further, compounds 64-66, 68, 75-77 and 84 were found to be selective (selectivity index >50) in their action against Pf over a mammalian cell line, with compounds 66 and 75 offering the highest selectivity indexes of 178 and 223, respectively. Explorations into the action of lead compounds 66 and 75 revealed their selective cidal activity towards trophozoites and schizonts. In a ring-stage survival assay, 75 showed cidal activity against the early rings of artemisinin-resistant PfCam3.1R539T. Further, 66 and 75 in combination with artemisinin and pyrimethamine showed additive to weak synergistic interactions. Of these two in vitro lead molecules, only 66 restricted rise in the percentage of parasitemia to about 10% in P. berghei-infected mice with a median survival time of 28 days as compared to the untreated control, which showed the percentage of parasitemia >30%, and a median survival of 20 days. Promising antimalarial activity, high selectivity, and additive interaction with artemisinin and pyrimethamine indicate the potential of these compounds to be further optimized chemically as future drug candidates against malaria.

Diarylpentanoids, the privileged scaffolds in antimalarial and anti-infectives drug discovery: A review.

Asia is a hotspot for infectious diseases, including malaria, dengue fever, tuberculosis, and the pandemic COVID-19. Emerging infectious diseases have taken a heavy toll on public health and the economy and have been recognized as a major cause of morbidity and mortality, particularly in Southeast Asia. Infectious disease control is a major challenge, but many surveillance systems and control strategies have been developed and implemented. These include vector control, combination therapies, vaccine development, and the development of new anti-infectives. Numerous newly discovered agents with pharmacological anti-infective potential are being actively and extensively studied for their bioactivity, toxicity, selectivity, and mode of action, but many molecules lose their efficacy over time due to resistance developments. These facts justify the great importance of the search for new, effective, and safe anti-infectives. Diarylpentanoids, a curcumin derivative, have been developed as an alternative with better bioavailability and metabolism as a therapeutic agent. In this review, the mechanisms of action and potential targets of antimalarial drugs as well as the classes of antimalarial drugs are presented. The bioactivity of diarylpentanoids as a potential scaffold for a new class of anti-infectives and their structure-activity relationships are also discussed in detail.

Vinpocetine protects against chloroquine-induced cardiotoxicity by mitigating oxidative stress.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are classical antimalarial drugs, and recently have been used for other applications including coronavirus disease 2019 (COVID-19). Although they are considered safe, cardiomyopathy may associate CQ and HCQ applications particularly at overdoses. The goal of the present study was to evaluate the potential protective effect of the nootropic agent vinpocetine against CQ and HCQ adverse effects with a specific focus on the heart. For this purpose, a mouse model of CQ (0.5 up to 2.5g/kg)/HCQ (1 up to 2g/kg) toxicity was used, and the effect of vinpocetine was evaluated by survival, biochemical, as well as histopathological analyses. Survival analysis revealed that CQ and HCQ caused dose-dependent lethality, which was prevented by co-treatment with vinpocetine (100mg/kg, oral or intraperitoneal). To gain deeper understanding, a dose of 1g/kg CQ-which did not cause death within the first 24h after administration-was applied with and without vinpocetine administration (100mg/kg, intraperitoneal). The CQ vehicle group showed marked cardiotoxicity as evidenced by significant alterations of blood biomarkers including troponione-1, creatine phosphokinase (CPK), creatine kinase-myocardial band (CK-MB), ferritin, and potassium levels. This was confirmed at the tissue level by massive alteration of the heart tissue morphology and coincided with massive oxidative stress. Interestingly, co-administration of vinpocetine strongly ameliorated CQ-induced alterations and restored the antioxidant-defense system of the heart. These data suggest that vinpocetine could be used as an adjuvant therapy together with CQ/HCQ applications.

Antimalarial Drug Resistance: A Brief History of Its Spread in Indonesia.

