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NOT Open Access | Property activity refinement of 2-anilino 4-amino substituted quinazolines as antimalarials with fast acting asexual parasite activity

December 7, 2021 - 21:24 -- NOT Open Access
Ashton TD, Ngo A, Sleebs BE, et al.
Bioorg Chem. 2021 Dec;117:105359

Malaria is a devastating disease caused by Plasmodium parasites. Emerging resistance against current antimalarial therapeutics has engendered the need to develop antimalarials with novel structural classes. We recently described the identification and initial optimization of the 2-anilino quinazoline antimalarial class. Here, we refine the physicochemical properties of this antimalarial class with the aim to improve aqueous solubility and metabolism and to reduce adverse promiscuity. We show the physicochemical properties of this class are intricately balanced with asexual parasite activity and human cell cytotoxicity.

Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials

December 1, 2021 - 20:35 -- Open Access
Nerlich C, Epalle NH, Seick P, Beitz E
Pharmaceuticals (Basel). 2021 Nov 20;14(11):1191

Plasmodium spp. malaria parasites in the blood stage draw energy from anaerobic glycolysis when multiplying in erythrocytes. They tap the ample glucose supply of the infected host using the erythrocyte glucose transporter 1, GLUT1, and a hexose transporter, HT, of the parasite's plasma membrane.

An Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials

December 1, 2021 - 20:20 -- Open Access
Tse EG, Aithani L, Todd MH, et al.
J Med Chem. 2021 Nov 25;64(22):16450-16463

The Open Source Malaria (OSM) consortium is developing compounds that kill the human malaria parasite, Plasmodium falciparum, by targeting PfATP4, an essential ion pump on the parasite surface. The structure of PfATP4 has not been determined. Here, we describe a public competition created to develop a predictive model for the identification of PfATP4 inhibitors, thereby reducing project costs associated with the synthesis of inactive compounds.

NOT Open Access | Assessing the Impact of Substandard and Falsified Antimalarials in Benin

November 10, 2021 - 21:07 -- NOT Open Access
Bui V, Higgins CR, Laing S, Ozawa S
Am J Trop Med Hyg. 2021 Nov 8:tpmd210450

Substandard and falsified antimalarials contribute to the global malaria burden by increasing the risk of treatment failures, adverse events, unnecessary health expenditures, and avertable deaths, yet no study has examined this impact in western francophone Africa to date. In Benin, where malaria remains endemic and is the leading cause of mortality among children younger than 5 years, there is a lack of robust data to combat the issue effectively and inform policy decisions. We adapted the Substandard and Falsified Antimalarial Research Impact model to assess the health and economic impact of poor-quality antimalarials in this population.

NOT Open Access | Discovery and development of 2-aminobenzimidazoles as potent antimalarials

October 16, 2021 - 13:01 -- NOT Open Access
Devine SM, Challis MP, Kigotho JK, Siddiqui G, De Paoli A, MacRaild CA, Avery VM, Creek DJ, Norton RS, Scammells PJ
Eur J Med Chem. 2021 Oct 5;221:113518

The emergence of Plasmodium falciparum resistance to frontline antimalarials, including artemisinin combination therapies, highlights the need for new molecules that act via novel mechanisms of action. Herein, we report the design, synthesis and antimalarial activity of a series of 2-aminobenzimidazoles, featuring a phenol moiety that is crucial to the pharmacophore.

NOT Open Access | In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2

October 12, 2021 - 09:59 -- NOT Open Access
Hernández González JE, Salas-Sarduy E, Hernández Alvarez L, Barreto Gomes DE, Pascutti PG, Oostenbrink C, Leite VBP
J Comput Aided Mol Des. 2021 Oct 7

Falcipain-2 (FP-2) is a Plasmodium falciparum hemoglobinase widely targeted in the search for antimalarials. FP-2 can be allosterically modulated by various noncompetitive inhibitors that have been serendipitously identified. Moreover, the crystal structures of two inhibitors bound to an allosteric site, termed site 6, of the homolog enzyme human cathepsin K (hCatK) suggest that the equivalent region in FP-2 might play a similar role.

Real-time PCR assays for detection and quantification of early P. falciparum gametocyte stages

October 5, 2021 - 10:50 -- Open Access
Gadalla AAH, Siciliano G, Farid R, Alano P, Ranford-Cartwright L, McCarthy JS, Thompson J, Babiker HA
Sci Rep. 2021 Sep 27;11(1):19118

The use of quantitative qRT-PCR assays for detection and quantification of late gametocyte stages has revealed the high transmission capacity of the human malaria parasite, Plasmodium falciparum. To understand how the parasite adjusts its transmission in response to in-host environmental conditions including antimalarials requires simultaneous quantification of early and late gametocytes.

The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis

September 8, 2021 - 17:07 -- Open Access
Chan XHS, Haeusler IL, White NJ, et al.
PLoS Med. 2021 Sep 7;18(9):e1003766

Amodiaquine is a 4-aminoquinoline antimalarial similar to chloroquine that is used extensively for the treatment and prevention of malaria. Data on the cardiovascular effects of amodiaquine are scarce, although transient effects on cardiac electrophysiology (electrocardiographic QT interval prolongation and sinus bradycardia) have been observed. We conducted an individual patient data meta-analysis to characterise the cardiovascular effects of amodiaquine and thereby support development of risk minimisation measures to improve the safety of this important antimalarial.

NOT Open Access | Ototoxic hearing loss from antimalarials: A systematic narrative review

September 8, 2021 - 17:04 -- NOT Open Access
Dillard LK, Fullerton AM, McMahon CM
Travel Med Infect Dis. 2021 Sep-Oct;43:102117 Background

Drugs used in curative and prophylactic antimalarial treatment may be ototoxic and lead to permanent hearing loss, but there is no consensus regarding prevalence and permanence of ototoxic hearing loss caused by antimalarials. The purpose of this systematic narrative review was to synthesize current evidence on antimalarial ototoxicity in human populations.

NOT Open Access | Cyclic Tetrapeptide HDAC Inhibitors with Improved Plasmodium falciparum Selectivity and Killing Profile

September 8, 2021 - 16:59 -- NOT Open Access
Collins JE, Lee JW, Bohmer MJ, Welden JD, Arshadi AK, Du L, Cichewicz RH, Chakrabarti D
ACS Infect Dis. 2021 Sep 7

Cyclic tetrapeptide histone deacetylase inhibitors represent a promising class of antiplasmodial agents that epigenetically disrupt a wide range of cellular processes in Plasmodium falciparum. Unfortunately, certain limitations, including reversible killing effects and host cell toxicity, prevented these inhibitors from further development and clinical use as antimalarials.


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