Antimalarial mechanism of action of the natural product 9-methoxystrobilurin G.

The natural product 9-methoxystrobilurin G (9MG) from spp basidiomycetes is a potent and selective antimalarial. The mechanism of action of 9MG is unknown. We induced 9MG resistance in 3D7 and Dd2 strains and identified mutations associated with resistance by genome sequencing.

Flexible 2,4-diaminopyrimidine bearing a butyrolactone as Plasmodium falciparum dihydrofolate reductase inhibitors.

Recently, P218, a new flexible antifolate targeting Plasmodium falciparum dihydrofolate reductase (PfDHFR), has entered its clinical trial with good safety profile and effective Pf infection prevention. However, it carries a free carboxyl terminal, which is hydrophilic and prone to metabolic glucuronidation. Here, a new series of P218 analogues carrying butyrolactone has been synthesized with the purpose of enhancing lipophilicity and minimizing metabolic instability.

folA thyA knockout E. coli as a suitable surrogate model for evaluation of antifolate sensitivity against PfDHFR-TS.

A new superior bacteria complementation model was achieved for testing antifolate compounds and investigating antifolate resistance in the dihydrofolate reductase (DHFR) enzyme of the malaria parasite. Earlier models depended on the addition of trimethoprim (TMP) to chemically suppress the host Escherichia coli (Ec) DHFR function. However, incomplete suppression of EcDHFR and potential interference of antibiotics needed to maintain plasmids for complementary gene expression can complicate the interpretations.

Novel flexible biphenyl DHFR inhibitors with improved antimalarial activity.

As pregnant women and young children remain the first victims of malaria worldwide, the search for new antimalarials has been focusing on compounds with a high safety profile and extended efficacy. In a previous study, a rigid biphenyl DHFR inhibitor was developed by fragment-based screening, displaying sub nM enzyme inhibition but poor antiparasitic activity, presumably due to its low flexibility. Here, we report a new series of compounds that combines the biphenyl fragment with a flexible linker.

Design, synthesis and Anti-Plasmodial activity of Mortiamide-Lugdunin conjugates.

In this study, two linear and corresponding cyclic heptapeptide versions of mortiamide A-lugdunin hybrids were designed and synthesized by integrating an anti-malarial peptide epitope derived from Mortiamide A, combined with four residues known for their membrane interactions. Using this synthetic strategy, the sequence of mortiamide A was partly re-engineered with an epitope sequence of lugdunin along with an amino acid replacement using all-L and D/L configurations. Importantly, the re-engineered cyclic mortiamides with all-L (3) and D/L (4) configurations exhibited promising anti-malarial activities against the P.

Antimalarial target vulnerability of the putative methionine synthase.

Background: possesses a cobalamin-dependent methionine synthase (MS). MS is putatively encoded by the PF3D7_1233700 gene, which is orthologous and syntenic in . However, its vulnerability as an antimalarial target has not been assessed.

Discovery of rigid biphenyl DHFR inhibitors using a fragment linking strategy.

dihydrofolate reductase (DHFR), a historical target for antimalarials, has been considered compromised due to resistance inducing mutations caused by pyrimethamine () overexposure. The clinical candidate has demonstrated that inhibitors could efficiently target both -sensitive and -resistant parasites through careful drug design. Yet, clinical development has been limited by its pharmacokinetic profile, incompatible with single dose regimen.

Susceptibility of Southeast Asian Plasmodium falciparum isolates to P218.

A major threat to the goal of eliminating malaria, particularly in Southeast Asia, is the spread of Plasmodium falciparum resistant to artemisinin-based combination therapies. P218 is a drug candidate designed to combat antifolate-sensitive and -resistant parasites. However, there is no evidence that P218 is effective against artemisinin-resistant P.

Antagonistic antimalarial properties of a methoxyamino chalcone derivative and 3-hydroxypyridinones in combination with dihydroartemisinin against .

Background: The spread of artemisinin (ART)-resistant threatens the control of malaria. Mutations in the propeller domains of Kelch13 () are strongly associated with ART resistance. Ferredoxin (Fd), a component of the ferredoxin/NADP reductase (Fd/FNR) redox system, is essential for isoprenoid precursor synthesis in the plasmodial apicoplast, which is important for K13-dependent hemoglobin trafficking and ART activation.

-Containing α-Mangostin Analogs via Smiles Rearrangement as the Promising Cytotoxic, Antitrypanosomal, and SARS-CoV-2 Main Protease Inhibitory Agents.

New -containing xanthone analogs of α-mangostin were synthesized via one-pot Smiles rearrangement. Using cesium carbonate in the presence of 2-chloroacetamide and catalytic potassium iodide, α-mangostin () was subsequently transformed in three steps to provide ether , amide , and amine in good yields at an optimum ratio of 1:3:3, respectively. The evaluation of the biological activities of α-mangostin and analogs - was described.

Transcriptomic complexity of the human malaria parasite Plasmodium falciparum revealed by long-read sequencing.

The Plasmodium falciparum human malaria parasite genome is incompletely annotated and does not accurately represent the transcriptomic diversity of this species. To address this need, we performed long-read transcriptomic sequencing. 5' capped mRNA was enriched from samples of total and nuclear-fractionated RNA from intra-erythrocytic stages and converted to cDNA library.

Molecular Docking Studies, Synthesis and Biological Evaluation of Substituted Pyrimidine-2,4-diamines as Inhibitors of Plasmodium falciparum Dihydrofolate Reductase.

A series of 5-[(phenethylamino)methyl]pyrimidine-2,4-diamines were assessed in silico as potential inhibitors of Plasmodium falciparum dihydrofolate reductase (PfDHFR), synthesised and tested for inhibitory activity against PfDHFR in vitro. The compounds displayed promising inhibitory activity against both wild-type (K 1.3-243 nM) and quadruple mutant (K 13-208 nM) PfDHFR in the biochemical enzyme assay, but were less potent in the whole-cell P.

Key interactions of pyrimethamine derivatives specific to wild-type and mutant dihydrofolate reductase based on 3D-QSAR, MD simulations and quantum chemical calculations.

dihydrofolate reductase-thymidylate synthase (DHFR-TS) is an important target enzyme in malarial chemotherapy. An understanding of how novel inhibitors interact with wild-type (wtDHFR), quadruple-mutant (qmDHFR), and human (DHFR) enzymes is required for the development of these compounds as antimalarials. This study is focused on a series of -Cl and -Cl phenyl analogs of pyrimethamine with various flexible 6-substituents.

Structural Insight into Effective Inhibitors' Binding to Dihydrofolate Reductase Thymidylate Synthase.

Pyrimethamine (Pyr), a known dihydrofolate reductase (DHFR) inhibitor, has long been used to treat toxoplasmosis caused by (Tg) infection. However, Pyr is effective only at high doses with associated toxicity to patients, calling for safer alternative treatments. In this study, we investigated a series of Pyr analogues, previously developed as DHFR inhibitors of bifunctional DHFR-thymidylate synthase (PfDHFR-TS), for their activity against DHFR-TS (TgDHFR-TS).

Assay Development and Identification of the First 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase Inhibitors.

In the fight towards eradication of malaria, identifying compounds active against new drug targets constitutes a key approach. 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase (HPPK) has been advanced as a promising target, as being part of the parasite essential folate biosynthesis pathway while having no orthologue in the human genome. However, no drug discovery efforts have been reported on this enzyme.

Semi-Synthesis of -Aryl Amide Analogs of Piperine from and Evaluation of Their Antitrypanosomal, Antimalarial, and Anti-SARS-CoV-2 Main Protease Activities.

