Identification of an N-phenylsulfonyl-2-(piperazin-1-yl)methyl-benzonitrile derivative as Zika virus entry inhibitor.

Zika virus (ZIKV) infection could cause severe neurological complications such as neonatal microcephaly, Guillain-Barré syndrome, and myelitis in adults. No vaccine or therapeutic drug is available for prevention and control of ZIKV infection yet. Based on previously reported anti-ZIKV hit compound 1, a series of novel N-benzoyl or phenylsulfonyl substituted 2-(piperazin-1-yl)methyl-benzonitrile (PMBN) derivatives was designed, synthesized, and investigated for the antiviral activity against ZIKV replication in different cell-based phenotypic assays. The results indicated that N-phenylsulfonyl-PMBN derivative 24 displayed the comparable antiviral activity and higher oral availability than hit compound 1. Meanwhile, mechanism of action study confirmed that compound 24 acts on the early entry stage of ZIKV life cycle. The identification of this new ZIKV entry inhibitor chemotype provided a promising lead for further optimization to develop new drug for ZIKV infection.

Piperazine ferulate protects against cardiac ischemia/reperfusion injury in rat via the suppression of NLRP3 inflammasome activation and pyroptosis.

Piperazine ferulate (PF) has been reported to protect cardiac from ischemia/reperfusion injury to achieve myocardial protection. NLRP3 inflammasome activation-mediated pyroptosis has been shown to the involvement in myocardial ischemia-reperfusion injury (MI/RI). Increasing evidence suggested that PF is used for cardiovascular diseases, whereas its protection of MI/RI and the mechanism are not fully understood. Rats' model of MI/RI was subjected by occlusion of the left anterior descending (LAD) coronary artery for 30 min followed by 120 min of reperfusion to investigate whether PF exhibited cardiac protection via modulating the NLRP3 inflammasome-mediated pyroptosis. Rats were intragastrically administrated with PF (100 mg/kg) for 7 consecutive days prior to I/R surgery. The results showed that PF remarkedly elevated left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), and decrease mitral early diastolic flow velocity/late diastolic flow velocity (E/A) of I/R injury rats compared with the I/R group. Besides, MI/RI contributes to increasing the cardiac infarction size and aggravates the myocardial injury as well as causes inflammation, whereas these detrimental alterations were ameliorated by PF pretreatment. Mechanically, the protein and gene expression levels of NLRP3, ASC, GSDMD, IL-Iß and caspase-1 in the PF-treated group were lower than those of the I/R group, which indicates that PF can evidently suppress the I/R-triggered NLRP3 inflammasome activation and pyroptosis in the heart. These results indicated that PF could prevent I/R-induced cardiac damages and cardiac dysfunction in the rats induced by I/R challenge, and it might be a potential therapeutic strategy for the treatment of ischemic heart disease.

Comparative therapeutic efficacies of oral and in-water administered levamisole, piperazine and fenbendazole against experimental Ascaridia galli infection in chickens.

Evidence on the current efficacy status of anthelmintics used in the Australian poultry sector is lacking. A controlled trial was conducted to evaluate the efficacy of three commonly used anthelmintics, namely levamisole (LEV), piperazine (PIP) and fenbendazole (FBZ) plus levamisole-piperazine combination (LEV-PIP) against a field strain of A. galli recovered following flock treatment with LEV. A total of 108 A. galli infected cockerels were randomized into nine experimental groups of 12 cockerels each (eight treatments and one untreated control) with each treatment administered by two routes (oral drench or in drinking water). Chickens received label-recommended doses of LEV (28 mg/kg) and PIP (100 mg/kg) while LEV-PIP involved both compounds co-administered at their full individual dose rates. FBZ was tested at two dose rates; 10 mg/kg as a single oral drench or 5 mg/kg in drinking water over 5 days. Anthelmintic efficacies were assessed by worm count reduction (WCR%) and excreta egg count reduction (EECR%) estimated by two methods. Ten days post treatment, the untreated control birds harboured significantly higher worm counts (P < 0.0001) than those in all treatment groups irrespective of the mode drug of application. Oral drenching caused a greater reduction in worm and egg counts (P < 0.05) than medication in drinking water. Based on geometric worm counts the percentage efficacies for the oral drench were 99.1, 96.3, 97.2 and 100 % respectively for LEV, PIP, FBZ and LEV-PIP, and for administration in water 96.4, 93.7, 88.7 and 97.7 % respectively. Efficacies based on EECR% were consistent with WCR% with strong positive linear association between efficacy values. In conclusion, our results demonstrate no evidence of loss of susceptiblity of the test A. galli isolate to both LEV and PIP contrary to our hypothesis. Additional efficacy studies are needed using A. galli isolates sourced from different poultry flocks across Australia.

