Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Bioisosteric replacement of central 1,2,4-oxadiazole ring of high affinity CB2 ligands by regioisomeric 1,3,4-oxadiazole ring.

ABSTRACT: It has been reported that bioisosteric replacement of an 1,2,4-oxadiazole ring by an 1,3,4-oxadiazole ring leads to higher polarity, reduced metabolic degradation by human liver microsomes and reduced interaction with hERG channels. In a seven to eight step synthesis 1,3,4-oxadiazles 9a-c were synthesized as bioisosteric analogs of high-affinity but rather lipophilic CB2 ligands 1a-c containing an 1,2,4-oxadiazole ring. The 1,3,4-oxadiazole derivatives 9a and 9b show 10- and 50-fold reduced CB2 affinity compared to the 1,2,4-oxadiazole derivatives 1a and 1b, respectively. However, the 1,3,4-oxadiazole 9a has high CB2 affinity (Ki = 25 nM) and high selectivity over the CB1 receptor.

SUBMITTER: Heimann D

PROVIDER: S-EPMC6072079 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Publications

Bioisosteric replacement of central 1,2,4-oxadiazole ring of high affinity CB2 ligands by regioisomeric 1,3,4-oxadiazole ring.

Heimann Dominik D Lueg Corinna C de Vries Henk H Frehland Bastian B Schepmann Dirk D Heitman Laura H LH Wünsch Bernhard B

MedChemComm 20170719 8

It has been reported that bioisosteric replacement of an 1,2,4-oxadiazole ring by an 1,3,4-oxadiazole ring leads to higher polarity, reduced metabolic degradation by human liver microsomes and reduced interaction with hERG channels. In a seven to eight step synthesis 1,3,4-oxadiazles 9a-c were synthesized as bioisosteric analogs of high-affinity but rather lipophilic CB2 ligands 1a-c containing an 1,2,4-oxadiazole ring. The 1,3,4-oxadiazole derivatives 9a and 9 ...[more]

PMID: 30108881

Similar Datasets

Electrocyclic Ring-Opening of 1,2,4-Oxadiazole[4,5-a]piridinium Chloride: a New Route to 1,2,4-Oxadiazole Dienamino Compounds.

Project description:1,2,4-Oxadiazole[4,5-a]piridinium chloride adds nucleophiles to undergo electrocyclic ring opening affording 1,2,4-oxadiazole dienamino derivatives. These pyridinium salts represent a special class of Zincke salts that are prone to rearrange when treated with primary amines or in the presence of bicarbonate to give the pyridones. The pivotal tuning of the experimental conditions leads to a straightforward synthesis of valuable 1,2,4-oxadiazole dienamine derivatives. The mechanism is also discussed in the light of NMR experiments and theoretical calculations.

| S-EPMC6739692 | biostudies-literature

1,3,4-Oxadiazole and Heteroaromatic-Fused 1,2,4-Triazole Synthesis using Diverted Umpolung Amide Synthesis.

Project description:Umpolung Amide Synthesis (UmAS) has emerged as a superior alternative to conventional amide synthesis methods based on carbonyl electrophiles in a range of situations, particularly when epimerization-prone couplings are prescribed. In an unanticipated development during our most recent studies, it was discovered that diacyl hydrazide products from UmAS were not formed as intermediates when using an acyl hydrazide as the amine acceptor. This resulted in a new preparation of 1,3,4-oxadiazoles from α-bromonitroalkane donors. We hypothesized that a key tetrahedral intermediate in UmAS was diverted toward a more direct pathway to the heterocycle product rather than through formation of the diacyl hydrazide, a typical oxadiazole progenitor. In studies reported here, diversion to 1,2,4-triazole products is described, a behavior hypothesized to also result from an analogous tetrahedral intermediate, but one formed from heteroaromatic hydrazine acceptors.

| S-EPMC5833303 | biostudies-literature

Synthesis of new, highly luminescent bis(2,2'-bithiophen-5-yl) substituted 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole.

