Development and Validation of Stability-Indicating Assay Method for a Novel Oxazolidinone (PH-192) with Anticonvulsant Activity by Using UHPLC-QToF-MS.

The treatment of seizure disorders with currently available pharmacotherapeutic agents is not optimal due to the failure of some patients to respond, coupled with occurrences of side effects. There is therefore a need for research into the development of new chemical entities as potential anticonvulsant agents, which are different structurally from the existing class of drugs. We recently identified a novel triazolyl-oxazolidinone derivative, PH-192, as a potential anticonvulsant agent.

Anti-allergic, anti-asthmatic and anti-inflammatory effects of an oxazolidinone hydroxamic acid derivative (PH-251) - A novel dual inhibitor of 5-lipoxygenase and mast cell degranulation.

We have recently reported the discovery of a series of oxazolidinone hydroxamic acid derivatives that are potent inhibitors of 5-lipoxygenase (5-LO) [arachidonate 5-lipoxygenase; EC 1.13.11.

GYY4137 attenuates functional impairment of corpus cavernosum and reduces fibrosis in rats with STZ-induced diabetes by inhibiting the TGF-β1/Smad/CTGF pathway.

Erectile dysfunction (ED) is a common diabetic complication. Recent evidence has illuminated the role of hydrogen sulfide (HS) as a dynamic mediator of the erection process. HS is a potent endogenous relaxant gas.

Anti-progressive Effects of a Series of Glycinyl and Alaninyl Triazolyl-oxazolidinones on Kelly Neuroblastoma Cell Line.

Background/aim: Neuroblastoma (NB), the most common extracranial malignant childhood tumor accounts for about 15% of cancer-related deaths in children. Despite the intensive treatment of patients with high-risk scarification of NB, clinical outcomes indicate tumor recurrence greater than 50% and late severe adverse effects. Oxazolidinones are 5-membered heterocyclic compounds with antibacterial activity against resistant bacterial strains.

Synthesis and structure-activity relationships of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives as 5-lipoxygenase inhibitors.

Oxazolidinone hydroxamic acid derivatives were synthesised and evaluated for inhibitory activity against leukotriene (LT) biosynthesis in three cell-based test systems and on direct inhibition of recombinant human 5-lipoxygenase (5-LO). Thirteen of the 19 compounds synthesised were considered active ((50% inhibitory concentration (IC) ≤ 10 µM in two or more test systems)). Increasing alkyl chain length on the hydroxamic acid moiety enhanced activity and morpholinyl-containing derivatives were more active than -acetyl-piperizinyl derivatives.

HS donor GYY4137 ameliorates paclitaxel-induced neuropathic pain in mice.

Paclitaxel-induced neuropathic pain (PINP) is a dose-limiting side effect that largely affects the patient's quality of life and may limit the use of the drug as a chemotherapeutic agent for treating metastatic breast cancer and other solid tumors. Recently, a putative role for the gaseous mediator hydrogen sulfide (HS) in nociception modulation has been suggested. The aim of the present study was to investigate the potential efficacy of the slow release HS donor GYY4137 to alleviate and prevent PINP.

A novel oxazolidinone derivative PH192 demonstrates anticonvulsant activity in vivo in rats and mice.

The pharmacotherapeutic management of seizure disorders with currently available medications is not optimal due to side effects and failure of some patients to respond to all available medications. As such there is the need to develop new antiseizure drugs by looking at new chemical classes of compounds. We recently screened, in vitro, a new class of compounds, the oxazolidinones, for actions in the brain that may indicate potential for antiseizure activity.

Alleviation of impaired reactivity in the corpus cavernosum of STZ-diabetic rats by slow-release HS donor GYY4137.

GYY4137 is a novel hydrogen sulfide (HS) releasing molecule with vasodilator activity. The objectives of this study were to investigate: (1) the pharmacological effect of GYY4137 on the reactivity of the corpus cavernosum (CC) from normal and diabetic rats; (2) the contribution of ATP-sensitive potassium (K-ATP) channels and nitric oxide (NO) pathway; (3) the reactivity to vasoactive agonists following ex vivo incubation of the diabetic rat CC with GYY4137. Longitudinal strips of CC from control and diabetic male Sprague-Dawley (SD) rats (n = 5-6 animals per group) were suspended in organ-baths.

Structure-Antibacterial Activity Relationships of -Substituted-(-/-Alaninyl) 1-1,2,3-Triazolylmethyl Oxazolidinones.

