A5066790315- Malaria Research and Control
- Vector-borne infectious diseases
- Inorganic Fluorides and Related Compounds
- Fluorine in Organic Chemistry
- Mosquito-borne diseases and control
- Insect and Pesticide Research
- Toxoplasma gondii Research Studies
- Insect Pest Control Strategies
- HIV/AIDS drug development and treatment
- Cancer therapeutics and mechanisms
- Phenothiazines and Benzothiazines Synthesis and Activities
- Computational Drug Discovery Methods
- Pharmacological Effects and Toxicity Studies
- Research on Leishmaniasis Studies
- Synthesis and biological activity
- Herpesvirus Infections and Treatments
- Microbial Natural Products and Biosynthesis
- Microbial Metabolism and Applications
- Drug Transport and Resistance Mechanisms
- Synthesis and Biological Evaluation
- Parasitic Infections and Diagnostics
- Synthesis and Catalytic Reactions
- Organic and Molecular Conductors Research
- Neonatal Health and Biochemistry
- Toxin Mechanisms and Immunotoxins
Portland State University
2003-2024
Portland VA Medical Center
2007-2024
VA Portland Health Care System
2018-2024
Oregon Health & Science University
2020
Washington State University
2020
Abstract Human babesiosis is a malaria-like illness caused by tick-borne intraerythrocytic Babesia parasites of the Apicomplexa phylum. Whereas several species can cause severe disease in humans, ability to propagate duncani both vitro human erythrocytes and mice makes it unique pathogen study biology pathogenesis. Here we report an optimized B. culture–in mouse (ICIM) model that combines continuous culture parasite with precise lethal infection mice. We demonstrate duncani–infected as well...
Leishmaniasis is a neglected tropical disease that estimated to afflict over 12 million people. Current drugs for leishmaniasis suffer from serious deficiencies, including toxicity, high cost, modest efficacy, primarily parenteral delivery, and emergence of widespread resistance. We have discovered developed natural product-inspired tambjamine chemotype, known be effective against Plasmodium spp, as novel class antileishmanial agents. Herein, we report in vitro vivo activities, detailed...
Building from our previous lead compound T111 (1) possessing activity against both Plasmodium falciparum asexual blood-stage (ABS) and berghei liver-stage (LS) parasites, next-generation antimalarial acridones were systematically designed synthesized. A large number of newly generated displayed excellent activities ABS LS with feasible safety metabolic profiles. In a high-throughput hypnozoitocidal assay using cynomolgi, these significantly inhibited schizont hypnozoite formation in...
Cytochrome bc1 inhibitors have been broadly studied as human and veterinary medicines agricultural fungicides. For the most part, cytochrome compete with ubiquinol at oxidation (Qo) site or ubiquinone quinone reduction (Qi) site. 4(1 H)-Quinolones 3-position substituents may inhibit either based on quinolone ring substituents. that Qi are highly effective against toxoplasmosis, malaria, babesiosis do not bc1. We tested a series of wild-type drug resistant strains Toxoplasma gondii Plasmodium...
New treatments for tuberculosis infection are critical to combat the emergence of multidrug- and extensively drug-resistant Mycobacterium (Mtb). We report characterization a diphenylether-modified adamantyl 1,2-diamine that we refer as TBL-140, which has minimal inhibitory concentration (MIC99) 1.2 μg/mL. TBL-140 is effective against Mtb nonreplicating bacteria. In addition, eliminates expansion in cell culture assays at its MIC. To define mechanism action this compound, performed...
Toxoplasmosis is a potentially fatal infection for immunocompromised people and the developing fetus. Current medicines toxoplasmosis have high rates of adverse effects that interfere with therapeutic prophylactic regimens. Endochin-like quinolones (ELQs) are potent inhibitors Toxoplasma gondii proliferation in vitro animal models acute latent infection. ELQ-316, particular, was found to be effective orally against mice highly selective T. cytochrome b over human .
