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Advanced Biology Aug 2023Artemisinin (ART) and its derivatives have great therapeutical utility as antimalarials and can be repurposed for other indications, such as viral infections, autoimmune... (Review)
Review
Artemisinin (ART) and its derivatives have great therapeutical utility as antimalarials and can be repurposed for other indications, such as viral infections, autoimmune diseases, and cancer. This review presents a comprehensive overview of the therapeutic effects of ART-based drugs, beyond their antimalarial effects. This review also summarizes the information on their repurposing in other pathologies, with the hope that it will guide the future optimization of the use of ART-based drugs and of the treatment strategies for the listed diseases. By reviewing related literature, ART extraction and structure as well as the synthesis and structure of its derivatives are presented. Subsequently, the traditional roles of ART and its derivatives against malaria are reviewed, including antimalarial mechanism and occurrence of antimalarial resistance. Finally, the potential of ART and its derivatives to be repurposed for the treatment of other diseases are summarized. The great repurposing potential of ART and its derivatives may be useful for the control of emerging diseases with corresponding pathologies, and future research should be directed toward the synthesis of more effective derivatives or better combinations.
Topics: Humans; Antimalarials; Drug Repositioning; Artemisinins; Malaria; Folic Acid Antagonists
PubMed: 37178448
DOI: 10.1002/adbi.202300086 -
Current Medicinal Chemistry 2019Malaria remains a major health problem, especially because of the emergence of resistant P. falciparum strains to artemisinin derivatives. In this context, safe and... (Review)
Review
Malaria remains a major health problem, especially because of the emergence of resistant P. falciparum strains to artemisinin derivatives. In this context, safe and affordable antimalarial drugs are desperately needed. New proteins have been investigated as molecular targets for research and development of innovative compounds with welldefined mechanism of action. In this review, we highlight genetically and clinically validated plasmodial proteins as drug targets for the next generation of therapeutics. The enzymes described herein are involved in hemoglobin hydrolysis, the invasion process, elongation factors for protein synthesis, pyrimidine biosynthesis, post-translational modifications such as prenylation, phosphorylation and histone acetylation, generation of ATP in mitochondrial metabolism and aminoacylation of RNAs. Significant advances on proteomics, genetics, structural biology, computational and biophysical methods provided invaluable molecular and structural information about these drug targets. Based on this, several strategies and models have been applied to identify and improve lead compounds. This review presents the recent progresses in the discovery of antimalarial drug candidates, highlighting the approaches, challenges, and perspectives to deliver affordable, safe and low single-dose medicines to treat malaria.
Topics: Animals; Antimalarials; Drug Discovery; Humans; Malaria; Plasmodium falciparum
PubMed: 28875841
DOI: 10.2174/0929867324666170830103003 -
Biochemical Pharmacology Dec 2023The search for effective antimalarial agents remains a critical priority because malaria is widely spread and drug-resistant strains are becoming more prevalent. In this... (Review)
Review
The search for effective antimalarial agents remains a critical priority because malaria is widely spread and drug-resistant strains are becoming more prevalent. In this review, a variety of small molecules capable of modulating redox processes were showcased for their potential as antimalarial agents. The compounds were designed to target the redox balance of Plasmodium parasites, which has a pivotal function in their ability to survive and multiply within the host organism. A thorough screening method was utilized to assess the effectiveness of these compounds against both drug-sensitive and drug-resistant strains of Plasmodium falciparum, the malaria-causing parasite. The results revealed that several of the tested compounds exhibited significant effectiveness against malaria, displaying IC values at a low micromolar range. Furthermore, these compounds displayed promising selectivity for the parasite, as they exhibited low cytotoxicity towards mammalian cells. Thorough mechanistic studies were undertaken to clarify how the active compounds exert their mode of action. The findings revealed that these compounds disrupted the parasites' redox balance, causing oxidative stress and interfering with essential cellular functions. Additionally, the compounds showed synergistic effects when combined with existing antimalarial drugs, suggesting their potential for combination therapies to combat drug resistance. Overall, this study highlights the potential of redox-modulating small molecules as effective antimalarial agents. The identified compounds demonstrate promising antimalarial activity, and their mechanism of action offers insights into targeting the redox balance of Plasmodium parasites. Further optimization and preclinical studies are warranted to determine their efficacy, safety, and potential for clinical development as novel antimalarial therapeutics.