Bacterial resistance towards the existing class of antibacterial drugs continues to increase, posing a significant threat to the clinical usefulness of these drugs. These increasing and alarming rates of antibacterial resistance development and the decline in the number of new antibacterial drugs' approval continue to serve as a major impetus for research into the discovery and development of new antibacterial agents. We synthesized a series of -/-alaninyl substituted triazolyl oxazolidinone derivatives and evaluated their antibacterial activity against selected standard Gram-positive and Gram-negative bacterial strains.

Antimycobacterial Activities of N-Substituted-Glycinyl 1H-1,2,3-Triazolyl Oxazolidinones and Analytical Method Development and Validation for a Representative Compound.

Twelve -substituted-glycinyl triazolyl oxazolidinone derivatives were screened for antimycobacterial activity against susceptible ( ( H37Rv) and resistant (isoniazid (INH)-resistant (SRI 1369), rifampin (RMP)-resistant (SRI 1367), and ofloxacin (OFX)-resistant (SRI 4000)) strains. Most of the compounds showed moderate to strong antimycobacterial activity against all strains tested, with minimum inhibitory concentration (MIC) value ranges of 0.5-11.

Comparative Pharmacokinetic Study for Linezolid and Two Novel Antibacterial Oxazolidinone Derivatives in Rabbits: Can Differences in the Pharmacokinetic Properties Explain the Discrepancies between Their In Vivo and In Vitro Antibacterial Activities?

This is a comparative pharmacokinetics study of linezolid (Lzd), and two novel oxazolidinone antibacterial agents-PH027 and PH051-in rabbits to determine if the discrepancy between the in vitro and in vivo activities of the novel compounds is due to pharmacokinetic factors. The pharmacokinetics after IV and oral administration, plasma protein binding and tissue distribution for the three compounds were compared. The elimination half-lives were 52.

A validated UPLC-MS/MS method for the analysis of linezolid and a novel oxazolidinone derivative (PH027) in plasma and its application to tissue distribution study in rabbits.

Objectives: Linezolid is the first approved oxazolidinone antibacterial agent, whereas PH027 is a novel compound of the same class that exhibits good in vitro antibacterial activity. The objective of this study was to develop an UPLC-MS/MS assay for the analysis of linezolid and PH027 in plasma and to apply the method for comparative pharmacokinetic and tissue distribution studies of both compounds.

Method: Plasma samples and calibrators were extracted with diethyl ether after addition of the internal standard solution.

Oxazolidinone antimicrobials: a patent review (2012-2015).

Introduction: Antimicrobial resistance in Gram-positive bacteria is a major health care issue. This review summarizes patent publications from 2012 to 2015 that divulged novel oxazolidinones as antibacterial agents.

Areas Covered: A total of 25 patents obtained from Espacenet, WIPO Patentscope and FreePatentsOnline, and AcclaimIP search engines were reviewed.

Antiproliferative activity of a series of 5‑(1H‑1,2,3‑triazolyl) methyl‑ and 5‑acetamidomethyl‑oxazolidinone derivatives.

In the face of increasing resistance to the existing antibiotics, oxazolidinones (exemplified by linezolid) have been developed as promising antibacterial agents, but may have other useful actions. In the present study, a series of 5‑(1H‑1,2,3‑triazoly) l‑methyl‑, 5‑acetamidomethyl‑morpholino and N‑substituted‑piperazino oxazolidinone derivatives were investigated to determine whether they are active against eukaryotic cells. An MTT assay, validated by cell counting, was used to assess the effect of nine oxazolidinone derivatives (concentrations 100 nM‑10 µM) on the proliferation of MCF7 human breast cancer cells.

Synthesis and biological evaluation of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives.

Research activities on the oxazolidinone antibacterial class of compounds continue to focus on developing newer derivatives with improved potency, broad-spectrum activity and safety profiles superior to linezolid. Among the safety concerns with the oxazolidinone antibacterial agents is inhibition of monoamine oxidases (MAO) resulting from their structural similarity with toloxatone, a known MAO inhibitor. Diverse substitution patterns at the C-5 position of the oxazolidinone ring have been shown to significantly affect both antibacterial activity and MAO inhibition to varying degrees.

Evaluation of the monoamine oxidases inhibitory activity of a small series of 5-(azole)methyl oxazolidinones.

Oxazolidinone class of compounds continue to generate interest as promising agents effective against sensitive and resistant Gram-positive pathogenic bacteria strains. Recent focus is to develop new potent derivatives with improved broad-spectrum activity and safety profile superior to linezolid. An important toxicity issue for this class of compounds arises from the structural similarity with toloxatone, a known MAO inhibitor.

