5395-67-5Relevant articles and documents
Synthesis of C-14 labeled GABAA α2/α3 selective partial agonists and the investigation of late-occurring and long-circulating metabolites of GABAA receptor modulator AZD7325
Artelsmair, Markus,Gu, Chungang,Lewis, Richard J.,Elmore, Charles S.
, p. 415 - 426 (2018)
Anxiolytic activity has been associated with GABAA α2 and α3 subunits. Several target compounds were identified and required in C-14 labeled form to enable a better understanding of their drug metabolism and pharmacokinetic properties. AZD7325 is a selective GABAA α2 and α3 receptor modulator intended for the treatment of anxiety through oral administration. A great number of AZD7325 metabolites were observed across species in vivo, whose identification was aided by [14C]AZD7325. An interesting metabolic cyclization and aromatization pathway leading to the tricyclic core of M9 and the oxidative pathways to M10 and M42 are presented.
Probing phenylcarbamoylazinane-1,2,4-triazole amides derivatives as lipoxygenase inhibitors along with cytotoxic, ADME and molecular docking studies
Muzaffar, Saima,Shahid, Wardah,Riaz, Naheed,Saleem, Muhammad,Ashraf, Muhammad,Aziz-ur-Rehman,Bashir, Bushra,Kaleem, Ayesha,al-Rashida, Mariya,Baral, Bikash,Bhattarai, Keshab,Gross, Harald
, (2020/12/21)
Hunting small molecules as anti-inflammatory agents/drugs is an expanding and successful approach to treat several inflammatory diseases such as cancer, asthma, arthritis, and psoriasis. Besides other methods, inflammatory diseases can be treated by lipoxygenase inhibitors, which have a profound influence on the development and progression of inflammation. In the present study, a series of new N-alkyl/aralky/aryl derivatives (7a-o) of 2-(4-phenyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)acetamide was synthesized and screened for their inhibitory potential against the enzyme 15-lipoxygenase. The simple precursor ethyl piperidine-4-carboxylate (a) was successively converted into phenylcarbamoyl derivative (1), hydrazide (2), semicarbazide (3) and N-phenylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4), then in combination with electrophiles (6a-o) through further multistep synthesis, final products (7a-o) were generated. All the synthesized compounds were characterized by FTIR, 1H, 13C NMR spectroscopy, EIMS, and HREIMS spectrometry. Almost all the synthesized compounds showed excellent inhibitory potential against the tested enzyme. Compounds 7c, 7f, 7d, and 7g displayed potent inhibitory potential (IC50 9.25 ± 0.26 to 21.82 ± 0.35 μM), followed by the compounds 7n, 7h, 7e, 7a, 7b, 7l, and 7o with IC50 values in the range of 24.56 ± 0.45 to 46.91 ± 0.57 μM. Compounds 7c, 7f, 7d exhibited 71.5 to 83.5% cellular viability by MTT assay compared with standard curcumin (76.9%) when assayed at 0.125 mM concentration. In silico ADME studies supported the drug-likeness of most of the molecules. In vitro inhibition studies were substantiated by molecular docking wherein the phenyl group attached to the triazole ring was making a π-δ interaction with Leu607. This work reveals the possibility of a synthetic approach of compounds in relation to lipoxygenase inhibition as potential lead compounds in drug discovery.
Identification of phenylcarbamoylazinane-1,3,4-oxadiazole amides as lipoxygenase inhibitors with expression analysis and in silico studies
Bashir, Bushra,Shahid, Wardah,Ashraf, Muhammad,Saleem, Muhammad,Aziz-ur-Rehman,Muzaffar, Saima,Imran, Muhammad,Amjad, Hira,Bhattarai, Keshab,Riaz, Naheed
, (2021/08/19)
In search for new anti-inflammatory agents that inhibit the enzymes of arachidonic acid pathway as the drug targets, the present article describes the screening of 1,3,4-oxadiazole analogues against lipoxygenase (LOX) enzyme. The work is based on the synthesis of new N-alkyl/aralky/aryl derivatives (6a-o) of 2-(4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,3,4-oxadiazol-3-ylthio)acetamide which were obtained by the reaction of 1,3,4-oxadiazole (3) with various electrophiles (5a-o), in KOH. The synthesized analogues showed potent to moderate inhibitory activity against the soybean 15-LOX enzyme; especially 6g, 6b, 6a and 6l displayed the potent inhibitory potential with IC50 values 7.15 ± 0.26, 9.32 ± 0.42, 15.83 ± 0.45 & 18.37 ± 0.53 μM, respectively, while excellent to moderate inhibitory profiles with IC50 values in the range of 26.13–98.21 μM were observed from the compounds 6k, 6m, 6j, 6o, 6h, 6f, 6n and 6c. Most of the active compounds exhibited considerable cell viability against blood mononuclear cells (MNCs) at 0.25 mM by MTT assay except 6f, 6h, 6k and 6m which showed around 50% cell viability. Flow cytometry studies of the selected compounds 6a, 6j and 6n revealed that these caused 79.5–88.51% early apoptotic changes in MNCs compared with 4.26% for control quercetin at their respective IC50 values. The relative expression of 5-LOX gene was monitored in MNCs after treatment with these three molecules and all down-regulated the enzyme activity. In silico ADME and molecular docking studies further supported these studies of oxadiazole derivatives and considered it as potential ‘lead’ compounds in drug discovery and development.
