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European Journal of Medicinal Chemistry Nov 2019Numerous modifications of the well-known antimalarial drug primaquine, both at the quinoline ring and at the primary amino group, have been reported, mostly to obtain... (Review)
Review
Numerous modifications of the well-known antimalarial drug primaquine, both at the quinoline ring and at the primary amino group, have been reported, mostly to obtain antimalarial agents with improved bioavailability, reduced toxicity and/or prolonged activity. Modifications of the terminal amino group were made with the main idea to prevent the metabolic pathway leading to inactive and toxic carboxyprimaquine (follow-on strategy), but also to get compounds with different activity (repurposing strategy). The modifications undertaken until 2009 were included in a review published in the same year. The present review covers various classes of primaquine N-derivatives with diverse biological profiles, prepared in the last decade by our research group as well as the others. We have summarized the synthetic procedures applied for their preparation and discussed the main biological results. Several hits for the development of novel antiplasmodial, anticancer, antimycobacterial and antibiofilm agents were identified.
Topics: Animals; Anti-Bacterial Agents; Antimalarials; Antineoplastic Agents; Biofilms; Dose-Response Relationship, Drug; Humans; Molecular Structure; Primaquine; Structure-Activity Relationship
PubMed: 31472472
DOI: 10.1016/j.ejmech.2019.111640 -
Molecules (Basel, Switzerland) Mar 2023Quinazolinedione is one of the most outstanding heterocycles in medicinal chemistry thanks to its wide ranges of biological activities including antimalarial,...
Quinazolinedione is one of the most outstanding heterocycles in medicinal chemistry thanks to its wide ranges of biological activities including antimalarial, anticancer, and anti-inflammatory. TCMDC-125133 containing a quinazolinedione pharmacophore displays promising antimalarial activity and low toxicity, as described in the GlaxoSmithKline (GSK) report. Herein, the design and synthesis of novel quinazolinedione derivatives is described on the basis of our previous work on the synthesis of TCMDC-125133, where low-cost chemicals and greener alternatives were used when possible. The initial SAR study focused on the replacement of the valine linker moiety; according to the in silico prediction using SwissADME, concise four-step syntheses toward compounds - were developed. The in-house synthesized compounds - were assayed for antimalarial activity against 3D7, and the result revealed that only the compound containing a valine linker was tolerated. Another round of lead optimization focused on the replacement of the -anisidine moiety in compound . A library of 12 derivatives was prepared, and the antimalarial assay showed that potent antimalarial activity could be maintained by replacing the methoxy group in the meta position of the phenyl side chain with a fluorine or chlorine atom (: IC = 36 ± 5 nM, : IC = 22 ± 5 nM). Further lead optimization is underway to enhance the antimalarial activity of this class of compound. The compounds included in the study possess little to no antiproliferative activity against MCF-7 cells.
Topics: Humans; Antimalarials; MCF-7 Cells; Plasmodium falciparum; Structure-Activity Relationship
PubMed: 37049762
DOI: 10.3390/molecules28072999 -
Infectious Diseases of Poverty Nov 2016Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America. Novel approaches to combating the disease have emerged... (Review)
Review
Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America. Novel approaches to combating the disease have emerged in recent years and several drug candidates are now being tested clinically. However, it is long before these novel drugs can hit the market, especially due to a scarcity of safety and efficacy data.To reduce the malaria burden, the Medicines for Malaria Venture (MMV) was established in 1999 to develop novel medicines through industry and academic partners' collaboration. However, no reviews were focused following various preclinical and clinical studies published since the MMV initiation (2000) to till date.We identify promising approaches in the global portfolio of antimalarial medicines, and highlight challenges and patient specific concerns of these novel molecules. We discuss different clinical studies focusing on the evaluation of novel drugs against malaria in different human trials over the past five years.The drugs KAE609 and DDD107498 are still being evaluated in Phase I trials and preclinical developmental studies. Both the safety and efficacy of novel compounds such as KAF156 and DSM265 need to be assessed further, especially for use in pregnant women. Synthetic non-artemisinin ozonides such as OZ277 raised concerns in terms of its insufficient efficacy against high parasitic loads. Aminoquinoline-based scaffolds such as ferroquine are promising but should be combined with good partner drugs for enhanced efficacy. AQ-13 induced electrocardiac events, which led to prolonged QTc intervals. Tafenoquine, the only new anti-relapse scaffold for patients with a glucose-6-phosphate dehydrogenase deficiency, has raised significant concerns due to its hemolytic activity. Other compounds, including methylene blue (potential transmission blocker) and fosmidomycin (DXP reductoisomerase inhibitor), are available but cannot be used in children.At this stage, we are unable to identify a single magic bullet against malaria. Future studies should focus on effective single-dose molecules that can act against all stages of malaria in order to prevent transmission. Newer medicines have also raised concerns in terms of efficacy and safety. Overall, more evidence is needed to effectively reduce the current malaria burden. Treatment strategies that target the blood stage with transmission-blocking properties are needed to prevent future drug resistance.