Evaluation of anticonvulsant actions of dibromophenyl enaminones using in vitro and in vivo seizure models.

Epilepsy and other seizure disorders are not adequately managed with currently available drugs. We recently synthesized a series of dibromophenyl enaminones and demonstrated that AK6 and E249 were equipotent to previous analogs but more efficacious in suppressing neuronal excitation. Here we examined the actions of these lead compounds on in vitro and in vivo seizure models.

Synthesis, neuronal activity and mechanisms of action of halogenated enaminones.

Due to the excellent anticonvulsant activity of previously synthesized halogenated enaminones, more disubstituted analogs were synthesized and evaluated in vitro. The new enaminones either had no effect, depressed, or enhanced population spike (PS) amplitude in the rat hippocampus in a concentration-dependent manner. Structure-activity relationship (SAR) analysis indicated that compounds 21 and 25 (with dibromo substituents) were equipotent, and more potent than compound 2 (with dichloro substituents), with compound 25 being the most efficacious of all tested compounds.

Synthesis and antibacterial activities of N-substituted-glycinyl 1H-1,2,3-triazolyl oxazolidinones.

A series of 1H-1,2,3-triazolyl piperazino oxazolidinone analogs with optionally varied glycinyl substitutions were synthesized and their antibacterial activity assessed against a panel of susceptible and resistant Gram-positive and selected Gram-negative bacteria including clinical isolates. The N-aroyl- and N-heteroaroyl-glycinyl (MIC: 0.06-4 μg/ml) derivatives were more potent than the N-acylglycinyl (2-8 μg/ml) derivatives against all Gram-positive bacteria tested.

Novel actions of oxazolidinones: in vitro screening of a triazolyloxazolidinone for anticonvulsant activity.

Objective: To test the hypothesis that a triazolyloxazolidinone (PH084) has anticonvulsant activity by examining its effects on in vitro seizure models in the rat hippocampus.

Materials And Methods: Whole-cell synaptic currents, action potentials and extracellular population spikes (PS) were recorded in the cell body area of rat hippocampal CA1 region in acutely prepared slices. Chemical [picrotoxin (100 µM) and zero magnesium] and electrical seizures were induced and the effect of PH084 (10 µM) was tested on cellular responses, multiple spikes and spontaneous bursting frequencies.

Effects of varied substituents on the antibacterial activity of triazolylmethyl oxazolidinones.

A number of 1,2,3-triazolylmethyl piperazino oxazolidinone derivatives with optionally varied substituents at the 4N-piperazine position were synthesized and their antibacterial activity evaluated against a panel of susceptible and resistant Gram-positive and selected Gram-negative bacteria. Substitution with 5-membered heteroaroyl and dinitrobenzoyl moieties potentiated activity against staphylococci and enterococci strains. Furthermore, the compounds having dinitrobenzoyl 7n, 7o, and 5-nitrofuroyl 7t substitutions were four- to eightfold more potent than linezolid against M.

Antimycobacterial Activities of Novel 5-(1H-1,2,3-Triazolyl)Methyl Oxazolidinones.

The antibacterial activities of a series of triazolyl oxazolidinones against Mycobacterium tuberculosis strain in vitro and in vivo in a mice model are presented. Most active compounds were noncytotoxic against VERO cells with acceptable selectivity indexes (SI) as measures of compound tolerability. Structure activity relationships (SARs) revealed that analogs with alkylcarbonyl (IC(90): < 0.

The effect of systematic structural modifications on the antibacterial activity of novel oxazolidinones.

A novel series of tetraethylene glycol (TEG) triazolyl and squaramide containing oxazolidinones were synthesized and tested for their antibacterial activity against a selected panel of Gram-positive and Gram-negative bacteria. The 4-TEG-triazolyl derivatives were prepared by 'click reaction'. The introduction of the TEG and squaramide groups did not favor antibacterial activity.

Assessment of the stability of novel antibacterial triazolyl oxazolidinones using a stability-indicating high-performance liquid chromatography method.

Objectives: To evaluate the stability of 12 triazolyl oxazolidinone (TOZ) derivatives in simulated gastric and intestinal fluids as well as in human plasma at 37 ± 1°C.

Materials And Methods: A stability-indicating high-performance liquid chromatography (HPLC) procedure with a C(8) column (250 × 40 mm, 5 μm particle size) and a mobile phase of acetonitrile/H(2)O (50/50 v/v) at 1.0 ml/min was used.