Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis and Antiprotozoal Profile of 3,4,5-Trisubstituted Isoxazoles.

ABSTRACT: A series of 60 4-aminomethyl 5-aryl-3-substituted isoxazoles were synthesized by an efficient method and evaluated in vitro against Leishmania amazonensis and Trypanosoma cruzi, protozoa that cause the neglected tropical diseases leishmaniasis and Chagas disease, respectively. Thirteen compounds exhibited a selective index greater than 10. The series of 3-N-acylhydrazone isoxazole derivatives bearing the bithiophene core exhibited the best antiparasitic effects.

SUBMITTER: Rosa FA

PROVIDER: S-EPMC8485799 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Synthesis and Antiprotozoal Profile of 3,4,5-Trisubstituted Isoxazoles.

Rosa Fernanda Andreia FA Mendes de Souza Melo Samara S Pianoski Karlos Eduardo KE Poletto Julia J Dos Santos Mariellen Guilherme MG Vieira da Silva Michael Jackson MJ Lazarin-Bidóia Danielle D Volpato Hélito H Moura Sidnei S Nakamura Celso Vataru CV

ChemistryOpen 20210730 10

A series of 60 4-aminomethyl 5-aryl-3-substituted isoxazoles were synthesized by an efficient method and evaluated in vitro against Leishmania amazonensis and Trypanosoma cruzi, protozoa that cause the neglected tropical diseases leishmaniasis and Chagas disease, respectively. Thirteen compounds exhibited a selective index greater than 10. The series of 3-N-acylhydrazone isoxazole derivatives bearing the bithiophene core exhibited the best antiparasitic effects. ...[more]

PMID: 34331350

Similar Datasets

Tandem grinding reactions involving aldol condensation and Michael addition in sequence for synthesis of 3,4,5-trisubstituted isoxazoles.

Project description:A one-pot, base-catalyzed, tandem grinding process involving carrying out aldol condensation and Michael addition in sequence to produce 3,4,5-trisubstituted isoxazoles from 3,5-dimethyl-4-nitroisoxazole, aromatic aldehydes and activated methylene compounds has been developed. In the presence of 10 mol% of pyrrolidine, aldol condensations of 3,5-dimethyl-4-nitroisoxazole with various aromatic aldehydes were performed with 3-10 minutes of grinding to provide 5-styryl-3-methyl-4-nitroisoxazoles in good to quantitative yields without further purification. Then, Michael additions between 5-styryl-3-methyl-4-nitroisoxazoles and activated methylene compounds (including ethyl 2-nitroacetate and alkyl 2-cyanoacetates) were carried out in the presence of 10 mol% of Et3N in the same mortar with 3-5 minutes of continuous grinding to produce 3,4,5-trisubstituted isoxazoles in good to excellent yields.

| S-EPMC9071175 | biostudies-literature

Synthesis of 3,4,5-trisubstituted isoxazoles in water via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides.

Project description:Herein we report a method for the synthesis of 3,4,5-trisubstituted isoxazoles in water under mild basic conditions at room temperature via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides. We optimized the reaction conditions to control the selectivity of the production of isoxazoles and circumvent other competing reactions, such as O-imidoylation or hetero [3 + 2]-cycloaddition. The reaction happens fast in water and completes within 1-2 hours, which provides an environmentally friendly access to 3,4,5-trisubstituted isoxazoles, an important class of structures found in numerous bioactive natural products and pharmaceuticals. Additionally, we optimized the reaction conditions to produce trifluoromethyl-substituted isoxazoles, a prevalent scaffold in biomedical research and drug discovery programs. We also proposed a plausible mechanism for the selectivity of the [3 + 2]-cycloaddition reaction to produce 3,4,5-trisubstituted isoxazoles. Not to be overlooked are our optimized reaction conditions for the dimerization of hydroximoyl chlorides to form furoxans also known as 1,2,5-oxadiazole 2-oxides, a class of structures with important biological activities due to their unique electronic nature and coordination ability.

| S-EPMC9039522 | biostudies-literature

3-Thio-3,4,5-trisubstituted-1,2,4-triazoles: high affinity somatostatin receptor-4 agonist synthesis and structure-activity relationships.

Project description:Somatostatin receptor-4 (SST4) is a therapeutic target for several conditions, including Alzheimer's disease, seizures, neuropsychiatric disorders, and pain. Our previous work on 1,2,4-triazole derivatives led to enhanced SST4 binding affinity, selectivity, and functional activity. Herein we report the discovery of 3-thio-1,2,4-triazole series as selective and high affinity SST4 agonists. Thirty-three compounds show <100 nM binding affinity, five of which had sub-nanomolar binding affinity and >300-fold selectivity over other SST subtypes. SST4 cAMP inhibition assay activity data aligned with the ligand binding affinity. Comparative docking results of the ligands under investigation with the cryo-EM and most recent model-built SST4 structures suggest similar trends in binding. Amino acids responsible for high and moderate affinity were identified, whereas poorer ligand conformations and limited interactions were observed with the low-affinity compounds. In summary, this study presents a novel series of high affinity SST4 agonists with corresponding in vitro activity, demonstrating viable therapeutic potential.

| S-EPMC11660163 | biostudies-literature

Synthesis and structure-activity relationships of 3,4,5-trisubstituted-1,2,4-triazoles: high affinity and selective somatostatin receptor-4 agonists for Alzheimer's disease treatment.

