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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 -
Future Medicinal Chemistry Aug 2013Recent initiatives to develop more effective and affordable drugs, controlling mosquitoes and development of a preventative vaccine have been launched with the goal of... (Review)
Review
Recent initiatives to develop more effective and affordable drugs, controlling mosquitoes and development of a preventative vaccine have been launched with the goal of completely eradicating malaria. To this end, Novartis (Surrey, UK) and GlaxoSmithKline (Middlesex, UK) screened their chemical libraries of approximately two million small molecules for antimalarial properties, which resulted in a set of over 20,000 'highly druggable' initial hits. Efforts in academia are centered on specific pathway targets. One such high-throughput screening effort has been focused on hemozoin formation, a unique heme detoxification pathway found in the malaria parasite. This review discusses the current approaches and limitations of high-throughput screening discovery of hemozoin inhibitors. In the future, new methods must be developed to validate the mechanism of action of these hit compounds within the parasite.
Topics: Animals; Antimalarials; Drug Evaluation, Preclinical; Heme; Hemeproteins; High-Throughput Screening Assays; Humans; Malaria; Plasmodium falciparum
PubMed: 23919553
DOI: 10.4155/fmc.13.113 -
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 -
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 -
The Journal of Antimicrobial... May 2013Atovaquone is used as a fixed-dose combination with proguanil (Malarone) for treating children and adults with uncomplicated malaria or as chemoprophylaxis for... (Review)
Review
Atovaquone is used as a fixed-dose combination with proguanil (Malarone) for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travellers. Indeed, in the USA, between 2009 and 2011, Malarone prescriptions accounted for 70% of all antimalarial pre-travel prescriptions. In 2013 the patent for Malarone will expire, potentially resulting in a wave of low-cost generics. Furthermore, the malaria scientific community has a number of antimalarial quinolones with a related pharmacophore to atovaquone at various stages of pre-clinical development. With this in mind, it is timely here to review the current knowledge of atovaquone, with the purpose of aiding the decision making of clinicians and drug developers involved in the future use of atovaquone generics or atovaquone derivatives.
Topics: Antimalarials; Atovaquone; Chemoprevention; Drug Combinations; Humans; Malaria; Proguanil; United States
PubMed: 23292347
DOI: 10.1093/jac/dks504 -
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 Oct 2018Despite the recent successes of artemisinin-based antimalarial drugs, many still die from severe malaria, and eradication efforts are hindered by the limited drugs... (Review)
Review
Despite the recent successes of artemisinin-based antimalarial drugs, many still die from severe malaria, and eradication efforts are hindered by the limited drugs currently available to target transmissible gametocyte parasites and liver-resident dormant Plasmodium vivax hypnozoites. Host-targeted therapy is a new direction for infectious disease drug development and aims to interfere with host molecules, pathways, or networks that are required for infection or that contribute to disease. Recent advances in our understanding of host pathways involved in parasite development and pathogenic mechanisms in severe malaria could facilitate the development of host-targeted interventions against Plasmodium infection and malaria disease. This review discusses new opportunities for host-targeted therapeutics for malaria and the potential to harness drug polypharmacology to simultaneously target multiple host pathways using a single drug intervention.
Topics: Antimalarials; Drug Delivery Systems; Host-Parasite Interactions; Humans; Immunologic Factors
PubMed: 30122551
DOI: 10.1016/j.pt.2018.07.011