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Bioorganic & Medicinal Chemistry Aug 2015Quinoline-containing compounds, such as quinine and chloroquine, have a long-standing history as potent antimalarial agents. However, the increasing resistance of the... (Review)
Review
Quinoline-containing compounds, such as quinine and chloroquine, have a long-standing history as potent antimalarial agents. However, the increasing resistance of the Plasmodium parasite against these drugs and the lack of licensed malaria vaccines have forced chemists to develop synthetic strategies toward novel biologically active molecules. A strategy that has attracted considerable attention in current medicinal chemistry is based on the conjugation of two biologically active molecules into one hybrid compound. Since quinolines are considered to be privileged antimalarial building blocks, the synthesis of quinoline-containing antimalarial hybrids has been elaborated extensively in recent years. This review provides a literature overview of antimalarial hybrid molecules containing a quinoline core, covering publications between 2009 and 2014.
Topics: Animals; Antimalarials; Drug Discovery; Humans; Malaria; Plasmodium; Quinolines
PubMed: 25593097
DOI: 10.1016/j.bmc.2014.12.018 -
Revista Espanola de Quimioterapia :... Sep 2016Malaria is one of the most widespread infectious diseases around the world with 214 million cases and 438,000 deaths in 2015. In the early twentieth century it was... (Review)
Review
Malaria is one of the most widespread infectious diseases around the world with 214 million cases and 438,000 deaths in 2015. In the early twentieth century it was described for the first time the resistance to quinine and, since then, drug resistance to antimalarial drugs has spread up to represent a global challenge in the fight and control of malaria. Understanding the mechanisms, geography and monitoring tools that we can act against resistance to antimalarial drugs is critical to prevent its expansion.
Topics: Antimalarials; Drug Resistance; Humans; Malaria; Plasmodium; Quinine
PubMed: 27608319
DOI: No ID Found -
Drug Research Jan 2021Drug repositioning is a strategy that identifies new uses of approved drugs to treat conditions different from their original purpose. Current efforts to treat Covid-19...
Drug repositioning is a strategy that identifies new uses of approved drugs to treat conditions different from their original purpose. Current efforts to treat Covid-19 are based on this strategy. The first drugs used in patients infected with SARS-CoV-2 were antimalarial drugs. It is their mechanism of action, i. e., rise in endosomal pH, which recommends them against the new coronavirus. Disregarding their side effects, the study of their antiviral activity provides valuable hints for the choice and design of drugs against SARS-CoV-2. One prominent drug candidate is thymoquinone, an antimalarial substance contained in Nigella sativa - most likely one of the first antimalarial drugs in human history. Since the outbreak of the pandemic, the number of articles relating thymoquinone to Covid-19 continuously increases. Here, we use it as an exemplary model drug, compare its antiviral mechanism with that of conventional antimalarial drugs and establish an irreducible parametric scheme for the identification of drugs with a potential in Covid-19.Translation into the laboratory is simple. Starting with the discovery of Nigella sativa seeds in the tomb of Pharaoh Tutankhamun, we establish a physicochemical model for the interaction of thymoquinone with both coronavirus and cells. Exploiting the predictive capability of the model, we provide a generalizable scheme for the systematic choice and design of drugs for Covid-19. An unexpected offshoot of our research is that Tutankhamun could not have died of malaria, a finding contrary to the mainstream theory.
Topics: Antimalarials; Antiviral Agents; Benzoquinones; Drug Repositioning; Egypt; Famous Persons; History, Ancient; Humans; Nigella sativa; COVID-19 Drug Treatment
PubMed: 33128226
DOI: 10.1055/a-1274-1264 -
Natural Product Reports May 2022Covering 1972 to 2021Malaria remains a significant public health problem in some regions of the world. The great efforts to control malaria have been severely... (Review)
Review
Covering 1972 to 2021Malaria remains a significant public health problem in some regions of the world. The great efforts to control malaria have been severely compromised due to the widespread resistance of to nearly all frontline drugs. Pursuit of novel molecules from the sea will potentially result in new interventions against malaria, which are urgently needed to combat the increase of resistance. Focusing on the strategy of the "Blue Drug Bank", the molecules highlighted here can serve as an inspiration for future medicinal chemistry campaigns. This review covers the developments in the field of antimalarial marine lead compounds reported between 1972 and July 2021, and offers a comprehensive overview on their progresses and potentials. We selected 60 representative potential candidate molecules from 361 marine natural products, and highlighted their structure-activity relationships, molecular mechanisms of targets, and drug-like properties in order to assess their full potential to be developed. We summarized 107 clinically proven or potential antimalarial targets and their subcellular locations in the relevant target proteins, which linked the molecules to the target proteins at the subcellular level. Hence, it could be expected that natural products targeting different mechanisms may prove to be an effective strategy in antimalarial drug research and development in the future.