Project description:Somatostatin receptor-4 (SST4) is highly expressed in brain regions affiliated with learning and memory. SST4 agonist treatment may act to mitigate Alzheimer's disease (AD) pathology. An integrated approach to SST4 agonist lead optimization is presented herein. High affinity and selective agonists with biological efficacy were identified through iterative cycles of a structure-based design strategy encompassing computational methods, chemistry, and preclinical pharmacology. 1,2,4-Triazole derivatives of our previously reported hit (4) showed enhanced SST4 binding affinity, activity, and selectivity. Thirty-five compounds showed low nanomolar range SST4 binding affinity, 12 having a K i < 1 nM. These compounds showed >500-fold affinity for SST4 as compared to SST2A. SST4 activities were consistent with the respective SST4 binding affinities (EC50 < 10 nM for 34 compounds). Compound 208 (SST4 K i = 0.7 nM; EC50 = 2.5 nM; >600-fold selectivity over SST2A) display a favorable physiochemical profile, and was advanced to learning and memory behavior evaluations in the senescence accelerated mouse-prone 8 model of AD-related cognitive decline. Chronic administration enhanced learning with i.p. dosing (1 mg kg-1) compared to vehicle. Chronic administration enhanced memory with both i.p. (0.01, 0.1, 1 mg kg-1) and oral (0.01, 10 mg kg-1) dosing compared to vehicle. This study identified a novel series of SST4 agonists with high affinity, selectivity, and biological activity that may be useful in the treatment of AD.

| S-EPMC8372316 | biostudies-literature

Structure-Activity Relationship Studies of Trisubstituted Isoxazoles as Selective Allosteric Ligands for the Retinoic-Acid-Receptor-Related Orphan Receptor γt.

Project description:The inhibition of the nuclear receptor retinoic-acid-receptor-related orphan receptor γt (RORγt) is a promising strategy in the treatment of autoimmune diseases. RORγt features an allosteric binding site within its ligand-binding domain that provides an opportunity to overcome drawbacks associated with orthosteric modulators. Recently, trisubstituted isoxazoles were identified as a novel class of allosteric RORγt inverse agonists. This chemotype offers new opportunities for optimization into selective and efficacious allosteric drug-like molecules. Here, we explore the structure-activity relationship profile of the isoxazole series utilizing a combination of structure-based design, X-ray crystallography, and biochemical assays. The initial lead isoxazole (FM26) was optimized, resulting in compounds with a ∼10-fold increase in potency (low nM), significant cellular activity, promising pharmacokinetic properties, and a good selectivity profile over the peroxisome-proliferated-activated receptor γ and the farnesoid X receptor. We envisage that this work will serve as a platform for the accelerated development of isoxazoles and other novel chemotypes for the effective allosteric targeting of RORγt.

| S-EPMC8273893 | biostudies-literature

Improved synthesis of 3-aryl isoxazoles containing fused aromatic rings.

Project description:A critical comparison of methods to prepare sterically hindered 3-aryl isoxazoles containing fused aromatic rings using the nitrile oxide cycloaddition (NOC) reveal that modification of the method of Bode, Hachisu, Matsuura, and Suzuki (BHMS), utilizing either triethylamine as base or sodium enolates of the diketone, ketoester, and ketoamide dipolarophiles, respectively, was the method of choice for this transformation.

| S-EPMC3601750 | biostudies-literature

Synthesis of Highly Reactive Ketenimines via Photochemical Rearrangement of Isoxazoles.

Project description:Ketenimines are highly electrophilic species with multiple applications as building blocks in organic synthesis; however, the effective preparation of these versatile entities remains a synthetic challenge. Here we report a continuous photochemical process that generates ketenimines via skeletal rearrangement of trisubstituted isoxazoles. The resulting flow process is noteworthy, as it provides for the first time a straightforward entry into these ketenimines that were previously only observed spectroscopically. The value of this methodology toward heterocyclic transposition reactions is demonstrated by converting isoxazoles via isolable ketenimines into pharmaceutically relevant pyrazoles.

| S-EPMC10496124 | biostudies-literature

Synthesis of enantiopure, trisubstituted cryptophane-A derivatives.

Project description:The efficient synthesis of enantiopure, trisubstituted cryptophane-A derivatives, organic host molecules with unusually high xenon affinity, is reported. Synthesis and chromatographic separation of (±) tri-Mosher's acid substituted cryptophane diastereomers gave ready access to the enantiopure cryptophanes, which are critical components in the design of enantiomerically pure (129)Xe biosensors. Hyperpolarized (129)Xe NMR spectroscopy identified single resonances for both trisubstituted cryptophane diastereomers that were separated by 9.5 ppm. This highlights opportunities for using enantiopure xenon biosensors in the simultaneous detection of (129)Xe in different biochemical environments.

| S-EPMC3484212 | biostudies-literature

Asymmetric synthesis of 2,4,5-trisubstituted ?2-thiazolines.

Project description:?(2)-Thiazolines are interesting heterocycles that display a wide variety of biological characteristics. They are also common in chiral ligands used for asymmetric syntheses and as synthetic intermediates. Herein, we present asymmetric routes to 2,4,5-trisubstituted ?(2)-thiazolines. These ?(2)-thiazolines were synthesized from readily accessible/commercially available ?,?-unsaturated methyl esters through a Sharpless asymmetric dihydroxylation and an O?N acyl migration reaction as key steps. The final products were obtained in good yields with up to 97?% enantiomeric excess.

| S-EPMC3784040 | biostudies-literature

The synthesis of highly substituted isoxazoles by electrophilic cyclization: an efficient synthesis of valdecoxib.

Project description:A large number of functionally substituted 2-alkyn-1-one O-methyl oximes have been cyclized under mild reaction conditions in the presence of ICl to give the corresponding 4-iodoisoxazoles in moderate to excellent yields. The resulting 4-iodoisoxazoles undergo various palladium-catalyzed reactions to yield 3,4,5-trisubstituted isoxazoles, including valdecoxib.

| S-EPMC2529460 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data