Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials.

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.

ELQ-331 as a prototype for extremely durable chemoprotection against malaria.

BACKGROUND: 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. METHODS: 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 h to 5½ months after injection. RESULTS: 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 (< 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). CONCLUSIONS: Extrapolation of these results to humans predicts that ELQ-331 should be capable of meeting and far-exceeding currently published duration-of-effect goals for anti-malarial LAI-C. Furthermore, the distinctive pharmacokinetic profile of ELQ-300 after treatment with ELQ-331 may facilitate durable protection and enable protection for far longer than 3 months. These findings suggest that ELQ-331 warrants consideration as a leading prototype for LAI-C.

Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials.

Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.

Antiplasmodial evaluation of Anacardium occidentale and alkyl-phenols

Abstract The ethanol crude extract from cashew (Anacardium occidentale L. Anacardiaceae) displayed significant antiplasmodial activity (IC50 0.577 µg/ml). Liquid chromatography-high resolution Mass spectrometry analysis was performed to identify the main compounds existing in the ethanol extract. The occurrence of anacardic acids, cardols, and 2-methylcardols derivatives was confirmed in the extract. The IC50 obtained, when the main isolated compounds were evaluated in Plasmodium falciparum D6 strain, ranged from 5.39 µM to >100 µM. Tested here for the first time, the data showed that cardol triene 1 (IC50 = 5.69 µM) and 2-methylcardol triene 4 (IC50 = 5.39 µM) demonstrated good antimalarial activity. In conclusion, Anacardium occidentale nuts presented relevant biological potential, and further studies should be considered.

Evaluation and lead optimization of anti-malarial acridones.

With 2-methoxy-6-chloroacridone as a lead compound, we synthesized and tested acridone derivatives to develop a better understanding of the anti-malarial structure-activity relationships. Over 30 acridone derivatives were synthesized. The most potent compounds contained extended alkyl chains terminated by trifluoromethyl groups and located at the 3-position of the tricyclic system. Acridones optimized in the length of the side chain and the nature of the terminal fluorinated moiety exhibited in vitro anti-malarial IC(50) values in the low nanomolar and picomolar range and were without cytotoxic effects on the proliferation and differentiation of human bone marrow progenitors or mitogen-activated murine lymphocytes at concentrations up to 100,000-fold higher. Based on a structural similarity to known anti-malarial agents it is proposed that the haloalkoxyacridones exert their anti-malarial effects through inhibition of the Plasmodium cytochrome bc(1) complex. Haloalkoxyacridones represent an extraordinarily potent novel class of chemical compounds with the potential for development as therapeutic agents to treat or prevent malaria in humans.