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Nature Reviews. Drug Discovery Oct 2023Recent antimalarial drug discovery has been a race to produce new medicines that overcome emerging drug resistance, whilst considering safety and improving dosing... (Review)
Review
Recent antimalarial drug discovery has been a race to produce new medicines that overcome emerging drug resistance, whilst considering safety and improving dosing convenience. Discovery efforts have yielded a variety of new molecules, many with novel modes of action, and the most advanced are in late-stage clinical development. These discoveries have led to a deeper understanding of how antimalarial drugs act, the identification of a new generation of drug targets, and multiple structure-based chemistry initiatives. The limited pool of funding means it is vital to prioritize new drug candidates. They should exhibit high potency, a low propensity for resistance, a pharmacokinetic profile that favours infrequent dosing, low cost, preclinical results that demonstrate safety and tolerability in women and infants, and preferably the ability to block Plasmodium transmission to Anopheles mosquito vectors. In this Review, we describe the approaches that have been successful, progress in preclinical and clinical development, and existing challenges. We illustrate how antimalarial drug discovery can serve as a model for drug discovery in diseases of poverty.
Topics: Animals; Female; Humans; Antimalarials; Plasmodium; Drug Resistance; Drug Discovery
PubMed: 37652975
DOI: 10.1038/s41573-023-00772-9 -
Scientific Reports Aug 2017Divergent synthesis of antimalarial troponoids, including naturally occurring compounds, some of which were identified and isolated by our group, has been achieved...
Divergent synthesis of antimalarial troponoids, including naturally occurring compounds, some of which were identified and isolated by our group, has been achieved utilizing the total synthetic route of puberulic acid. Structure-activity relationships of natural products and simple troponoids inspired us to explore more detailed properties of this class of compounds. Access to new derivatives was facilitated through intermediate compounds generated during the total synthesis of puberulic acid by a stepwise oxidation-aromatization sequence to provide 7-hydroxytropolones and bromination for conversion of the carboxylic acid moiety. The first total synthesis of viticolin A, as well as the synthesis of different methyl-substituted derivatives, has also been achieved. In vitro antimalarial activity and cytotoxicity of novel derivatives were evaluated and fundamental information to facilitate the discovery of more promising antimalarials was obtained.
Topics: Antimalarials; Biological Products; Carboxylic Acids; Cell Line; Cell Survival; Chemistry Techniques, Synthetic; Humans; Inhibitory Concentration 50; Molecular Structure; Oxidation-Reduction; Parasitic Sensitivity Tests; Plasmodium falciparum; Structure-Activity Relationship; Tropolone
PubMed: 28775291
DOI: 10.1038/s41598-017-07718-3 -
Chemical & Pharmaceutical Bulletin 2021Novel derivatives of puberulic acid were synthesized and their antimalarial properties were evaluated in vitro against the Plasmodium falciparum K1 parasite strain,...
Novel derivatives of puberulic acid were synthesized and their antimalarial properties were evaluated in vitro against the Plasmodium falciparum K1 parasite strain, cytotoxicity against a human diploid embryonic cell line MRC-5, and in vivo efficacy using a Plasmodium berghei-infected mouse model. From previous information that three hydroxy groups on the tropone framework were essential for antimalarial activity, we converted the carboxylic acid moiety into the corresponding esters, amides, and ketones. These derivatives showed antimalarial activity against chloroquine-resistant Plasmodium in vitro equivalent to puberulic acid. We identified that the pentane-3-yl ester, cyclohexyl ester, iso-butyl ketone, cyclohexyl methyl ketone all show an especially potent antiparasitic effect in vivo at an oral dose of 15 mg/kg without any apparent toxicity. These esters were more effective than the existing commonly used antimalarial drug, artesunate.
Topics: Animals; Antimalarials; Carboxylic Acids; Cell Line; Cell Survival; Disease Models, Animal; Humans; Malaria; Male; Mice; Mice, Inbred ICR; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium; Tropolone
PubMed: 34078803
DOI: 10.1248/cpb.c21-00132 -
Molecules (Basel, Switzerland) Oct 2019Malaria and cancer are chronic diseases. The challenge with drugs available for the treatment of these diseases is drug toxicity and resistance. Ferrocene is a potent... (Review)
Review
Malaria and cancer are chronic diseases. The challenge with drugs available for the treatment of these diseases is drug toxicity and resistance. Ferrocene is a potent organometallic which have been hybridized with other compounds resulting in compounds with enhanced biological activity such as antimalarial and anticancer. Drugs such as ferroquine were developed from ferrocene and chloroquine. It was tested in the 1990s as an antimalarial and is still an effective antimalarial. Many researchers have reported ferrocene compounds as potent compounds useful as anticancer and antimalarial agents when hybridized with other pharmaceutical scaffolds. This review will be focused on compounds with ferrocene moieties that exhibit either an anticancer or antimalarial activity.
Topics: Aminoquinolines; Antimalarials; Antineoplastic Agents; Chloroquine; Drug Resistance, Neoplasm; Drug Therapy, Combination; Ferrous Compounds; Humans; Malaria; Metallocenes; Neoplasms; Plasmodium falciparum
PubMed: 31591298
DOI: 10.3390/molecules24193604 -
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 -
Trends in Parasitology Jun 2021The Malaria Drug Accelerator (MalDA) is a consortium of 15 leading scientific laboratories. The aim of MalDA is to improve and accelerate the early antimalarial drug... (Review)
Review
The Malaria Drug Accelerator (MalDA) is a consortium of 15 leading scientific laboratories. The aim of MalDA is to improve and accelerate the early antimalarial drug discovery process by identifying new, essential, druggable targets. In addition, it seeks to produce early lead inhibitors that may be advanced into drug candidates suitable for preclinical development and subsequent clinical testing in humans. By sharing resources, including expertise, knowledge, materials, and reagents, the consortium strives to eliminate the structural barriers often encountered in the drug discovery process. Here we discuss the mission of the consortium and its scientific achievements, including the identification of new chemically and biologically validated targets, as well as future scientific directions.