Topics: Animals; Humans; Antimalarials; Malaria; Plasmodium falciparum; Oxidation-Reduction; Oxidative Stress; Mammals
PubMed: 37992998
DOI: 10.1016/j.bcp.2023.115927 -
Current Opinion in Microbiology Dec 2022Phenotypic screening methods have placed numerous preclinical candidates into the antimalarial drug-discovery pipeline. As more chemically validated targets become... (Review)
Review
Phenotypic screening methods have placed numerous preclinical candidates into the antimalarial drug-discovery pipeline. As more chemically validated targets become available, efforts are shifting to target-based drug discovery. Here, we briefly review some of the most attractive targets that have been identified in recent years.
Topics: Antimalarials; Drug Discovery
PubMed: 36228458
DOI: 10.1016/j.mib.2022.102220 -
Molecules (Basel, Switzerland) Nov 2023Peptide compounds play a significant role in medicinal chemistry as they can inhibit the activity of species that cause malaria. This literature review summarizes the... (Review)
Review
Peptide compounds play a significant role in medicinal chemistry as they can inhibit the activity of species that cause malaria. This literature review summarizes the isolation of antimalarial peptides, the synthesis method with the detailed structure and sequences of each peptide, and discusses the biological activity of the isolated and synthesized compounds. The synthetic routes and reactions for cyclic and linear antimalarial peptides are systematically highlighted in this review including preparing building blocks, protection and deprotection, coupling and cyclization reactions until the target compound is obtained. Based on the literature data and the results, this review's aim is to provide information to discover and synthesize more antimalarial peptide for future research.
Topics: Humans; Antimalarials; Peptides; Malaria; Cyclization; Chemistry, Pharmaceutical; Peptides, Cyclic
PubMed: 38067508
DOI: 10.3390/molecules28237778 -
Biometals : An International Journal on... Apr 2023Despite advances in chemotherapeutic interventions for the treatment of malaria, there is a continuing need for the development of new antimalarial agents. Previous...
Despite advances in chemotherapeutic interventions for the treatment of malaria, there is a continuing need for the development of new antimalarial agents. Previous studies indicated that co-administration of chloroquine with antioxidants such as the iron chelator deferoxamine (DFO) prevented the development of persistent cognitive damage in surrogate models of cerebral malaria. The work described herein reports the syntheses and antimalarial activities of covalent conjugates of both natural (siderophores) and artificial iron chelators, namely DFO, ferricrocin and ICL-670, with antimalarial 1,2,4-trioxolanes (ozonides). All of the synthesized conjugates had potent antimalarial activities against the in vitro cultures of drug resistant and drug sensitive strains of Plasmodium falciparum. The work described herein provides the basis for future development of covalent combination of iron chelators and antimalarial chemotherapeutic agents for the treatment of cerebral malaria.
Topics: Humans; Antimalarials; Siderophores; Malaria, Cerebral; Amides; Esters; Iron Chelating Agents
PubMed: 35229216
DOI: 10.1007/s10534-022-00375-8 -
International Journal For Parasitology.... Dec 2022New antimalarial compounds with novel mechanisms of action are urgently needed to combat the recent rise in antimalarial drug resistance. Phenotypic high-throughput... (Review)
Review
New antimalarial compounds with novel mechanisms of action are urgently needed to combat the recent rise in antimalarial drug resistance. Phenotypic high-throughput screens have proven to be a successful method for identifying new compounds, however, do not provide mechanistic information about the molecular target(s) responsible for antimalarial action. Current and emerging target identification methods such as in vitro resistance generation, metabolomics screening, chemoproteomic approaches and biophysical assays measuring protein stability across the whole proteome have successfully identified novel drug targets. This review provides an overview of these techniques, comparing their strengths and weaknesses and how they can be utilised for antimalarial target identification.
