A5038214802- Malaria Research and Control
- Parasites and Host Interactions
- Helminth infection and control
- Synthesis and Catalytic Reactions
- Chemical Reactions and Mechanisms
- Parasite Biology and Host Interactions
- Computational Drug Discovery Methods
- Research on Leishmaniasis Studies
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Oxidative Organic Chemistry Reactions
- Mosquito-borne diseases and control
- Asymmetric Synthesis and Catalysis
- Phenothiazines and Benzothiazines Synthesis and Activities
- Synthesis and Biological Evaluation
- Synthesis and Characterization of Heterocyclic Compounds
- Hedgehog Signaling Pathway Studies
- Hormonal Regulation and Hypertension
- Synthesis and biological activity
- Synthesis of heterocyclic compounds
- Chemical Synthesis and Analysis
- Inorganic and Organometallic Chemistry
- Trypanosoma species research and implications
- Cancer-related Molecular Pathways
- Fluorine in Organic Chemistry
Nebraska Medical Center
2015-2025
University of Nebraska Medical Center
2016-2025
Anhui Jianzhu University
2024
Suzhou University of Science and Technology
2024
University of Tennessee Health Science Center
2019
Monash University
2016
China Aerospace Science and Industry Corporation (China)
2013
Prevention Institute
2004-2008
Institute of Soil Science
2008
Chinese Academy of Sciences
2005-2008
Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide single-dose oral cure in humans. has successfully completed Phase I clinical trials, where it was shown be safe at doses up 1,600 mg and currently undergoing IIa trials malaria patients. Herein, we describe the discovery of exceptional pharmacokinetic properties that led its selection as development candidate. In vitro, fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC 50...
ABSTRACT Schistosomiasis is a parasitic disease that remains of considerable public health significance in tropical and subtropical environments. Since the mainstay schistosomiasis control chemotherapy with single drug, praziquantel, drug resistance concern. Here, we present new data on antischistosomal properties representative synthetic 1,2,4-trioxolanes (OZs). Exposure adult Schistosoma mansoni for 24 h to medium containing 20 μg/ml OZ209 reduced worm motor activity, induced tegumental...
Plasmodium falciparum causes the most lethal form of malaria. Peroxide antimalarials based on artemisinin underpin frontline treatments for malaria, but resistance is rapidly spreading. Synthetic peroxide antimalarials, known as ozonides, are in clinical development and offer a potential alternative. Here, we used chemoproteomics to investigate protein alkylation targets ozonide probes, including an analogue candidate, artefenomel. We greatly expanded list proteins alkylated by identified...
The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarials with heme has been investigated to provide further insight into the mechanism action for this important class antimalarials. A series trioxolanes various antimalarial potencies was found be unreactive in presence Fe(III) hemin, but all were rapidly degraded by reduced Fe(II) heme. major product from heme-mediated degradation biologically active an alkylated adduct resulting addition a radical intermediate. Under standardized...
The structure and stereochemistry of the cyclohexane substituents analogues arterolane (OZ277) had little effect on potency against Plasmodium falciparum in vitro. Weak base functional groups were not required for high antimalarial potency, but they essential efficacy P. berghei-infected mice. Five new ozonides with ADME profiles superior or equal to that identified.
To ascertain the structure–activity relationship of core 1,2,4-trioxolane substructure dispiro ozonides OZ277 and OZ439, we compared antimalarial activities ADME profiles 1,2-dioxolane, 1,2,4-trioxane, 1,2,4,5-tetraoxane isosteres. Consistent with previous data, both dioxolanes had very weak properties. For series, trioxane isostere best profile, but its overall efficacy was not superior to that trioxolane or tetraoxane OZ439 there a good correlation between in rank order > tetraoxane. As...
This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure−activity relationship in context physicochemical, biopharmaceutical, toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) which trioxolane is flanked by spiroadamantane spirocyclohexane was rapidly identified as lead compound. Nonperoxidic 1,3-dioxolane isosteres 3 were inactive trioxolanes without spiroadamantane. The substantially less effective standard...