Topics: Antimalarials; Biological Products; Humans; Malaria; Plasmodium falciparum; Structure-Activity Relationship
PubMed: 35156111
DOI: 10.1039/d1np00075f -
ACS Infectious Diseases Oct 2023We discovered dibenzannulated medium-ring keto lactams (11,12-dihydro-5-dibenzo[,]azonine-6,13-diones) as a new antimalarial chemotype. Most of these had chromatographic...
We discovered dibenzannulated medium-ring keto lactams (11,12-dihydro-5-dibenzo[,]azonine-6,13-diones) as a new antimalarial chemotype. Most of these had chromatographic LogD values ranging from <0 to 3 and good kinetic solubilities (12.5 to >100 μg/mL at pH 6.5). The more polar compounds in the series (LogD values of <2) had the best metabolic stability (CL values of <50 μL/min/mg protein in human liver microsomes). Most of the compounds had relatively low cytotoxicity, with IC values >30 μM, and there was no correlation between antiplasmodial activity and cytotoxicity. The four most potent compounds had IC values of 4.2 to 9.4 nM and selectivity indices of 670 to >12,000. They were more than 4 orders-of-magnitude less potent against three other protozoal pathogens (, , and ) but did have relatively high potency against , with IC values ranging from 80 to 200 nM. These keto lactams are converted into their poorly soluble 4(1)-quinolone transannular condensation products in culture medium and in mouse blood. The similar antiplasmodial potencies of three keto lactam-quinolone pairs suggest that the quinolones likely contribute to the antimalarial activity of the lactams.
Topics: Mice; Animals; Humans; Antimalarials; Lactams; Trypanosoma brucei rhodesiense; Trypanosoma cruzi; Quinolones
PubMed: 37695781
DOI: 10.1021/acsinfecdis.3c00245 -
Frontiers in Cellular and Infection... 2024Malaria has always been a serious infectious disease prevalent in the world. Antimalarial drugs such as chloroquine and artemisinin have been the main compounds used to... (Review)
Review
BACKGROUND
Malaria has always been a serious infectious disease prevalent in the world. Antimalarial drugs such as chloroquine and artemisinin have been the main compounds used to treat malaria. However, the massive use of this type of drugs accelerates the evolution and spread of malaria parasites, leading to the development of resistance. A large number of related data have been published by researchers in recent years. CiteSpace software has gained popularity among us researchers in recent years, because of its ability to help us obtain the core information we want in a mass of articles. In order to analyze the hotspots and develop trends in this field through visual analysis, this study used CiteSpace software to summarize the available data in the literature to provide insights.
METHOD
Relevant literature was collected from the Web of Science Core Collection (WOSCC) from 1 January 2015 to 29 March 2023. CiteSpace software and Microsoft Excel were used to analyze and present the data, respectively.
RESULTS
A total of 2,561 literatures were retrieved and 2,559 literatures were included in the analysis after the removal of duplicates. An irrefutable witness of the ever-growing interest in the topic of antimalarial drug resistance could be expressed by the exponentially increased number of publications and related citations from 2015 to 2022, and its sustained growth trend by 2023. During the past 7 years, USA, Oxford University, and David A Fidock are the country, institution, and author with the most publications in this field of research, respectively. We focused on the references and keywords from literature and found that the research and development of new drugs is the newest hotspot in this field. A growing number of scientists are devoted to finding new antimalarial drugs.
CONCLUSION
This study is the first visual metrological analysis of antimalarial drug resistance, using bibliometric methods. As a baseline information, it is important to analyze research output published globally on antimalarial drug resistance. In order to better understand the current research situation and future research plan agenda, such baseline data are needed accordingly.
Topics: Humans; Antimalarials; Chloroquine; Bibliometrics; Folic Acid Antagonists; Malaria
PubMed: 38410722
DOI: 10.3389/fcimb.2024.1270060 -
Trends in Parasitology Nov 2023Nutrient import and waste efflux are critical dependencies for intracellular Plasmodium falciparum parasites. Nutrient transport proteins are often lineage specific and... (Review)
Review
Nutrient import and waste efflux are critical dependencies for intracellular Plasmodium falciparum parasites. Nutrient transport proteins are often lineage specific and can provide unique targets for antimalarial drug development. P. falciparum nutrient transport pathways can be a double-edged sword for the parasite, not only mediating the import of nutrients and excretion of waste products but also providing an access route for drugs. Here we briefly summarise the nutrient acquisition pathways of intracellular P. falciparum blood-stage parasites and then highlight how these pathways influence many aspects relevant to antimalarial drugs, resulting in complex and often underappreciated interdependencies.
