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NOT Open Access | Novel Antimalarial Tetrazoles and Amides Active against the Hemoglobin Degradation Pathway in Plasmodium falciparum

February 25, 2021 - 09:46 -- NOT Open Access
Lawong A, Gahalawat S, Phillips MA, et al.
J Med Chem. 2021 Feb 23

Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified a novel tetrazole-based series that shows fast-kill kinetics and a relatively low propensity to develop high-level resistance. Preliminary structure-activity relationships were established including identification of a subseries of related amides with antiplasmodial activity.

Applying the CiPA Approach to Evaluate Cardiac Proarrhythmia Risk of some Antimalarials Used Off-label in the First Wave of COVID-19

February 25, 2021 - 09:44 -- Open Access
Delaunois A, Abernathy M, Valentin JP, et al.
Clin Transl Sci. 2021 Feb 23

We applied a set of in silico and in vitro assays, compliant with the CiPA (Comprehensive In Vitro Proarrhythmia Assay) paradigm, to assess the risk of chloroquine or hydroxychloroquine-mediated QT prolongation and Torsades de Pointes (TdP), alone and combined with erythromycin and azithromycin, drugs repurposed during the first wave of COVID-19. Each drug or drug combination was tested in patch clamp assays on 7 cardiac ion channels, in in silico models of human ventricular electrophysiology (Virtual Assay® ) using control (healthy) or high-risk cell populations, and in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes.

MAIP: a web service for predicting blood-stage malaria inhibitors

February 25, 2021 - 08:15 -- Open Access
Bosc N, Felix E, Leach AR, et al.
J Cheminform. 2021 Feb 22;13(1):13

Malaria is a disease affecting hundreds of millions of people across the world, mainly in developing countries and especially in sub-Saharan Africa. It is the cause of hundreds of thousands of deaths each year and there is an ever-present need to identify and develop effective new therapies to tackle the disease and overcome increasing drug resistance. Here, we extend a previous study in which a number of partners collaborated to develop a consensus in silico model that can be used to identify novel molecules that may have antimalarial properties.

Antiplasmodial activity of Ethanolic extract of Cassia spectabilis DC leaf and its inhibition effect in Heme detoxification

February 23, 2021 - 12:50 -- Open Access
Ekasari W, Basuki DR, Arwati H, Wahyuni TS
BMC Complement Med Ther. 2021 Feb 19;21(1):71

In previous studies, Cassia spectabilis DC leaf has shown a good antiplasmodial activity. Therefore, this study is a follow-up study of the extract of leaf of C. spectabilis DC on its in vitro and in vivo antiplasmodial activity and mechanism as an antimalarial.

The Role of the Histone Methyltransferase PfSET10 in Antigenic Variation by Malaria Parasites: a Cautionary Tale

February 9, 2021 - 09:57 -- Open Access
Ngwa CJ, Gross MR, Musabyimana JP, Pradel G, Deitsch KW
mSphere. 2021 Feb 3;6(1):e01217-20

The virulence of the malaria parasite Plasmodium falciparum is due in large part to its ability to avoid immune destruction through antigenic variation. This results from changes in expression within the multicopy var gene family that encodes the surface antigen P. falciparum erythrocyte protein one (PfEMP1). Understanding the mechanisms underlying this process has been a high-profile research focus for many years. The histone methyltransferase PfSET10 was previously identified as a key enzyme required both for parasite viability and for regulating var gene expression, thus making it a prominent target for developing antimalarial intervention strategies and the subject of considerable research focus. Here, however, we show that disruption of the gene encoding PfSET10 is not lethal and has no effect on var gene expression, in sharp contrast with previously published reports. The contradictory findings highlight the importance of reevaluating previous conclusions when new technologies become available and suggest the possibility of a previously unappreciated plasticity in epigenetic gene regulation in P. falciparum.

NOT Open Access | Discovery of Novel Plasmodium falciparum HDAC1 Inhibitors with Dual-Stage Antimalarial Potency and Improved Safety Based on the Clinical Anticancer Drug Candidate Quisinostat

February 8, 2021 - 10:25 -- NOT Open Access
Li R, Ling D, Li J, et al.
J Med Chem. 2021 Feb 4

Previously, we identified the clinical anticancer drug candidate quisinostat as a novel and potent antimalarial lead compound. To further enhance the antimalarial effect and improve safety, 31 novel spirocyclic hydroxamic acid derivatives were synthesized based on the structure of quisinostat, and their antimalarial activities and cytotoxicity were evaluated. Among them, compound 11 displayed broad potency in vitro against several multiresistant malarial parasites, especially two artemisinin-resistant clinical isolates.

Bloodstream infection with Acinetobacter baumanii in a Plasmodium falciparum positive infant: a case report

February 8, 2021 - 10:24 -- Open Access
Akenten CW, Boahen KG, Marfo KS, Sarpong N, Dekker D, Struck NS, Osei-Tutu L, May J, Amuasi JH, Eibach D
J Med Case Rep. 2021 Feb 5;15(1):46

The increasing incidence of multi-antibiotic-resistant bacterial infections, coupled with the risk of co-infections in malaria-endemic regions, complicates accurate diagnosis and prolongs hospitalization, thereby increasing the total cost of illness. Further, there are challenges in making the correct choice of antibiotic treatment and duration, precipitated by a lack of access to microbial culture facilities in many hospitals in Ghana. The aim of this case report is to highlight the need for blood cultures or alternative rapid tests to be performed routinely in malaria patients, to diagnose co-infections with bacteria, especially when symptoms persist after antimalarial treatment.

Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites

January 26, 2021 - 15:14 -- Open Access
Dorjsuren D, Eastman RT, Fidock DA, et al.
Sci Rep. 2021 Jan 22;11(1):2121

The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration-response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages.

NOT Open Access | Antimalarial application of quinones: A recent update

January 20, 2021 - 08:02 -- NOT Open Access
Patel OPS, Beteck RM, Legoabe LJ
Eur J Med Chem. 2021 Jan 15;210:113084

Atovaquone belongs to a naphthoquinone class of drugs and is used in combination with proguanil (Malarone) for the treatment of acute, uncomplicated malaria caused by Plasmodium falciparum (including chloroquine-resistant P. falciparum/P. vivax). Numerous quinone-derived compounds have attracted considerable attention in the last few decades due to their potential in antimalarial drug discovery.

Diatretol, an α, α'-dioxo-diketopiperazine, is a potent in vitro and in vivo antimalarial

January 19, 2021 - 16:04 -- Open Access
Ishiyama A, Hokari R, Nonaka K, Chiba T, Miura H, Otoguro K, Iwatsuki M
J Antibiot (Tokyo). 2021 Jan 14:1-3

A fungal metabolite, diatretol, has shown to be a promising antimalarial agent.


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