Project description:A new synthetic approach towards the preparation of functionalised, soluble, donor-acceptor (DA) alkylbithiophene derivatives of oxadiazole, thiadiazole and triazole is reported. Taking advantage of the Fiesselmann reaction, reactive bithiophene synthons having alkyl or alkoxy substituents at designated positions are prepared. Following a synthetic strategy, featuring the bottom-up approach, sequential structural elements are built, starting from a simple thiophene compound, until the target molecule is obtained, all in good yield. Supplementing the well established methods of oxadiazole and thiadiazole synthesis, efficient ring closure reaction affording a 4H-1,2,4-triazole unit is presented. All target ambipolar compounds display strong photoluminescence with measured quantum yields up to 0.59. Modification of the demonstrated synthetic routes may be exploited for the preparation of longer, specifically functionalised oligothiophenes, coupled to other heteroaromatic cores.

| S-EPMC4142979 | biostudies-literature

Electrophilically Activated Nitroalkanes in Double Annulation of [1,2,4]Triazolo[4,3-a]quinolines and 1,3,4-Oxadiazole Rings.

Project description:Nitroalkanes activated with polyphosphoric acid could serve as efficient electrophiles in reactions with amines and hydrazines, enabling various cascade transformations toward heterocyclic systems. This strategy was developed for an innovative synthetic protocol employing simultaneous or sequential annulation of two different heterocyclic cores, affording [1,2,4]triazolo[4,3-a]quinolines with 1,3,4-oxadiazole substituents.

| S-EPMC8464891 | biostudies-literature

π-π Noncovalent Interaction Involving 1,2,4- and 1,3,4-Oxadiazole Systems: The Combined Experimental, Theoretical, and Database Study.

Project description:A series of N-pyridyl ureas bearing 1,2,4- (1a, 2a, and 3a) and 1,3,4-oxadiazole moiety (1b, 2b, 3b) was prepared and characterized by HRMS, 1H and 13C NMR spectroscopy, as well as X-ray diffraction. The inspection of the crystal structures of (1-3)a,b and the Hirshfeld surface analysis made possible the recognition of the (oxadiazole)···(pyridine) and (oxadiazole)···(oxadiazole) interactions. The presence of these interactions was confirmed theoretically by DFT calculations, including NCI analysis for experimentally determined crystal structures as well as QTAIM analysis for optimized equilibrium structures. The preformed database survey allowed the verification of additional examples of relevant (oxadiazole)···π interactions both in Cambridge Structural Database and in Protein Data Bank, including the cocrystal of commercial anti-HIV drug Raltegravir.

| S-EPMC8466036 | biostudies-literature

New Alpha9 nAChR Ligands Based on a 5-(Quinuclidin-3-ylmethyl)-1,2,4-oxadiazole Scaffold.

Project description:Several lines of evidence have indicated that nicotinic acetylcholine receptors (nAChR) that contain α9 subunits, probably in combination with α10 subunits, may be valuable targets for the management of pain associated with inflammatory diseases through a cholinergic anti-inflammatory system (CAS), which has also been associated with α7 nAChR. Both α7- and α9-containing neuronal nAChR can be pharmacologically distinguished from the high-affinity nicotinic receptors of the brain by their sensitivity to α-bungarotoxin, but in other ways, they have quite distinct pharmacological profiles. The early association of α7 with CAS led to the development of numerous new ligands, variously characterized as α7 agonists, partial agonists, or silent agonists that desensitized α7 receptors without activation. Subsequent reinvestigation of one such family of α7 ligands based on an N,N-diethyl-N'-phenylpiperazine scaffold led to the identification of potent agonists and antagonists for α9. In this paper, we characterize the α9/α10 activity of a series of compounds based on a 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazole (QMO) scaffold and identify two new potent ligands of α9, QMO-28, an agonist, and QMO-17, an antagonist. We separated the stereoisomers of these compounds to identify the most potent agonist and discovered that only the 3R isomer of QMO-17 was an α9 antagonist, permitting an in silico model of α9 antagonism to be developed. The α9 activity of these compounds was confirmed to be potentially useful for CAS management of inflammatory pain in cell-based assays of cytokine release.

| S-EPMC11274740 | biostudies-literature

Novel Hydroxamic Acids Containing Aryl-Substituted 1,2,4- or 1,3,4-Oxadiazole Backbones and an Investigation of Their Antibiotic Potentiation Activity.