Malaria remains to be a national and global challenge and priority, as stated in the strategic plan of the Indonesian Ministry of Health and Sustainable Development Goals. In Indonesia, it is targeted that malaria elimination can be achieved by 2030. Unfortunately, the development and spread of antimalarial resistance inflicts a significant risk to the national malaria control programs which can lead to increased malaria morbidity and mortality. In Indonesia, resistance to widely used antimalarial drugs has been reported in two human species, Plasmodium falciparum and Plasmodium vivax. With the exception of artemisinin, resistance has surfaced towards all classes of antimalarial drugs. Initially, chloroquine, sulfadoxine-pyrimethamine, and primaquine were the most widely used antimalarial drugs. Regrettably, improper use has supported the robust spread of their resistance. Chloroquine resistance was first reported in 1974, while sulfadoxine-pyrimethamine emerged in 1979. Twenty years later, most provinces had declared treatment failures of both drugs. Molecular epidemiology suggested that variations in pfmdr1 and pfcrt genes were associated with chloroquine resistance, while dhfr and dhps genes were correlated with sulfadoxine-pyrimethamine resistance. Additionally, G453W, V454C and E455K of pfk13 genes appeared to be early warning sign to artemisinin resistance. Here, we reported mechanisms of antimalarial drugs and their development of resistance. This insight could provide awareness toward designing future treatment guidelines and control programs in Indonesia.

Ganaplacide plus lumefantrine solid dispersion formulation: considerations for development and rollout

Due to reliance on antimalarials for clinical case management, drug resistance is a recurrent challenge for malaria control and elimination that requires relentless discovery and development of novel medicines with new modes of action. 1 Feachem RGA Chen I Akbari O et al. Malaria eradication within a generation: ambitious, achievable, and necessary. Lancet. 2019; 394: 1056-1112 Summary Full Text Full Text PDF PubMed Scopus (167) Google Scholar Since the widespread use of chloroquine in the 1950s, resistance has compromised the efficacy of all major classes of antimalarial drugs that are widely used to treat Plasmodium falciparum. These drugs include sulfadoxine–pyrimethamine and since 2007, 2 Fairhurst RM Dondorp AM Artemisinin-resistant Plasmodium falciparum malaria. Microbiol Spectr. 2016; 4 (10.1128/microbiolspec.EI10-0013-2016.) Crossref PubMed Scopus (174) Google Scholar artemisinin-class medicines and partner drugs, which have been crucial for preventing deaths from malaria in the past two decades. 1 Feachem RGA Chen I Akbari O et al. Malaria eradication within a generation: ambitious, achievable, and necessary. Lancet. 2019; 394: 1056-1112 Summary Full Text Full Text PDF PubMed Scopus (167) Google Scholar , 3 Ishengoma DS Saidi Q Sibley CH Roper C Alifrangis M Deployment and utilization of next-generation sequencing of Plasmodium falciparum to guide anti-malarial drug policy decisions in sub-Saharan Africa: opportunities and challenges. Malar J. 2019; 18: 267 Crossref PubMed Scopus (15) Google Scholar Partial resistance to artemisinin-based combinations threatens their efficacy throughout southeast Asia, and is now emerging rapidly in sub-Saharan Africa. 4 Rosenthal PJ Has artemisinin resistance emerged in Africa?. Lancet Infect Dis. 2021; 21: 1056-1057 Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar Although complete resistance has not yet been documented, this risk would be disastrous, necessitating urgent development of new antimalarial drugs that are effective against artemisinin-resistant parasites. Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: an open-label, multicentre, parallel-group, randomised, controlled, phase 2 trialGanaplacide plus lumefantrine-SDF was effective and well tolerated in patients, especially adults and adolescents, with uncomplicated P falciparum malaria. Ganaplacide 400 mg plus lumefantrine-SDF 960 mg once daily for 3 days was identified as the optimal treatment regimen for adults, adolescents, and children. This combination is being evaluated further in a phase 2 trial ( NCT04546633 ). Full-Text PDF

Comparative Susceptibility of Plasmodium ovale and Plasmodium falciparum Field Isolates to Reference and Lead Candidate Antimalarial Drugs in Ghana.