Topics: Antimalarials; Drug Discovery; Malaria; Plasmodium; Time
PubMed: 33648890
DOI: 10.1016/j.pt.2021.01.009 -
Biomedicine & Pharmacotherapy =... Jul 2023Artemisinin (ART) is a bioactive compound isolated from the plant Artemisia annua and has been traditionally used to treat conditions such as malaria, cancer, viral... (Review)
Review
Artemisinin (ART) is a bioactive compound isolated from the plant Artemisia annua and has been traditionally used to treat conditions such as malaria, cancer, viral infections, bacterial infections, and some cardiovascular diseases, especially in Asia, North America, Europe and other parts of the world. This comprehensive review aims to update the biomedical potential of ART and its derivatives for treating human diseases highlighting its pharmacokinetic and pharmacological properties based on the results of experimental pharmacological studies in vitro and in vivo. Cellular and molecular mechanisms of action, tested doses and toxic effects of artemisinin were also described. The analysis of data based on an up-to-date literature search showed that ART and its derivatives display anticancer effects along with a wide range of pharmacological activities such as antibacterial, antiviral, antimalarial, antioxidant and cardioprotective effects. These compounds have great potential for discovering new drugs used as adjunctive therapies in cancer and various other diseases. Detailed translational and experimental studies are however needed to fully understand the pharmacological effects of these compounds.
Topics: Humans; Artemisinins; Antimalarials; Malaria
PubMed: 37182516
DOI: 10.1016/j.biopha.2023.114866 -
Cell Host & Microbe Jul 2019Intensified treatment and control efforts since the early 2000s have dramatically reduced the burden of Plasmodium falciparum malaria. However, drug resistance threatens... (Review)
Review
Intensified treatment and control efforts since the early 2000s have dramatically reduced the burden of Plasmodium falciparum malaria. However, drug resistance threatens to derail this progress. In this review, we present four antimalarial resistance case studies that differ in timeline, technical approaches, mechanisms of action, and categories of resistance: chloroquine, sulfadoxine-pyrimethamine, artemisinin, and piperaquine. Lessons learned from prior losses of treatment efficacy, drug combinations, and control strategies will help advance mechanistic research into how P. falciparum parasites acquire resistance to current first-line artemisinin-based combination therapies. Understanding resistance in the clinic and laboratory is essential to prolong the effectiveness of current antimalarial drugs and to optimize the pipeline of future medicines.
Topics: Antimalarials; Drug Resistance; Drug Therapy, Combination; Humans; Malaria, Falciparum; Plasmodium falciparum
PubMed: 31295423
DOI: 10.1016/j.chom.2019.06.001 -
Frontiers in Cellular and Infection... 2021Parasites of the phylum Apicomplexa impact humans in nearly all parts of the world, causing diseases including to toxoplasmosis, cryptosporidiosis, babesiosis, and... (Review)
Review
Parasites of the phylum Apicomplexa impact humans in nearly all parts of the world, causing diseases including to toxoplasmosis, cryptosporidiosis, babesiosis, and malaria. Apicomplexan parasites have complex life cycles comprised of one or more stages characterized by rapid replication and biomass amplification, which enables accelerated evolutionary adaptation to environmental changes, including to drug pressure. The emergence of drug resistant pathogens is a major looming and/or active threat for current frontline chemotherapies, especially for widely used antimalarial drugs. In fact, resistant parasites have been reported against all modern antimalarial drugs within 15 years of clinical introduction, including the current frontline artemisinin-based combination therapies. Chemotherapeutics are a major tool in the public health arsenal for combatting the onset and spread of apicomplexan diseases. All currently approved antimalarial drugs have been discovered either through chemical modification of natural products or through large-scale screening of chemical libraries for parasite death phenotypes, and so far, none have been developed through a gene-to-drug pipeline. However, the limited duration of efficacy of these drugs in the field underscores the need for new and innovative approaches to discover drugs that can counter rapid resistance evolution. This review details both historical and current antimalarial drug discovery approaches. We also highlight new strategies that may be employed to discover resistance-resistant drug targets and chemotherapies in order to circumvent the rapid evolution of resistance in apicomplexan parasites.
Topics: Animals; Antimalarials; Drug Discovery; Drug Resistance; Humans; Malaria; Parasites; Plasmodium falciparum
PubMed: 34178727
DOI: 10.3389/fcimb.2021.691121 -
Medecine Et Sante Tropicales Feb 2019There is currently a hazardous debate between the rational use of antimalarial drugs based on artemisinin derivatives and the antimalarial efficacy of plant extracts of...
There is currently a hazardous debate between the rational use of antimalarial drugs based on artemisinin derivatives and the antimalarial efficacy of plant extracts of Artemisia spp. This article recall some fundamental rules guiding progresses in malaria treatment and use of artemisinin, with the aim to provide discussion elements to identify the safest place responding to health situations for drugs and phytotherapy.
Topics: Antimalarials; Artemisia annua; Health Services Accessibility; Humans; Plant Preparations; Plants, Medicinal
PubMed: 31031254
DOI: 10.1684/mst.2019.0868