Single electron reduction of the 1,2,4-trioxane heterocycle artemisinin (1) forms primary and secondary carbon-centered radicals. The complex structure 1 does not lend itself to a satisfactory dissection electronic steric effects that influence formation subsequent reaction these free To help demarcate effects, we characterized reactions achiral dispiro-1,2,4-trioxolane 4 dispiro-1,2,4-trioxanes 5−7 with ferrous bromide 4-oxo-TEMPO. Our results suggest small preference for attack Fe(II) on...
ABSTRACT Using nonperoxidic analogs of artemisinin and OZ277 (RBx11160), the strong in vitro antiplasmodial activities latter two compounds were shown to be peroxide bond dependent. In contrast, weak against six other protozoan parasites independent. These data support iron-dependent alkylation hypothesis.
ABSTRACT We evaluated the in vivo antischistosomal activities of 11 structurally diverse synthetic peroxides. Of all compounds tested, ozonide (1,2,4-trioxolane) OZ418 had highest activity against adult Schistosoma mansoni , with total and female worm burden reductions 80 90% ( P < 0.05), respectively. Furthermore, treatment S. haematobium -infected mice reduced by 86%. In conclusion, is a promising lead compound.
Building on insights gained from the discovery of antimalarial ozonide arterolane (OZ277), we now describe structure-activity relationship (SAR) artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary ozonides, consistent with their pKa lower log D7.4 values. For primary addition polar functional groups decreased in vivo efficacy. additional variable effects stability efficacy, but most effective members this series also highest H-bond donors...
Eleven novel dispiro-1,2,4,5-tetraoxanes 3 bearing unsaturated and polar functional groups were designed to enhance the oral antimalarial activity of prototype tetraoxane 2 (WR 148999). With exception 3g 3h, tetraoxanes available via peroxidation corresponding cyclohexanone derivatives in H2SO4/CH3CN. Tetraoxanes 3h prepared by hydrolysis ester 3e 3i, respectively. Five 11 inactive, but six had IC50 values 6−26 nM against K1 NF54 strains Plasmodium falciparum compared 28 39 for 2, 10 12...
The diastereoselectivity of the Griesbaum coozonolysis reaction with O-methyl 2-adamantanone oxime and 4-substituted cyclohexanones reveals that major tetrasubstituted ozonide isomers possess cis configurations, suggesting a preferred axial attack carbonyl oxide on cyclohexanone dipolarophiles. It is evident these ozonides are quite stable to triphenylphosphine, borohydrides, hydrazine, alkyllithiums, Grignard reagents, mercaptides, aqueous KOH as illustrated by synthesis amine, alcohol,...
Sixteen alkyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecanes) were synthesized to explore dispiro-1,2,4,5-tetraoxane SAR and identify tetraoxanes with better oral antimalarial activity than prototype tetraoxane 1 (WR 148999). The prepared either by peroxidation of the corresponding cyclohexanone derivatives in H2SO4/CH3CN or ozonolysis methyl oximes. Those alkyl substituents at 10 positions formed as single stereoisomers, whereas five without...
Journal Article Cardiovascular Characteristics in American Youth With Prehypertension: Get access Haidong Zhu, Zhu 1Georgia Prevention Institute, Department of Pediatrics, Medical College Georgia, Augusta, Georgia. Search for other works by this author on: Oxford Academic PubMed Google Scholar Weili Yan, Yan Dongliang Ge, Ge Frank A. Treiber, Treiber Gregory Harshfield, Harshfield Gaston Kapuku, Kapuku Harold Snieder, Snieder Yanbin Dong Address correspondence and reprint requests to Dr....
Peroxidic antimalarials such as the semisynthetic artemisinins are critically important in treatment of drug-resistant malaria. Nevertheless, their peroxide bond-dependent mode action is still not well understood. Using combination experiments with cultured Plasmodium falciparum cells, we investigated interactions nitroxide radical spin trap, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and four its analogs artemisinin ozonide drug development candidate OZ277. The antagonism observed for...