Topics: Humans; Malaria, Falciparum; Plasmodium falciparum; Antimalarials; Biological Transport; Nutrients; Protozoan Proteins
PubMed: 37716852
DOI: 10.1016/j.pt.2023.08.008 -
European Journal of Medicinal Chemistry Oct 2017Malaria, in particular infection with P. falciparum (the most lethal of the human malaria parasite species, responsible for nearly one million deaths every year), is... (Review)
Review
Malaria, in particular infection with P. falciparum (the most lethal of the human malaria parasite species, responsible for nearly one million deaths every year), is one of the most devastating and common infectious disease throughout the world. Beginning with quinine, quinoline containing compounds have long been used in clinical treatment of malaria and remained the mainstays of chemotherapy against malaria. The emergence of P. falciparum strains resistant to almost all antimalarials prompted medicinal chemists and biologists to study their effective replacement with an alternative mechanism of action and new molecules. Combination with variety of quinolines and other active moieties may increase the antiplasmodial and antimalarial activities and reduce the side effects. Thus, hybridization is a very attractive strategy to develop novel antimalarials. This review aims to summarize the recent advances towards the discovery of antiplasmodial and antimalarial hybrids including quinoline skeleton to provide an insight for rational designs of more active and less toxic quinoline hybrids antimalarials.
Topics: Antimalarials; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium falciparum; Quinolines
PubMed: 28800458
DOI: 10.1016/j.ejmech.2017.07.061 -
European Journal of Medicinal Chemistry Aug 2023Malaria is the fifth most lethal parasitic infection in the world. Antimalarial medications have played a crucial role in preventing and eradicating malaria. Numerous... (Review)
Review
Malaria is the fifth most lethal parasitic infection in the world. Antimalarial medications have played a crucial role in preventing and eradicating malaria. Numerous heterocyclic moieties have been incorporated into the creation of effective antimalarial drugs. The 4-aminoquinoline moiety is favoured in antimalarial drug discovery due to the diverse biological applications of its derivative. Since the 1960s, 4-aminoquinoline has been an important antimalarial drug due to its low toxicity, high tolerability, and rapid absorption after administration. This review focused on the antimalarial efficacy of the 4-aminoquinoline moiety hybridised with various heterocyclic scaffolds developed by scientists since 2018 against diverse Plasmodium clones. It could aid in the future development of more effective antimalarial agents.
Topics: Humans; Antimalarials; Plasmodium falciparum; Aminoquinolines; Malaria
PubMed: 37163950
DOI: 10.1016/j.ejmech.2023.115458 -
Antimicrobial Agents and Chemotherapy Feb 2022The emergence and spread of parasite resistance to currently available antimalarials has highlighted the importance of developing novel antimalarials. This scoping... (Review)
Review
The emergence and spread of parasite resistance to currently available antimalarials has highlighted the importance of developing novel antimalarials. This scoping review provides an overview of antimalarial drug candidates undergoing phase I and II studies between 1 January 2016 and 28 April 2021. PubMed, Web of Science, Embase, clinical trial registries, and reference lists were searched for relevant studies. Information regarding antimalarial compound details, clinical trial characteristics, study population, and drug pharmacokinetics and pharmacodynamics (PK-PD) were extracted. A total of 50 studies were included, of which 24 had published their results and 26 were unpublished. New antimalarial compounds were evaluated as monotherapy (28 studies, 14 drug candidates) and combination therapy (9 studies, 10 candidates). Fourteen active compounds were identified in the current antimalarial drug development pipeline together with 11 compounds that are inactive, 6 due to insufficient efficacy. PK-PD data were available from 24 studies published as open-access articles. Four unpublished studies have made their results publicly available on clinical trial registries. The terminal elimination half-life of new antimalarial compounds ranged from 14.7 to 483 h. The log parasite reduction ratio over 48 h and parasite clearance half-life for Plasmodium falciparum following a single-dose monotherapy were 1.55 to 4.1 and 3.4 to 9.4 h, respectively. The antimalarial drug development landscape has seen a number of novel compounds, with promising PK-PD properties, evaluated in phase I and II studies over the past 5 years. Timely public disclosure of PK-PD data is crucial for informative decision-making and drug development strategy.
Topics: Antimalarials; Drug Development; Drug Resistance; Humans; Malaria, Falciparum; Plasmodium falciparum
PubMed: 34843390
DOI: 10.1128/AAC.01659-21