Malaria treatments resulted in the decline of the deadliest Plasmodium falciparum globally while species, such as P. ovale, infections have been increasingly detected across sub-Saharan Africa. Currently, no experimental drug sensitivity data are available to guide effective treatment and management of P. ovale infections, which is necessary for effective malaria elimination. We conducted a prospective study to evaluate P. ovale epidemiology over 1 year and determined ex vivo susceptibility of the field isolates to existing and lead advanced discovery antimalarial drugs. We report that while P. falciparum dominated both symptomatic and asymptomatic malaria cases, P. ovale in mono or co-infections caused 7.16% of symptomatic malaria. Frontline antimalarials artesunate and lumefantrine inhibited P. ovale as potently as P. falciparum. Chloroquine, which has been withdrawn in Ghana, was also highly inhibitory against both P. ovale and P. falciparum. In addition, P. ovale and P. falciparum displayed high susceptibility to quinine, comparable to levels observed with chloroquine. Pyrimethamine, which is a major drug for disease massive prevention, also showed great inhibition of P. ovale, comparable to effects on P. falciparum. Furthermore, we identified strong inhibition of P. ovale using GNF179, a close analogue of KAF156 imidazolopiperazines, which is a novel class of antimalarial drugs currently in clinical phase II testing. We further demonstrated that the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor, KDU691, is highly inhibitory against P. ovale and P. falciparum field isolates. Our data indicated that existing and lead advanced discovery antimalarial drugs are suitable for the treatment of P. ovale infections in Ghana. IMPORTANCE Current malaria control and elimination tools such as drug treatments are not specifically targeting P.ovale. P. ovale can form hypnozoite and cause relapsing malaria. P. ovale is the third most dominant species in Africa and requires radical cure treatment given that it can form liver dormant forms called hypnozoites that escape all safe treatments. The inappropriate treatment of P. ovale would sustain its transmission in Africa where the medical need is the greatest. This is a hurdle for successful malaria control and elimination. Here, we provided experiment data that were lacking to guide P. ovale treatment and disease control policy makers using reference antimalarial drugs. We also provided key experimental data for 2 clinical candidate drugs that can be used for prioritization selection of lead candidate's identification for clinical development.

7-N-Substituted-3-oxadiazole Quinolones with Potent Antimalarial Activity Target the Cytochrome bc1 Complex.

The development of new antimalarials is required because of the threat of resistance to current antimalarial therapies. To discover new antimalarial chemotypes, we screened the Janssen Jumpstarter library against the P. falciparum asexual parasite and identified the 7-N-substituted-3-oxadiazole quinolone hit class. We established the structure-activity relationship and optimized the antimalarial potency. The optimized analog WJM228 (17) showed robust metabolic stability in vitro, although the aqueous solubility was limited. Forward genetic resistance studies uncovered that WJM228 targets the Qo site of cytochrome b (cyt b), an important component of the mitochondrial electron transport chain (ETC) that is essential for pyrimidine biosynthesis and an established antimalarial target. Profiling against drug-resistant parasites confirmed that WJM228 confers resistance to the Qo site but not Qi site mutations, and in a biosensor assay, it was shown to impact the ETC via inhibition of cyt b. Consistent with other cyt b targeted antimalarials, WJM228 prevented pre-erythrocytic parasite and male gamete development and reduced asexual parasitemia in a P. berghei mouse model of malaria. Correcting the limited aqueous solubility and the high susceptibility to cyt b Qo site resistant parasites found in the clinic will be major obstacles in the future development of the 3-oxadiazole quinolone antimalarial class.