, or black pepper, produces piperine, an alkaloid that has diverse pharmacological activities. In this study, -aryl amide piperine analogs were prepared by semi-synthesis involving the saponification of piperine () to yield piperic acid () followed by esterification to obtain compounds , , and . The compounds were examined for their antitrypanosomal, antimalarial, and anti-SARS-CoV-2 main protease activities.

New Insights into Antimalarial Chemopreventive Activity of Antifolates.

Antifolates targeting dihydrofolate reductase (DHFR) are antimalarial compounds that have long been used for malaria treatment and chemoprevention (inhibition of infection from mosquitoes to humans). Despite their extensive applications, a thorough understanding of antifolate activity against hepatic malaria parasites, especially resistant parasites, has yet to be achieved. Using a transgenic Plasmodium berghei harboring quadruple mutant from Plasmodium falciparum (::-4M), we demonstrated that quadruple mutations on confer complete chemoprevention resistance to pyrimethamine, the previous generation of antifolate, but not to a new class of antifolate designed to overcome the resistance, such as P218.

Synthesis and evaluation of tetrahydroisoquinoline derivatives against Trypanosoma brucei rhodesiense.

Human African Trypanosomiasis (HAT) is a neglected tropical disease caused by the parasitic protozoan Trypanosoma brucei (T. b.), and affects communities in sub-Saharan Africa.

Identifying transcript 5' capped ends in .

Background: The genome of the human malaria parasite is poorly annotated, in particular, the 5' capped ends of its mRNA transcripts. New approaches are needed to fully catalog transcripts for understanding gene function and regulation in this organism.

Methods: We developed a transcriptomic method based on next-generation sequencing of complementary DNA (cDNA) enriched for full-length fragments using eIF4E, a 5' cap-binding protein, and an unenriched control.

Isolation of bioactive compounds from medicinal plants used in traditional medicine: Rautandiol B, a potential lead compound against Plasmodium falciparum.

Background: Neorautanenia mitis, Hydnora abyssinica, and Senna surattensis are medicinal plants with a variety of traditional uses. In this study, we sought to isolate the bioactive compounds responsible for some of these activities, and to uncover their other potential medicinal properties.

Methods: The DCM and ethanol extracts of the roots of N.

5-Phenoxy Primaquine Analogs and the Tetraoxane Hybrid as Antimalarial Agents.

The rapid emergence of drug resistance to the current antimalarial agents has led to the urgent need for the discovery of new and effective compounds. In this work, a series of 5-phenoxy primaquine analogs with 8-aminoquinoline core (-) was synthesized and investigated for their antimalarial activity against . Most analogs showed improved blood antimalarial activity compared to the original primaquine.

Transgenic pyrimethamine-resistant plasmodium falciparum reveals transmission-blocking potency of P218, a novel antifolate candidate drug.

Antimalarial drugs capable of targeting multiple parasite stages, particularly the transmissible stages, can be valuable tools for advancing the malaria elimination agenda. Current antifolate drugs such as pyrimethamine can inhibit replicative parasite stages in both humans and mosquitoes, but antifolate resistance remains a challenge. The lack of reliable gametocyte-producing, antifolate-resistant Plasmodium falciparum laboratory strain hinders the study of new antifolate compounds that can overcome antifolate resistance including development stages in the mosquito.

Discovery of new non-pyrimidine scaffolds as DHFR inhibitors by fragment-based screening.

In various malaria-endemic regions, the appearance of resistance has precluded the use of pyrimidine-based antifolate drugs. Here, a three-step fragment screening was used to identify new non-pyrimidine dihydrofolate reductase (DHFR) inhibitors. Starting from a 1163-fragment commercial library, a two-step differential scanning fluorimetry screen identified 75 primary fragment hits.

Unique polyacetylenic ester-neolignan derivatives from Mitrephora tomentosa and their antimalarial activities.

The phytochemical investigation of the methanol extracts of the leaves and twigs of Mitrephora tomentosa Hook. f. & Thomson resulted in the isolation and identification of undescribed polyacetylenic ester-neolignan derivatives, along with six known compounds.