Topics: Antimalarials; Clinical Trials as Topic; Humans; Malaria
PubMed: 27809883
DOI: 10.1186/s40249-016-0196-8 -
Expert Opinion on Therapeutic Targets Feb 2023The deployment of Artemisinin-based combination therapies and transmission control measures led to a decrease in the global malaria burden over the recent decades.... (Review)
Review
INTRODUCTION
The deployment of Artemisinin-based combination therapies and transmission control measures led to a decrease in the global malaria burden over the recent decades. Unfortunately, this trend is now reversing, in part due to resistance against available treatments, calling for the development of new drugs against untapped targets to prevent cross-resistance.
AREAS COVERED
In view of their demonstrated druggability in noninfectious diseases, protein kinases represent attractive targets. Kinase-focussed antimalarial drug discovery is facilitated by the availability of kinase-targeting scaffolds and large libraries of inhibitors, as well as high-throughput phenotypic and biochemical assays. We present an overview of validated kinase targets and their inhibitors, and briefly discuss the potential of host cell kinases as targets for host-directed therapy.
EXPERT OPINION
We propose priority research areas, including (i) diversification of kinase targets (at present most efforts focus on a very small number of targets); (ii) polypharmacology as an avenue to limit resistance (kinase inhibitors are highly suitable in this respect); and (iii) preemptive limitation of resistance through host-directed therapy (targeting host cell kinases that are required for parasite survival) and transmission-blocking through targeting sexual stage-specific kinases as a strategy to protect curative drugs from the spread of resistance.
Topics: Animals; Humans; Antimalarials; Parasites; Malaria; Plasmodium; Drug Discovery
PubMed: 36942408
DOI: 10.1080/14728222.2023.2185511 -
Molecules (Basel, Switzerland) Jan 2021Malaria is among the deadliest infectious diseases in the world caused by parasites. Due to the high complexity of the parasite's life cycle, we partly depend on... (Review)
Review
Malaria is among the deadliest infectious diseases in the world caused by parasites. Due to the high complexity of the parasite's life cycle, we partly depend on antimalarial drugs to fight this disease. However, the emergence of resistance, mainly by , has dethroned most of the antimalarials developed to date. Given recent reports of resistance to artemisinin combination therapies, first-line treatment currently recommended by the World Health Organization, in Western Cambodia and across the Greater Mekong sub-region, it seems very likely that artemisinin and its derivatives will follow the same path of other antimalarial drugs. Consequently, novel, safe and efficient antimalarial drugs are urgently needed. One fast and low-cost strategy to accelerate antimalarial development is by recycling classical pharmacophores. Quinacrine, an acridine-based compound and the first clinically tested synthetic antimalarial drug with potent blood schizonticide but serious side effects, has attracted attention due to its broad spectrum of biological activity. In this sense, the present review will focus on efforts made in the last 20 years for the development of more efficient, safer and affordable antimalarial compounds, through recycling the classical quinacrine drug.
Topics: Acridines; Animals; Antimalarials; Humans; Malaria, Falciparum; Plasmodium falciparum
PubMed: 33498868
DOI: 10.3390/molecules26030600 -
Journal of Natural Medicines Jul 20165-Nor stemmadenine alkaloids, isolated from the genus Tabernaemontana, display a range of bioactivity. 16-Hydroxy-16,22-dihydroapparicine, the active component of an... (Review)
Review
5-Nor stemmadenine alkaloids, isolated from the genus Tabernaemontana, display a range of bioactivity. 16-Hydroxy-16,22-dihydroapparicine, the active component of an extract from the Tabernaemontana sp. (dichotoma, elegans, and divaricate), exhibited potent antimalarial activity, representing the first such report of the antimalarial property of 5-nor stemmadenine alkaloids. We, therefore, decided to attempt the total synthesis of the compound to explore its antimalarial activity and investigate structure and bioactivity relationships. As a result, we completed the first total synthesis of 16-hydroxy-16,22-dihydroapparicine, by combining a phosphine-mediated cascade reaction, diastereoselective nucleophilic addition of 2-acylindole or methylketone via a Felkin-Anh transition state, and chirality transferring intramolecular Michael addition. We also clarified the absolute stereochemistries of the compound. Furthermore, we evaluated the activity of the synthetic compound, as well as that of some intermediates, all of which showed weak activity against chloroquine-resistant Plasmodium falciparum (K1 strain) malaria parasites.
