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NOT Open Access | Synthesis and antimalarial and anticancer evaluation of 7-chlorquinoline-4-thiazoleacetic derivatives containing aryl hydrazide moieties

March 9, 2021 - 15:46 -- NOT Open Access
Ramírez H, Fernandez E, Rodrigues J, Mayora S, Martínez G, Celis C, De Sanctis JB, Mijares M, Charris J
Arch Pharm (Weinheim). 2021 Mar 4:e2100002

Twelve 7-chloroquinoline derivatives were designed and synthesized using the principle of molecular hybridization through the coupling of 2-[2-(7-chloroquinolin-4-ylthio)-4-methylthiazol-5-yl]acetic acid 1 with various benzoyl hydrazines 2a-l. The synthetic compounds were tested as antimalarials. Some of them showed an efficient in vitro activity as inhibitors of β-hematin formation and an in vivo activity in a murine model, resulting in compounds 8 and 9 as the most active ones with IC50 values of 0.65 ± 0.09 and 0.64 ± 0.16 µM, respectively.

Benzimidazole Derivatives Are Potent against Multiple Life Cycle Stages of Plasmodium falciparum Malaria Parasites

March 9, 2021 - 15:42 -- Open Access
Leshabane M, Dziwornu GA, Birkholtz LM, et al.
ACS Infect Dis. 2021 Mar 5

The continued emergence of resistance to front-line antimalarial treatments is of great concern. Therefore, new compounds that potentially have a novel target in various developmental stages of Plasmodium parasites are needed to treat patients and halt the spread of malaria. Here, several benzimidazole derivatives were screened for activity against the symptom-causing intraerythrocytic asexual blood stages and the transmissible gametocyte stages of P. falciparum.

NOT Open Access | 3-Hydroxy-propanamidines, a New Class of Orally Active Antimalarials Targeting Plasmodium falciparum

March 9, 2021 - 15:29 -- NOT Open Access
Knaab TC, Held J, Kurz T, et al.
J Med Chem. 2021 Mar 5

3-Hydroxypropanamidines are a new promising class of highly active antiplasmodial agents. The most active compound 22 exhibited excellent antiplasmodial in vitro activity with nanomolar inhibition of chloroquine-sensitive and multidrug-resistant parasite strains of Plasmodium falciparum (with IC50 values of 5 and 12 nM against 3D7 and Dd2 strains, respectively) as well as low cytotoxicity in human cells.

Surveillance of Plasmodium falciparum pfcrt haplotypes in southwestern uganda by high‐resolution melt analysis

March 3, 2021 - 15:30 -- Open Access
Kennedy Kassaza, Anna C. Long, Yap Boum II, et al.
Malaria Journal 2021 20:114, 25 February 2021

Chloroquine (CQ) resistance is conferred by mutations in the Plasmodium falciparum CQ resistance transporter (pfcrt). Following CQ withdrawal for anti-malarial treatment, studies across malaria-endemic countries have shown a range of responses. In some areas, CQ sensitive parasites re-emerge, and in others, mutant haplotypes persist. Active surveillance of resistance mutations in clinical parasites is essential to inform treatment regimens; this effort requires fast, reliable, and cost-effective methods that work on a variety of sample types with reagents accessible in malaria-endemic countries.

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.


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