Topics: Antimalarials; Plasmodium falciparum; Drug Resistance; Metabolomics
PubMed: 36410177
DOI: 10.1016/j.ijpddr.2022.11.001 -
Current Medicinal Chemistry 2018Malaria caused by Plasmodium parasites is amongst many prevalent public health concerns in several tropical regions of the world. Nowadays, the parasite resistance... (Review)
Review
Malaria caused by Plasmodium parasites is amongst many prevalent public health concerns in several tropical regions of the world. Nowadays, the parasite resistance patterns to most currently used drugs in therapy and insecticides have created an urgent need for new chemical entities exhibiting new modes of action and management strategies. Fungus has been proven to be an excellent source of biologically active compounds, which have been screened for antiplasmodial activity as potential sources of new antimalarial drugs. This review summarizes the current 255 natural products from fungus, which may possess antimalarial activity and can be classified as sesquiterpenes, diterpenes, sesterterpenes, alkaloids, peptides depsipeptides, xanthones, anthraquinones, anthrones, bioxanthracenes, bixanthones, preussomerins, depsidones, phenols, trichothecenes, azaphliones, macrolides, and steroids. However, the treatments available for malaria are limited. Thus, the identification of novel antimicrobial agents should be continued, and all possible strategies should be explored. Carrying forward the antimalarial screening in exited terrestrial and marine natural products library, and finding the new natural products in new resources, particularly those living in marine environments, are still important approaches to find new antimalarial agents. Unusual marine environments are associated with chemical diversity, leading to a resource of novel active substances for the development of bioactive products. Finding new antimalarial natural products in marine fungus, particularly those living in deep-sea and special marine environments, is an important approach to identify novel active agents.
Topics: Animals; Antimalarials; Biological Products; Cell Line, Tumor; Fungi; Humans; Plasmodium falciparum; Structure-Activity Relationship
PubMed: 29532754
DOI: 10.2174/0929867325666180313105406 -
Expert Opinion on Drug Safety Jul 2016Antimalarial drugs are the primary weapon to treat parasite infection, save lives, and curtail further transmission. Accumulating data have indicated that at least some... (Review)
Review
INTRODUCTION
Antimalarial drugs are the primary weapon to treat parasite infection, save lives, and curtail further transmission. Accumulating data have indicated that at least some antimalarial drugs may contribute to severe neurological and/or psychiatric side effects which further complicates their use and limits the pool of available medications.
AREAS COVERED
In this review article, we summarize published scientific studies in search of evidence of the neuropsychiatric effects that may be attributed to the commonly used antimalarial drugs administered alone or in combination. Each individual drug was used as a search term in addition to keywords such as neuropsychiatric, adverse events, and neurotoxicity.
EXPERT OPINION
Accumulating data based on published reports over several decades have suggested that among the major commonly used antimalarial drugs, only mefloquine exhibited clear indications of serious neurological and/or psychiatric side effects. A more systematic approach to assess the neuropsychiatric adverse effects of new or repurposed antimalarial drugs on their safety, tolerability and efficacy phases of clinical studies and in post-marketing surveillance, is needed to ensure that these life-saving tools remain available and can be prescribed with appropriate caution and medical judgment.
Topics: Antimalarials; Humans; Malaria; Mefloquine; Mental Disorders; Neurotoxicity Syndromes
PubMed: 27077782
DOI: 10.1080/14740338.2016.1175428 -
Combinatorial Chemistry & High... 2015
Topics: Antimalarials; Computational Biology; Drug Discovery; Humans; Malaria; Plasmodium; Quantitative Structure-Activity Relationship
PubMed: 25692659
DOI: 10.2174/138620731802150215154014