New drugs to squash the spread of malaria

The human-infecting malaria parasite, Plasmodium falciparum (green), is depicted erupting from human red blood cells (red). Eight sexually mature parasites (male gametes, green) emerge from the human cell (red), with their replicating DNA shown in blue. This image is courtesy of Dr Sabrina Yahiya and Prof. Jake Baum. For permission to reuse, contact Jake Baum at jake.baum@unsw.edu.au.Malaria is a devastating disease, with 247 million cases and 619,000 deaths reported in 2021 alone. Drugs to treat malaria symptoms and insecticides to kill the mosquito vector have improved in recent decades, but the parasite – Plasmodium falciparum - and the mosquitoes are evolving to become resistant to these strategies. Therefore, there is an urgent need for new antimalarial drugs with new modes of action. An attractive target is to prevent P. falciparum transmission to the mosquito vector, a process that depends on sexual maturation of male and female parasites from their dormant gametocyte form into gametes, known as gametogenesis.With this aim, the Baum laboratory have been investigating the mode of action of a new class of antimalarial sulphonamides – known as N-[(4-hydroxychroman-4-yl)methyl]-sulphonamide (N-4HCS) compounds – which have previously been shown to potently block male gametogenesis. The authors cultured gametocytes in human erythrocytes and treated them with one of the N-4HCS compounds to identify potential targets. Using photo-affinity labelling and mass spectrometry, the authors identified the gametocyte-specific parasitophorous vacuole membrane (PVM) protein Pfs16 as having the most significant interaction with this N-4HCS compound. The team then used complementary techniques to confirm that this N-4HCS compound binds and blocks Pfs16 function, which is known to be indispensable for male gametogenesis.The authors proceeded to explore the activity window of this N-4HCS compound in male gametocytes. They activated the process of gametogenesis, and then treated the male gametocytes with the N-4HCS compound at staggered time points up to 25 minutes, which is the point of male gamete maturation. Impressively, the N-4HCS compound was able to traverse the erythrocyte membrane and act within zero to six minutes of male gametogenesis initiation to prevent completion of the process. Probing further, the team used immunofluorescence imaging to show that the N-4HCS compound blocked P. falciparum cytoskeleton rearrangements and prevented Pfs16-dependent breakdown of the PVM, both of which are essential for male gametogenesis.Overall, Baum and colleagues have identified how this new class of antimalarials block male gamete formation and, therefore, malaria transmission. Once thoroughly developed and tested, there is potential for N-4HCS compounds to be given to malaria patients alongside existing symptomatic therapies, or even delivered directly to mosquitoes by coating nets or sugar baits – both of which could diminish subsequent infection of humans. More research is under way to explore and refine the activity of this class of sulphonamides, but, nevertheless, this study expands the breadth of strategies available to be used in the fight against malaria.

Antimalarials: A Patents Landscape Study (2015-Present)

Abstract: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and P. knowlesi are five Plasmodium species that cause malaria, a life-threatening parasitic disease. In the developing world, the rapid development of Plasmodium falciparum resistance to currently available treatments has become a serious health concern. This work reports a patent landscape analysis of patent documents related to antimalarial. The patent search was conducted using the commercially available CAS SciFinder database and the open-source patent database, The Lens. Seven hundred ninety-seven patents from The Lens and 1172 patent Sci-finder were exported using the antimalarial drug as a keyword. After the initial screening, 58 patent documents were shortlisted for in-depth analysis. After analysis, it was found that most of the top applicants come from the United States and Switzerland, which shows that market protection is more important in these two countries. The top applicants come from private companies, universities, and public-private partnerships. The United States, Europe, China, Canada, and the Republic of Korea lead the patent race in this area. The most-recorded IPC code is A61P33/06, related to the chemical substances or pharmaceutical formulations showing antimalarials activity. Most of the time, antimalarial drugs were made from quinine, artemisinin, trioxolane, naphthoquinones, and isoquinoline derivatives. Quinine and artemisinin are well-established classes of antimalarials with the maximum number of antimalarial drugs in the market. The research and innovations disclosed in most patents were focused on exploring or evaluating the new scaffolds and their mechanism of action against the normal and resistant malarial parasite. In conclusion, it has been found that various scaffolds are needed to be explored further in search of new antimalarial compounds.

