Boron Trifluoride Etherate Promoted Microwave Assisted Synthesis of Antimalarial Acridones

A microwave-assisted, rapid and efficient method using boron trifluoride etherate (BF3.Et2O) for the synthesis of acridones, via an intramolecular acylation of N-phenylanthranilic acid derivatives, has been developed. The reaction proceeds under solvent-free conditions, tolerates a wide range of functional groups, and provides rapid access to a range of acridones in good to excellent yields. Several of the synthesized acridones exhibited potent antimalarial activities against CQ sensitive and multi-drug resistant (MDR) parasites

Total Synthesis and Antimalarial Activity of 2-(-Hydroxybenzyl)-Prodigiosins, Isoheptylprodigiosin, and Geometric Isomers of Tambjamine MYP1 Isolated from Marine Bacteria.

Highly efficient and straightforward synthetic routes toward the first total synthesis of 2-(-hydroxybenzyl)-prodigiosins (-), isoheptylprodigiosin (), and geometric isomers of tambjamine MYP1 ((/)-) have been developed. The crucial steps involved in these synthetic routes are the construction of methoxy-bipyrrole-carboxaldehydes (MBCs) and a 20-membered macrocyclic core and a regioselective demethylation of MBC analogues. These new synthetic routes enabled us to generate several natural prodiginines - in larger quantity. All of the synthesized natural products exhibited potent asexual blood-stage antiplasmodial activity at low nanomolar concentrations against a panel of parasites, with a great therapeutic index. Notably, prodiginines and - provided curative in vivo efficacy against erythrocytic at 25 mg/kg × 4 days via oral route in a murine model. No overt clinical toxicity or behavioral change was observed in any mice treated with prodiginines and tambjamines

Identifying Antimalarials That Disrupt Malaria Parasite Transmission when Fed to the Mosquito

A decade-long decline in malaria cases has plateaued, primarily due to parasite drug resistance and mosquito resistance to insecticides used in bed nets and indoor residual spraying. Here, we explore the innovative control strategy targeting Plasmodium with antimalarials during the mosquito stages. This strategy has the potential to reduce the risk of resistance emerging because a relatively small population of parasites within the mosquito is subject to selection. After validating mosquito feeding strategies, we screened a range of parasiticidal compounds by feeding them to mosquitoes already infected with mouse malaria (P. berghei). Three antimalarials showed activity against P. berghei in mosquitoes, apparently targeting specific stages of P. berghei development during transmission. Borrelidin, a threonyl-tRNA synthetase inhibitor, significantly reduced P. berghei sporozoite numbers. Azithromycin, an antibiotic targeting apicoplast protein synthesis, significantly lowered sporozoite infectivity in mice. T111, a next generation compound targeting the parasite electron transport chain, reduced sporozoite numbers in P. berghei at equivalent concentrations to the gold standard electron transport chain inhibitor, atovaquone. T111 also prevented sporozoite production in mosquitoes infected with human malaria, P. falciparum, even after very short exposure times. Encouragingly, T111 remained efficacious after being freeze-dried onto a substrate and later reconstituted with water, suggesting this compound would be effective in easy-to-distribute-and-deploy transmission control devices. Our findings suggest that several antimalarials can be used to target mosquito-stage parasites via sugar baits and limit malaria transmission. Importantly, mosquito feeding of antimalarials could vastly increase the range of potentially useful parasiticidal compounds to include those failing to meet the exacting standards required for human antimalarial drugs, potentially improving malaria control for minimal cost

Boron trifluoride etherate promoted microwave-assisted synthesis of antimalarial acridones

This method provides rapid access to a range of biologically active acridones in good to excellent yields.</p

ELQ-331 as a Prototype for Extremely Durable Chemoprotection Against Malaria

The potential benefits of long-acting injectable chemoprotection (LAI-C) against malaria have been recently recognized, prompting a call for suitable candidate drugs to help meet this need. On the basis of its known pharmacodynamic and pharmacokinetic profiles after oral dosing, ELQ-331, a prodrug of the parasite mitochondrial electron transport inhibitor ELQ-300, was selected for study of pharmacokinetics and efficacy as LAI-C in mice. Four trials were conducted in which mice were injected with a single intramuscular dose of ELQ-331 or other ELQ-300 prodrugs in sesame oil with 1.2% benzyl alcohol; the ELQ-300 content of the doses ranged from 2.5 to 30 mg/kg. Initial blood stage challenges with Plasmodium yoelii were used to establish the model, but the definitive study measure of efficacy was outcome after sporozoite challenge with a luciferase-expressing P.yoelii, assessed by whole-body live animal imaging. Snapshot determinations of plasma ELQ-300 concentration ([ELQ-300]) were made after all prodrug injections; after the highest dose of ELQ-331 (equivalent to 30 mg/kg ELQ-300), both [ELQ-331] and [ELQ-300] were measured at a series of timepoints from 6 hours to 5 ½ months after injection. A single intramuscular injection of ELQ-331 outperformed four other ELQ-300 prodrugs and, at a dose equivalent to 30 mg/kg ELQ-300, protected mice against challenge with P. yoelii sporozoites for at least 4 ½ months. Pharmacokinetic evaluation revealed rapid and essentially complete conversion of ELQ-331 to ELQ-300, a rapidly achieved (\u3c 6 hours) and sustained (4-5 months) effective plasma ELQ-300 concentration, maximum ELQ-300 concentrations far below the estimated threshold for toxicity, and a distinctive ELQ-300 concentration vs. time profile. Pharmacokinetic modeling indicates a high-capacity, slow-exchange tissue compartment which serves to accumulate and then slowly redistribute ELQ-300 into blood, and this property facilitates an extremely long period during which ELQ-300 concentration is sustained above a minimum fully-protective threshold (60-80 nM). A single intramuscular injection of ELQ-331 outperformed four other ELQ-300 prodrugs and, at a dose equivalent to 30 mg/kg ELQ-300, protected mice against challenge with P. yoelii sporozoites for at least 4½ months. Pharmacokinetic evaluation revealed rapid and essentially complete conversion of ELQ-331 to ELQ-300, a rapidly achieved (\u3c 6 h) and sustained (4–5 months) effective plasma ELQ-300 concentration, maximum ELQ-300 concentrations far below the estimated threshold for toxicity, and a distinctive ELQ-300 concentration versus time profile. Pharmacokinetic modeling indicates a high-capacity, slow-exchange tissue compartment which serves to accumulate and then slowly redistribute ELQ-300 into blood, and this property facilitates an extremely long period during which ELQ-300 concentration is sustained above a minimum fully-protective threshold (60–80 nM)

Acridones Are Highly Potent Inhibitors of Tachyzoites.

Acridone derivatives, which have been shown to have and activity against spp, inhibit proliferation at picomolar concentrations. Using enzymatic assays, we show that acridones inhibit both cytochrome and dihydroorotate dehydrogenase and identify acridones that bind preferentially to the Q site of cytochrome . We identify acridones that have efficacy in a murine model of systemic toxoplasmosis. Acridones have potent activity against and represent a promising new class of preclinical compounds