Project description:UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a zinc amidase that catalyzes the second step of the biosynthesis of lipid A, which is an outer membrane essential structural component of Gram-negative bacteria. Inhibitors of this enzyme can be attributed to two main categories, non-hydroxamate and hydroxamate inhibitors, with the latter being the most effective given the chelation of Zn2+ in the active site. Compounds containing diacetylene or acetylene tails and the sulfonic head, as well as oxazoline derivatives of hydroxamic acids, are among the LpxC inhibitors with the most profound antibacterial activity. The present article describes the synthesis of novel functional derivatives of hydroxamic acids-bioisosteric to oxazoline inhibitors-containing 1,2,4- and 1,3,4-oxadiazole cores and studies of their cytotoxicity, antibacterial activity, and antibiotic potentiation. Some of the hydroxamic acids we obtained (9c, 9d, 23a, 23c, 30b, 36) showed significant potentiation in nalidixic acid, rifampicin, and kanamycin against the growth of laboratory-strain Escherichia coli MG1655. Two lead compounds (9c, 9d) significantly reduced Pseudomonas aeruginosa ATCC 27853 growth in the presence of nalidixic acid and rifampicin.

| S-EPMC10779255 | biostudies-literature

Conversion of raltegravir carrying a 1,3,4-oxadiazole ring to a hydrolysis product upon pH changes decreases its antiviral activity.

Project description:Raltegravir (RAL), a human immunodeficiency virus (HIV)-1 integrase inhibitor, has been administered as part of antiretroviral therapy. Studies in patients with HIV-1 have shown high variability in the pharmacokinetics of RAL, and in healthy volunteers, coadministration of proton-pump inhibitors has been shown to increase the plasma RAL concentrations. Here, we found that RAL containing a 1,3,4-oxadiazole ring is converted to a hydrolysis product (H-RAL) with a cleaved 1,3,4-oxadiazole ring at pH 1.0 and 13.0 conditions in vitro, thereby reducing the anti-HIV activity of the drug. The inclusion of cyclodextrins (beta-cyclodextrin [βCD], random methyl-βCD [RAM-βCD], and hydroxypropyl-βCD [HP-βCD]) can protect RAL from pH-induced changes. The conversion of RAL to H-RAL was detected by using various mass spectrometry analyses. The chromatogram of H-RAL increased in a time-dependent manner similar to another 1,3,4-oxadiazole-containing drug, zibotentan, using high-performance liquid chromatography. Oral bioavailability and target protein interactions of H-RAL were predicted to be lower than those of RAL. Moreover, H-RAL exhibited significantly reduced anti-HIV-1 activity, whereas combinations with βCD, RAM-βCD, and HP-βCD attenuated this effect in cell-based assays. These findings suggest that βCDs can potentially protect against the conversion of RAL to H-RAL under acidic conditions in the stomach, thereby preserving the anti-HIV-1 effect of RAL. Although clinical trials are needed for evaluation, we anticipate that protective devices such as βCDs may improve the pharmacokinetics of RAL, leading to better treatment outcomes, including reduced dosing, long-term anti-HIV-1 activity, and deeper HIV-1 suppression.

| S-EPMC10758923 | biostudies-literature

2-Phenyl-5-(p-tol-yl)-1,3,4-oxadiazole.

Project description:The title compound, C(15)H(12)N(2)O, adopts the expected near-planar geometry, the phenyl and tolyl rings being inclined relative to the oxadiazole ring by 3.8 (3) and 8.3 (2)°, respectively. This allows adjacent mol-ecules to pack in a parallel fashion and form stacking along [010] via π-π inter-actions [centroid-centroid distances = 3.629 (2) and 3.723 (2) Å]. Further inter-molecular inter-actions include C-H⋯π inter-actions and weak C-H⋯N hydrogen bonds, giving rise to a crossed herringbone packing motif.

| S-EPMC3152068 | biostudies-literature

2,5-Bis(5-methyl-pyrazin-2-yl)-1,3,4-oxadiazole.

Project description:In the title mol-ecule, C(12)H(10)N(6)O, the dihedral angle between the two pyrazine rings [planar to within 0.009?(3) and 0.018?(3)?Å] is 5.62?(15)°. They deviate from the central oxadiazole ring [planar to within 0.005?(3)?Å] by 1.52?(16) and 5.55?(17)°, respectively. In the crystal, C-H?N inter-actions involving the pyrazine rings connect mol-ecules to form zigzag supramolecular chains propagating in [010].

| S-EPMC3120570 | biostudies-literature