A Postulated Mechanism of the Antimalarial Effect of Free Radicals Generated by Artemisinin on Plasmodium falciparum

Artemisinin and its derivatives, a class of antimalarial drugs, were first isolated from Artemisia annua. Artemisinin can alter the pH of the malaria parasite’s digestive vacuole from acidic to alkaline, leading to parasite death. However, the precise mechanism of artemisinin action in changing the digestive vacuole pH has not yet been confirmed. Previous studies reported that artemisinin and its derivatives could kill the parasites through the generation of oxidative stress by the free radicals they generate. This review aims to provide a better understanding of the possible mechanism of action of artemisinin, focusing on the antimalarial activity caused by the generated free radicals through the induction of mutation in the genes that encode the proton pump of the Plasmodium falciparum digestive vacuole.

Siccanin Is a Dual-Target Inhibitor of Plasmodium falciparum Mitochondrial Complex II and Complex III

Plasmodium falciparum contains several mitochondrial electron transport chain (ETC) dehydrogenases shuttling electrons from the respective substrates to the ubiquinone pool, from which electrons are consecutively transferred to complex III, complex IV, and finally to the molecular oxygen. The antimalarial drug atovaquone inhibits complex III and validates this parasite’s ETC as an attractive target for chemotherapy. Among the ETC dehydrogenases from P. falciparum, dihydroorotate dehydrogenase, an essential enzyme used in de novo pyrimidine biosynthesis, and complex III are the two enzymes that have been characterized and validated as drug targets in the blood-stage parasite, while complex II has been shown to be essential for parasite survival in the mosquito stage; therefore, these enzymes and complex II are considered candidate drug targets for blocking parasite transmission. In this study, we identified siccanin as the first (to our knowledge) nanomolar inhibitor of the P. falciparum complex II. Moreover, we demonstrated that siccanin also inhibits complex III in the low-micromolar range. Siccanin did not inhibit the corresponding complexes from mammalian mitochondria even at high concentrations. Siccanin inhibited the growth of P. falciparum with IC50 of 8.4 μM. However, the growth inhibition of the P. falciparum blood stage did not correlate with ETC inhibition, as demonstrated by lack of resistance to siccanin in the yDHODH-3D7 (EC50 = 10.26 μM) and Dd2-ELQ300 strains (EC50 = 18.70 μM), suggesting a third mechanism of action that is unrelated to mitochondrial ETC inhibition. Hence, siccanin has at least a dual mechanism of action, being the first potent and selective inhibitor of P. falciparum complexes II and III over mammalian enzymes and so is a potential candidate for the development of a new class of antimalarial drugs.

Selective Inhibition of Plasmodium falciparum ATPase 6 by Artemisinins and Identification of New Classes of Inhibitors after Expression in Yeast.

ABSTRACTTreatment failures with artemisinin combination therapies (ACTs) threaten global efforts to eradicate malaria. They highlight the importance of identifying drug targets and new inhibitors and of studying how existing antimalarial classes work. Here, we report the successful development of a heterologous expression-based compound-screening tool. The validated drug target Plasmodium falciparum ATPase 6 (PfATP6) and a mammalian orthologue (sarco/endoplasmic reticulum calcium ATPase 1a [SERCA1a]) were functionally expressed in Saccharomyces cerevisiae, providing a robust, sensitive, and specific screening tool. Whole-cell and in vitro assays consistently demonstrated inhibition and labeling of PfATP6 by artemisinins. Mutations in PfATP6 resulted in fitness costs that were ameliorated in the presence of artemisinin derivatives when studied in the yeast model. As previously hypothesized, PfATP6 is a target of artemisinins. Mammalian SERCA1a can be mutated to become more susceptible to artemisinins. The inexpensive, low-technology yeast screening platform has identified unrelated classes of druggable PfATP6 inhibitors. Resistance to artemisinins may depend on mechanisms that can concomitantly address multitargeting by artemisinins and fitness costs of mutations that reduce artemisinin susceptibility.

Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection study

New antimalarials with novel mechanisms of action are needed to combat the emergence of drug resistance. Triaminopyrimidines comprise a novel antimalarial class identified in a high-throughput screen against asexual blood-stage Plasmodium falciparum. This first-in-human study aimed to characterise the safety, pharmacokinetics, and antimalarial activity of the triaminopyrimidine ZY-19489 in healthy volunteers. A three-part clinical trial was conducted in healthy adults (aged 18-55 years) in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants enrolled into one of six dose groups (25, 75, 150, 450, 900, or 1500 mg) were randomly assigned (3:1) to ZY-19489 or placebo. Part two was an open-label, randomised, two-period cross-over, pilot food-effect study in which participants were randomly assigned (1:1) to a fasted-fed or a fed-fasted sequence. Part three was an open-label, randomised, volunteer infection study using the P falciparum induced blood-stage malaria model in which participants were enrolled into one of two cohorts, with participants in cohort one all receiving the same dose of ZY-19489 and participants in cohort two randomly assigned to receive one of two doses. The primary outcome for all three parts was the incidence, severity, and relationship to ZY-19489 of adverse events. Secondary outcomes were estimation of ZY-19489 pharmacokinetic parameters for all parts; how these parameters were affected by the fed state for part two only; and the parasite reduction ratio, parasite clearance half-life, recrudescent parasitaemia, and pharmacokinetic-pharmacodynamic modelling parameters for part three only. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12619000127101, ACTRN12619001466134, and ACTRN12619001215112). 48 participants were enrolled in part one (eight per cohort for 25-1500 mg cohorts), eight in part two (four in each group, all dosed with 300 mg), and 15 in part three (five dosed with 200 mg, eight with 300 mg, and two with 900 mg). In part one, the incidence of drug-related adverse events was higher in the 1500 mg dose group (occurring in all six participants) than in lower-dose groups and the placebo group (occurring in one of six in the 25 mg group, two of six in the 75 mg group, three of six in the 150 mg group, two of six in the 450 mg group, four of six in the 900 mg group, and four of 12 in the placebo group), due to the occurrence of mild gastrointestinal symptoms. Maximum plasma concentrations occurred 5-9 h post-dosing, and the elimination half-life was 50-97 h across the dose range. In part two, three of seven participants had a treatment-related adverse event in the fed state and four of eight in the fasted state. Dosing in the fed state delayed absorption (maximum plasma concentration occurred a median of 12·0 h [range 7·5-16·0] after dosing in the fed state vs 6·0 h [4·5-9·1] in the fasted state) but had no effect on overall exposure (difference in area under the concentration-time curve from time 0 [dosing] extrapolated to infinity between fed and fasted states was -0·013 [90% CI -0·11 to 0·08]). In part three, drug-related adverse events occurred in four of five participants in the 200 mg group, seven of eight in the 300 mg group, and both participants in the 900 mg group. Rapid initial parasite clearance occurred in all participants following dosing (clearance half-life 6·6 h [95% CI 6·2-6·9] for 200 mg, 6·8 h [95% CI 6·5-7·1] for 300 mg, and 7·1 h [95% CI 6·6-7·6] for 900 mg). Recrudescence occurred in four of five participants in the 200 mg group, five of eight in the 300 mg group, and neither of the two participants in the 900 mg group. Simulations done using a pharmacokinetic-pharmacodynamic model predicted that a single dose of 1100 mg would clear baseline parasitaemia by a factor of 109. The safety, pharmacokinetic profile, and antimalarial activity of ZY-19489 in humans support the further development of the compound as a novel antimalarial therapy. Cadila Healthcare and Medicines for Malaria Venture.