Topics: Animals; Antimalarials; Indole Alkaloids; Monoterpenes; Stereoisomerism
PubMed: 27324906
DOI: 10.1007/s11418-016-1012-2 -
Cell Reports. Medicine Oct 2021Host-directed therapy (HDT) is gaining traction as a strategy to combat infectious diseases caused by viruses and intracellular bacteria, but its implementation in the... (Review)
Review
Host-directed therapy (HDT) is gaining traction as a strategy to combat infectious diseases caused by viruses and intracellular bacteria, but its implementation in the context of parasitic diseases has received less attention. Here, we provide a brief overview of this field and advocate HDT as a promising strategy for antimalarial intervention based on untapped targets. HDT provides a basis from which repurposed drugs could be rapidly deployed and is likely to strongly limit the emergence of resistance. This strategy can be applied to any intracellular pathogen and is particularly well placed in situations in which rapid identification of treatments is needed, such as emerging infections and pandemics, as starkly illustrated by the current COVID-19 crisis.
Topics: Antimalarials; Drug Repositioning; Humans; Malaria
PubMed: 34693368
DOI: 10.1016/j.xcrm.2021.100423 -
Pharmaceutical Biology Dec 2024Tanzania has rich medicinal plant (MP) resources, and most rural inhabitants rely on traditional healing practices for their primary healthcare needs. However, available... (Review)
Review
CONTEXT
Tanzania has rich medicinal plant (MP) resources, and most rural inhabitants rely on traditional healing practices for their primary healthcare needs. However, available research evidence on antimalarial MPs is highly fragmented in the country.
OBJECTIVE
This systematic review compiles ethnomedicinal research evidence on MPs used by Tanzanians as antimalarials.
MATERIALS AND METHODS
A systematic web search was conducted using various electronic databases and grey materials to gather relevant information on antimalarial MPs utilized by Tanzanians. The review was per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The data were collected from 25 articles, and MS Excel software was used to analyse relevant ethnobotanical information using descriptive statistics.
RESULTS
A total of 227 MPs belonging to 67 botanical families and 180 genera were identified. Fabaceae (15.9%) is the most frequently utilized family. The ethnobotanical recipes analysis indicated leaves (40%) and trees (44%) are the preferred MPs part and life form, respectively. Decoctions (67%) are the dominant preparation method of remedies. Of the recorded MPs, 25.9% have been scientifically investigated for antimalarial activities with positive results. However, 74.1% of MPs have no scientific records on antimalarial activities, but they could be potential sources of remedies.
CONCLUSIONS
The study discloses a wealth of antimalarial MPs possessed by Tanzanians and suggests a need for research to authenticate the healing potential of antimalarial compounds from the unstudied MPs. Additionally, it indicates that some of the presented MPs are potential sources for developing safe, effective and affordable antimalarial drugs.
Topics: Humans; Plants, Medicinal; Antimalarials; Ethnobotany; Medicine, Traditional; East African People
PubMed: 38270178
DOI: 10.1080/13880209.2024.2305453 -
Molecular Biotechnology Nov 2022Malaria is one of the severe infectious diseases that has victimized about half a civilization billion people each year worldwide. The application of long-lasting... (Review)
Review
Malaria is one of the severe infectious diseases that has victimized about half a civilization billion people each year worldwide. The application of long-lasting insecticides is the main strategy to control malaria; however, a surge in antimalarial drug development is also taking a leading role to break off the infections. Although, recurring drug resistance can compromise the efficiency of both conventional and novel antimalarial medicines. The eradication of malaria is significantly contingent on discovering novel potent agents that are low cost and easy to administer. In this context, plant metabolites inhibit malaria infection progression and might potentially be utilized as an alternative treatment for malaria, such as artemisinin. Advances in genetic engineering technology, especially the advent of molecular farming, have made plants more versatile in producing protein drugs (PDs) to treat infectious diseases, including malaria. These recent developments in genetic modifications have enabled the production of native pharmaceutically active compounds and the accumulation of diverse heterologous proteins such as human antibodies, booster vaccines, and many PDs to treat infectious diseases and genetic disorders. This review will discuss the pivotal role of a plant-based production system that expresses natural antimalarial agents or host protein drugs to cure malaria infections. The potential of these natural and induced compounds will support modern healthcare systems in treating malaria infections, especially in developing countries to mitigate human fatalities.
Topics: Antimalarials; Artemisinins; Communicable Diseases; Humans; Insecticides; Malaria; Plants, Medicinal; Vaccines
PubMed: 35488142
DOI: 10.1007/s12033-022-00499-9 -
Cell Chemical Biology Feb 2022Acetyl-coenzyme A is an important metabolite and regulates diverse cellular processes, including metabolism and epigenetics. In this issue of Cell Chemical Biology,...
Acetyl-coenzyme A is an important metabolite and regulates diverse cellular processes, including metabolism and epigenetics. In this issue of Cell Chemical Biology, Summers et al. (2022) describe an essential parasite enzyme, acetyl-coenzyme A synthetase, as a target of two antimalarial small molecules active against liver and blood stages of the parasite.
Topics: Acetyl Coenzyme A; Animals; Antimalarials; Parasites; Plasmodium; Plasmodium falciparum
PubMed: 35180431
DOI: 10.1016/j.chembiol.2022.02.003