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Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439

June 15, 2021 - 14:50 -- Open Access
Shackleford DM, Chiu FCK, Charman SA, et al.
ACS Infect Dis. 2021 Jun 8

OZ439 is a potent synthetic ozonide evaluated for the treatment of uncomplicated malaria. The metabolite profile of OZ439 was characterized in vitro using human liver microsomes combined with LC/MS-MS, chemical derivatization, and metabolite synthesis. The primary biotransformations were monohydroxylation at the three distal carbon atoms of the spiroadamantane substructure, with minor contributions from N-oxidation of the morpholine nitrogen and deethylation cleavage of the morpholine ring.

NOT Open Access | Novel Dipeptides Bearing Sulfonamide as Antimalarial and Antitrypanosomal agents: Synthesis and Molecular Docking

June 9, 2021 - 07:20 -- NOT Open Access
Ekoh OC, Okoro U, Ugwu D, Ali R, Okafor S, Ugwuja D, Attah S
Med Chem. 2021 Jun 3

Protozoan parasites cause severe diseases, with human African trypanosomaisis (HAT) and malaria leading the list. The noted deficiencies of existing antitrypanosomal drugs and the worldwide resurgence of malaria, accompanied by the springing up of widespread drug-resistant protozoan parasites, represent a huge challenge in infectious disease treatment in tropical regions.

High Throughput Screening to Identify Selective and Nonpeptidomimetic Proteasome Inhibitors As Antimalarials

June 1, 2021 - 12:36 -- Open Access
Mata-Cantero L, Xie SC, Gomez-Lorenzo MG, et al.
ACS Infect Dis. 2021 May 28

The Ubiquitin Proteasome System is the main proteolytic pathway in eukaryotic cells, playing a role in key cellular processes. The essentiality of the Plasmodium falciparum proteasome is well validated, underlying its potential as an antimalarial target, but selective compounds are required to avoid cytotoxic effects in humans. Almost 550000 compounds were tested for the inhibition of the chymotrypsin-like activity of the P. falciparum proteasome using a Proteasome-GLO luminescence assay.

NOT Open Access | Artemether and lumefantrine dissolving microneedle patches with improved pharmacokinetic performance and antimalarial efficacy in mice infected with Plasmodium yoelii

May 19, 2021 - 15:26 -- NOT Open Access
Volpe-Zanutto F, Ferreira LT, Foglio MA, et al.
J Control Release. 2021 May 10;333:298-315

Malaria affects more than 200 million people annually around the world, killing a child every 2 min. Artemether (ART) and lumefantrine (LUM) are the gold standard choice to treat uncomplicated Plasmodium falciparum malaria; however, they are hydrophobic compounds with low oral bioavailability. Microneedle (MN) arrays consist of micron-sized needles on one side of a supporting base and have the ability to bypass the skin's stratum corneum barrier in a minimally invasive way, creating temporary channels through which drugs can diffuse, including those with poor water solubility.

Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials

May 19, 2021 - 14:14 -- Open Access
Duffey M, Blasco B, Burrows JN, Wells TNC, Fidock DA, Leroy D
Trends Parasitol. 2021 May 14:S1471-4922(21)00086-6

Strategies to counteract or prevent emerging drug resistance are crucial for the design of next-generation antimalarials. In the past, resistant parasites were generally identified following treatment failures in patients, and compounds would have to be abandoned late in development. An early understanding of how candidate therapeutics lose efficacy as parasites evolve resistance is important to facilitate drug design and improve resistance detection and monitoring up to the postregistration phase.

NOT Open Access | Aminoalkoxycarbonyloxymethyl Ether Prodrugs with a pH-Triggered Release Mechanism: A Case Study Improving the Solubility, Bioavailability, and Efficacy of Antimalarial 4(1H)-Quinolones with Single Dose Cures

May 19, 2021 - 13:31 -- NOT Open Access
Monastyrskyi A, Brockmeyer F, Manetsch R, et al.
J Med Chem. 2021 May 12

Preclinical and clinical development of numerous small molecules is prevented by their poor aqueous solubility, limited absorption, and oral bioavailability. Herein, we disclose a general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues that display significantly improved aqueous solubility and enhanced oral bioavailability, restoring key requirements typical for drug candidate profiles.

Chloroquine: Autophagy inhibitor, antimalarial, bitter taste receptor agonist in fight against COVID-19, a reality check

April 22, 2021 - 08:29 -- Open Access
Sharma P, McAlinden KD, Ghavami S, Deshpande DA
Eur J Pharmacol. 2021 Apr 15;897:173928

The recent SARS-CoV-2 pandemic poses one of the greatest challenges to modern medicine. Therefore, identification of new therapeutic strategies seems essential either based on novel vaccines or drugs or simply repurposing existing drugs. Notably, due to their known safety profile, repurposing of existing drugs is the fastest and highly efficient approach to bring a therapeutic to a clinic for any new indication. One such drug that has been used extensively for decades is chloroquine (CQ, with its derivatives) either for malaria, lupus and rheumatoid arthritis.

NOT Open Access | Antimalarial Quinacrine and Chloroquine Lose Their Activity by Decreasing Cationic Amphiphilic Structure with a Slight Decrease in pH

March 30, 2021 - 14:21 -- NOT Open Access
Kitagawa T, Matsumoto A, Terashima I, Uesono Y
J Med Chem. 2021 Mar 27

Quinacrine (QC) and chloroquine (CQ) have antimicrobial and antiviral activities as well as antimalarial activity, although the mechanisms remain unknown. QC increased the antimicrobial activity against yeast exponentially with a pH-dependent increase in the cationic amphiphilic drug (CAD) structure. CAD-QC localized in the yeast membranes and induced glucose starvation by noncompetitively inhibiting glucose uptake as antipsychotic chlorpromazine (CPZ) did.

NOT Open Access | Discovery of Potent and Fast-Acting Antimalarial Bis-1,2,4-triazines

March 26, 2021 - 16:11 -- NOT Open Access
Priebbenow DL, Mathiew M, Baell JB, et al.
J Med Chem. 2021 Mar 24

Novel 3,3'-disubstituted-5,5'-bi(1,2,4-triazine) compounds with potent in vitro activity against Plasmodium falciparum parasites were recently discovered. To improve the pharmacokinetic properties of the triazine derivatives, a new structure-activity relationship (SAR) investigation was initiated with a focus on enhancing the metabolic stability of lead compounds.

Antioxidant and antimalarial properties of Sophora exigua Craib. root extract in Plasmodium berghei-infected mice

March 24, 2021 - 14:11 -- Open Access
Kaewdana K, Chaniad P, Jariyapong P, Phuwajaroanpong A, Punsawad C
Trop Med Health. 2021 Mar 19;49(1):24

Sophora exigua Craib. is commonly used in Thailand to reduce fever and increase postpartum breast milk production in women who have hypogalactia. However, there has been no report on the antioxidant and antimalarial properties of this plant. This study aimed to investigate the antioxidant and antimalarial activities of S. exigua root extract and to evaluate its acute toxicity in mice to confirm its safety.


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