10 research outputs found
Dispiro-1,2,4-trioxane Analogues of a Prototype Dispiro-1,2,4-trioxolane: Mechanistic Comparators for Artemisinin in the Context of Reaction Pathways with Iron(II)
Single electron reduction of the 1,2,4-trioxane heterocycle of artemisinin (1) forms primary and secondary carbon-centered radicals. The complex structure of 1 does not lend itself to a satisfactory dissection of the electronic and steric effects that influence the formation and subsequent reaction of these carbon-centered free radicals. To help demarcate these effects, we characterized the reactions of achiral dispiro-1,2,4-trioxolane 4 and dispiro-1,2,4-trioxanes 5−7 with ferrous bromide and 4-oxo-TEMPO. Our results suggest a small preference for attack of Fe(II) on the nonketal peroxide oxygen atom of 1. For 4, but not for 5 and 6, there was a strong preference for attack of Fe(II) on the less hindered peroxide bond oxygen atom. The steric hindrance afforded by a spiroadamantane in a five-membered trioxolane is evidently much greater than that for a corresponding six-membered trioxane. Unlike 1, 5−7 fragment by entropically favored β-scission pathways forming relatively stable α-oxa carbon-centered radicals. These data suggest that formation of either primary or secondary carbon-centered radicals is a necessary but insufficient criterion for antimalarial activity of 1 and synthetic peroxides
A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease
An Unusual Electrochemical Reductive Cleavage of Azo Dye into Highly Redox Active Copolymeric Aniline Derivatives on a MWCNT Modified Electrode Surface at Neutral pH and Its Electroanalytical Features
Developments of new decomposition
or degradation methods of environmentally
hazardous azo dyes from textile industries are very important. Usually,
strong acid-based chemical/electrochemical and neutral pH-based bacterial
decomposition methods were widely used. Here, we report a mild, simple,
and facile electrochemical method for decomposition of azo dye (Sudan
yellow; SY) into a highly redox active copolymer of polyanilines via
aniline derivatives as intermediates on a MWCNT modified glassy carbon
electrode (GCE/MWCNT) surface unusually in a neutral pH using phosphate
buffer solution (PBS) (GCE/MWCNT@SY-CoPANI<sub>pH7</sub>). One of
the intermediate products, aniline (<i>M</i><sub>w</sub> = 93 mol g<sup>–1</sup>, calculated) was identified by an
in situ cyclic voltammetry-electrochemical quartz crystal balance
experiment. No such SY electrochemical reaction was observed on a
naked GCE surface. Physico-chemical characterizations by TEM, Raman,
IR, and UV–vis spectroscopic methods supported the formation
of polymeric product on MWCNT surface (GCE/MWCNT@SY-CoPANI<sub>pH7</sub>). Electroanalytical performance of this new electrode was tested
using ascorbic acid (AA) and FeÂ(CN)<sub>6</sub><sup>3–</sup>, as models. Interestingly, a dilute solution of Nafion (Nf) casted
modified electrode system (GCE/MWCNT@SY-CoPANI<sub>pH7</sub>/Nf) showed
improved electroanalytical performance, unlike the conventional Nafion
modified system (GCE/MWCNT/Nf) with vanished peak current response
due to the electrostatic repulsive interaction between the anionic
AA (p<i>K</i><sub>a</sub> = 4.10), FeÂ(CN)<sub>6</sub><sup>3–</sup> ion, and anionic sulfonic acid groups in Nafion.
A zwitter ionic complex between a polaronic copolyaniline and sulfonic
acid of Nafion is proposed as a possible structure for the newly developed
hybrid system. Using the GCE/MWCNT@SY-CoPANI<sub>pH7</sub>/Nf, a selective
flow injection analysis of AA has been demonstrated as an analytical
application with good recovery values
Structure-activity relationship of an ozonide carboxylic acid (OZ78) against Fasciola hepatica
In this paper, we describe the SAR of ozonide carboxylic acid OZ78 (1) as the first part of our search for a trematocidal synthetic peroxide drug development candidate. We found that relatively small structural changes to 1 resulted most commonly in loss of activity against Fasciola hepatica in vivo. A spiroadamantane substructure and acidic functional group (or ester prodrug) were required for activity. Of 26 new compounds administered at single 100 mg/kg oral doses to F. hepatica infected rats, 8 had statistically significant worm burden reductions, 7 were partially curative, and 1 (acylsulfonamide 6) was completely curative and comparable to 1 in flukicidal efficacy. This study also showed that the activity of 1 is peroxide-bond-dependent, suggesting that its flukicidal efficacy depends upon hemoglobin digestion in F. hepatic
The activity of dispiro peroxides against Fasciola hepatica
Dispiro 1,2,4-trioxanes and 1,2,4,5-tetraoxanes had superior efficacy against Fasciola hepatica than the corresponding ozonides (1,2,4-trioxolanes). For highest efficacy, spiroadamantane and carboxymethyl substructures were required. Three compounds completely cured F. hepatica-infected mice at single oral doses of 50mg/kg and two were partially curative at single doses of 25mg/k
A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease
We previously identified structurally diverse small molecule (non-peptidic) inhibitors (SMNPIs) of the botulinum neurotoxin serotype A (BoNT/A) light chain (LC). Of these, several (including antimalarial drugs) contained a 4-amino-7-chloroquinoline (ACQ) substructure and a separate positive ionizable amine component. The same antimalarials have also been found to interfere with BoNT/A translocation into neurons, via pH elevation of the toxin-mediated endosome. Thus, this structural class of small molecules may serve as dual-function BoNT/A inhibitors. In this study, we used a refined pharmacophore for BoNT/A LC inhibition to identify four new, potent inhibitors of this structural class (IC50’s ranged from 3.2 to 17 ÃM). Molecular docking indicated that the binding modes for the new SMNPIs are consistent with those of other inhibitors that we have identified, further supporting our structure-based pharmacophore. Finally, structural motifs of the new SMNPIs, as well as two structure-based derivatives, were examined for activity, providing valuable information about pharmacophore component contributions to inhibition
Structure-activity relationship of antischistosomal ozonide carboxylic acids
Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 (; 2; ) and OZ165 (; 3; ). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with; para; -substituted carboxymethoxy and; N; -benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult; Schistosoma mansoni; by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity
Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439
OZ439 is a potent synthetic ozonide evaluated for the treatment of uncomplicated malaria. The metabolite profile of OZ439 was characterized in vitro using human liver microsomes combined with LC/MS-MS, chemical derivatization, and metabolite synthesis. The primary biotransformations were monohydroxylation at the three distal carbon atoms of the spiroadamantane substructure, with minor contributions from N-oxidation of the morpholine nitrogen and deethylation cleavage of the morpholine ring. Secondary transformations resulted in the formation of dihydroxylation metabolites and metabolites containing both monohydroxylation and morpholine N-oxidation. With the exception of two minor metabolites, none of the other metabolites had appreciable antimalarial activity. Reaction phenotyping indicated that CYP3A4 is the enzyme responsible for the metabolism of OZ439, and it was found to inhibit CYP3A via both direct and mechanism-based inhibition. Elucidation of the metabolic pathways and kinetics will assist with efforts to predict potential metabolic drug–drug interactions and support physiologically based pharmacokinetic (PBPK) modeling
Structure-activity relationship of the antimalarial ozonide artefenomel (OZ439)
Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity