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antimalarials

NOT Open Access | Intrinsic fluorescence properties of antimalarial pyrido[1,2-a]benzimidazoles facilitate subcellular accumulation and mechanistic studies in the human malaria parasite Plasmodium falciparum

October 21, 2020 - 09:27 -- NOT Open Access
Author(s): 
Korkor CM, Garnie LF, Amod L, Egan TJ, Chibale K
Reference: 
Org Biomol Chem. 2020 Oct 20

The intrinsic fluorescence properties of two related pyrido[1,2-a]benzimidazole antimalarial compounds suitable for the cellular imaging of the human malaria parasite Plasmodium falciparum without the need to attach extrinsic fluorophores are described. Although these compounds are structurally related, they have been shown by confocal microscopy to not only accumulate selectively within P. falciparum but to also accumulate differently in the organelles investigated.

Melatonin action in Plasmodium infection: Searching for molecules that modulate the asexual cycle as a strategy to impair the parasite cycle

October 7, 2020 - 16:04 -- Open Access
Author(s): 
Pereira PHS, Garcia CRS
Reference: 
J Pineal Res. 2020 Oct 6:e12700

Half of the world's population lives in countries at risk of malaria infection, which results in approximately 450,000 deaths annually. Malaria parasites infect erythrocytes in a coordinated manner, with cycle durations in multiples of 24 hours, which reflects a behavior consistent with the host's circadian cycle. Interference in cycle coordination can help the immune system to naturally fight infection.

Memory CD73+IgM+ B cells protect against Plasmodium yoelii infection and express Granzyme B

September 8, 2020 - 12:00 -- Open Access
Author(s): 
Parra M, Weitner M, Yang A, Akue A, Liu X, Schmidt T, Allman WR, Akkoyunlu M, Derrick SC
Reference: 
PLoS One. 2020 Sep 4;15(9):e0238493

To better understand anti-malaria protective immune responses, we examined the cellular mechanisms that govern protective immunity in a murine Plasmodium yoelii 17X NL (PyNL) re-infection model. Initially, we confirmed that immune B cells generated during a primary PyNL infection were largely responsible for protection from a second PyNL infection.

Not Open Access | In vitro and in vivo evaluation of the antimalarial MMV665831 and structural analogs

September 5, 2020 - 15:53 -- NOT Open Access
Author(s): 
Ding S, Fike KR, Klemba M, Carlier PR
Reference: 
Bioorg Med Chem Lett. 2020 Sep 1;30(17):127348

Antimalarial candidates possessing novel mechanisms of action are needed to control drug resistant Plasmodium falciparum. We were drawn to Malaria Box compound 1 (MMV665831) by virtue of its excellent in vitro potency, and twelve analogs were prepared to probe its structure–activity relationship. Modulation of the diethyl amino group was fruitful, producing compound 25, which was twice as potent as 1 against cultured parasites.

Repurposing Heparin as Antimalarial: Evaluation of Multiple Modifications Toward In Vivo Application

September 2, 2020 - 11:45 -- Open Access
Author(s): 
Lantero E, Aláez-Versón CR, Romero P, Sierra T, Fernàndez-Busquets X
Reference: 
Pharmaceutics 2020, 12(9), 825

Heparin is a promising antimalarial drug due to its activity in inhibiting Plasmodium invasion of red blood cells and to the lack of resistance evolution by the parasite against it, but its potent anticoagulant activity is preventing the advance of heparin along the clinical pipeline. We have determined, in in vitro Plasmodium falciparum cultures, the antimalarial activity of heparin-derived structures of different origins and sizes, to obtain formulations having a good balance of in vitro safety (neither cytotoxic nor hemolytic), low anticoagulant activity (≤23 IU/mL according to activated partial thromboplastin time assays), and not too low antimalarial activity (IC50 at least around 100 µg/mL).

The potential antimalarial efficacy of hemocompatible silver nanoparticles from Artemisia species against P. falciparum parasite

September 2, 2020 - 08:39 -- Open Access
Author(s): 
Avitabile E, Senes N, D'Avino C, Tsamesidis I, Pinna A, Medici S, Pantaleo A
Reference: 
PLoS One. 2020 Sep 1;15(9):e0238532

Malaria represents one of the most common infectious diseases which becoming an impellent public health problem worldwide. Antimalarial classical medications include quinine-based drugs, like chloroquine, and artesunate, a derivative of artemisinin, a molecule found in the plant Artemisia annua. Such therapeutics are very effective but show heavy side effects like drug resistance. In this study, "green" silver nanoparticles (AgNPs) have been prepared from two Artemisia species (A. abrotanum and A. arborescens), traditionally used in folk medicine as a remedy for different conditions, and their potential antimalarial efficacy have been assessed.

Driving antimalarial design through understanding of target mechanism

September 2, 2020 - 08:35 -- Open Access
Author(s): 
Calic PPS, Mansouri M, Scammells PJ, McGowan S
Reference: 
Biochem Soc Trans. 2020 Sep 1:BST20200224

Malaria continues to be a global health threat, affecting approximately 219 million people in 2018 alone. The recurrent development of resistance to existing antimalarials means that the design of new drug candidates must be carefully considered.

NOT Open Access | Identification of the natural compound inhibitors against Plasmodium falciparum plasmepsin-II via common feature based screening and molecular dynamics simulations

August 18, 2020 - 14:45 -- NOT Open Access
Author(s): 
Manhas A, Kumar S, Jha PC
Reference: 
J Biomol Struct Dyn. 2020 Aug 14:1-13

Malaria is counted amongst the deadly disease caused by Plasmodium falciparum. Recently, plasmepsin-II enzyme has gained much importance as an attractive drug target for the exploration of antimalarials. Therefore, the common feature pharmacophore models were generated from the crystallized complexes of the plasmepsin-II proteome. These models were subjected to a series of validation procedures, i.e. test set and Güner Henry studies to enlist the representative models. The selected representative hypotheses incorporating the most essential chemical features (common ZHHA) were screened against the natural product database to retrieve the potential candidates.

Development of Potent PfCLK3 Inhibitors Based on TCMDC-135051 as a New Class of Antimalarials

August 17, 2020 - 13:13 -- Open Access
Author(s): 
Mahindra A, Janha O, Mapesa K, Sanchez-Azqueta A, Alam MM, Amambua-Ngwa A, Nwakanma DC, Tobin AB, Jamieson AG
Reference: 
J Med Chem. 2020 Aug 11

The protein kinase PfCLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for the survival of blood stage Plasmodium falciparum. We recently validated PfCLK3 as a drug target in malaria that offers prophylactic, transmission blocking, and curative potential. Herein, we describe the synthesis of our initial hit TCMDC-135051 (1) and efforts to establish a structure-activity relationship with a 7-azaindole-based series.

Plasmodium falciparum ATP4 inhibitors to treat malaria: worthy successors to artemisinin

August 3, 2020 - 15:51 -- Open Access
Author(s): 
Ashley EA, Phyo AP
Reference: 
Lancet Infect Dis. 2020 Aug; (8):883-885

Progress in controlling malaria has slowed in recent years and the annual death toll remains above 400 000 globally, with most deaths caused by Plasmodium falciparum.

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