A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for ability to enhance potency quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. number acridone derivatives, bridged three or more carbon atoms apart between ring nitrogen nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity MDR strain P. (Dd2). Isobologram analysis...
An effective strategy to control blood-borne diseases and prevent outbreak recrudescence involves targeting conserved metabolic processes that are essential for pathogen viability. One such target Plasmodium Babesia , the infectious agents of malaria babesiosis, respectively, is mitochondrial cytochrome bc 1 protein complex, which can be inhibited by endochin-like quinolones (ELQ) atovaquone.
Highly efficient and straightforward synthetic routes toward the first total synthesis of 2-(p-hydroxybenzyl)-prodigiosins (2–5), isoheptylprodigiosin (6), geometric isomers tambjamine MYP1 ((E/Z)-7) have been developed. The crucial steps involved in these are construction methoxy-bipyrrole-carboxaldehydes (MBCs) a 20-membered macrocyclic core regioselective demethylation MBC analogues. These new enabled us to generate several natural prodiginines 24–27 larger quantity. All synthesized...
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 its known pharmacodynamic and pharmacokinetic profiles after oral dosing, ELQ-331, prodrug parasite mitochondrial electron transport inhibitor ELQ-300, was selected study pharmacokinetics efficacy as LAI-C in mice. Four trials were conducted which mice injected with single intramuscular dose...
The endochin-like quinolone (ELQ) compound class may yield effective, safe treatments for a range of important human and animal afflictions. However, to access the public health potential this series, synthetic route needed be devised, which would lower costs amenable large-scale production. In new described here, substituted β-keto ester, formed by an Ullmann reaction subsequent acylation, is reacted with aniline via Conrad–Limpach produce 3-substituted 4(1H)-quinolones such as ELQ-300...
A microwave-assisted, rapid and efficient method using boron trifluoride etherate (BF3.Et2O) for the synthesis of acridones, via an intramolecular acylation N-phenylanthranilic acid derivatives, has been developed. The reaction proceeds under solvent-free conditions, tolerates a wide range functional groups, provides access to acridones in good excellent yields. Several synthesized exhibited potent antimalarial activities against CQ sensitive multi-drug resistant (MDR) parasites.
Malaria remains one of the deadliest diseases in world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage blood-stage malaria. Several lead compounds generated from structural optimization large library acridones exhibit efficacy following systems: (1) picomolar inhibition vitro Plasmodium falciparum growth...
The most common apicomplexan parasites causing bovine babesiosis are Babesia bovis and B. bigemina, while caballi Theileria equi responsible for equine piroplasmosis. Treatment control of these diseases usually achieved using potentially toxic chemotherapeutics, such as imidocarb diproprionate, but drug-resistant emerging, alternative effective safer drugs needed. endochin-like quinolones (ELQ)-300 ELQ-316 have been proven to be safe efficacious against related apicomplexans, Plasmodium...
Malaria has been a deadly enemy of mankind throughout history, affecting over 200 million people annually, along with approximately half deaths. Resistance to current therapies is great concern, and there dire need for novel well-tolerated antimalarials that operate by clinically unexploited mechanisms. We have previously reported both tambjamines prodiginines are highly potent antiplasmodial agents, but they required rigor optimizations enhance the oral efficacy, safety, physicochemical...
The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and absence a clinically available vaccine, there is an urgent need for novel, affordable, safe drugs prevention treatment malaria. Previously, we described novel antimalarial acridone chemotype that potent against both blood-stage liver-stage parasites. Here, describe optimization process has produced second-generation series with significant improvements in...
Acridone derivatives, which have been shown to in vitro and vivo activity against Plasmodium spp, inhibit Toxoplasma gondii proliferation at picomolar concentrations. Using enzymatic assays, we show that acridones both T. cytochrome bc1 dihydroorotate dehydrogenase identify bind preferentially the Qi site of bc1. We efficacy a murine model systemic toxoplasmosis. Acridones potent represent promising new class preclinical compounds.