Discovery of a Candidate Containing an (S)-3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden Scaffold as a Highly Potent Pan-Inhibitor of the BCR-ABL Kinase Including the T315I-Resistant Mutant for the Treatment of Chronic Myeloid Leukemia.

BCR-ABL kinase inhibition is an effective strategy for the treatment of chronic myeloid leukemia (CML). Herein, we report compound 3a-P1, bearing a difluoro-indene scaffold, as a novel potent pan-inhibitor against BCR-ABL mutants, including the most refractory T315I mutant. As the privileged (S)-isomer compared to its (R)-isomer 3a-P2, 3a-P1 exhibited potent antiproliferative activities against K562 and Ku812 CML cells and BCR-ABL and BCR-ABLT315I BaF3 cells, with IC50 values of 0.4, 0.1, 2.1, and 4.7 nM, respectively. 3a-P1 displayed a good safety profile in a battery of assays, including single-dose toxicity, hERG K+, and genotoxicity. It also showed favorable mice pharmacokinetic properties with a good oral bioavailability (32%), a reasonable half-life (4.61 h), and a high exposure (1386 h·ng/mL). Importantly, 3a-P1 demonstrated a higher potency than ponatinib in a mice xenograft model of BaF3 harboring BCR-ABLT315I. Overall, the results indicate that 3a-P1 is a promising drug candidate for the treatment of CML to overcome the imatinib-resistant T315I BCR-ABL mutation.

Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure-Activity Relationships.

Depression is the single largest contributor to global disability with a huge economic and social burden on the world. There are a number of antidepressant drugs on the market, but treatment-resistant depression and relapse of depression in a large number of patients have increased problems for clinicians. One peculiarity observed in most of the marketed antidepressants is the presence of a piperazine substructure. Although piperazine is also used in the optimization of other pharmacological agents, it is almost extensively used for the development of novel antidepressants. One common understanding is that this is due to its favorable CNS pharmacokinetic profile; however, in the case of antidepressants, piperazine plays a much bigger role and is involved in specific binding conformations of these agents. Therefore, in this review, a critical analysis of the significance of the piperazine moiety in the development of antidepressants has been performed. An overview of current developments in the designing and synthesis of piperazine-based antidepressants (2015 onwards) along with SAR studies is also provided. The various piperazine-based therapeutic agents in early- or late-phase human testing for depression are also discussed. The preclinical compounds discussed in this review will help researchers understand how piperazine actually influences the design and development of novel antidepressant compounds. The SAR studies discussed will provide crucial clues about the structural features and optimizations required to enhance the efficacy and potency of piperazine-based antidepressants.

Novel piperazine-2,5-dione analogs bearing 1H-indole: Synthesis and biological effects.

In this work, a series of novel piperazine-2,5-dione derivatives bearing indole analogs (2a-2q) was designed and synthesized. The synthesized compounds were characterized by IR, 1H NMR, 13C NMR spectroscopy, and ESI-MS. They were then evaluated for their anti-depressant, anti-inflammatory, and analgesic activities in vivo. The experimental results revealed that all the compounds showed clear anti-depressant, anti-inflammatory, and analgesic effects at a dose of 10 mg/kg. Among them, compounds 2e and 2q exhibited the best anti-depressant effects (the percent decreases in the duration of immobility were 70.2% and 71.2%, respectively), which were similar to that of fluoxetine (67.9%) in the forced swim test. Additionally, compounds 2e and 2q also displayed good anti-inflammatory and analgesic activities. Literature reports have highlighted the anti-inflammatory and analgesic effects of anti-depressant drugs, suggesting that they may have a similar mechanism of action. Therefore, further studies to investigate the possible mechanisms of action of compounds 2e and 2q are warranted.

Therapeutic Efficacy of Piperazine Ferulate Combined With Irbesartan in Diabetic Nephropathy: A Systematic Review and Meta-analysis.

PURPOSE: Irbesartan is widely used clinically in the treatment of diabetic nephropathy (DN). It is believed that piperazine ferulate (PF) combined with irbesartan could result in an improved efficacy in the treatment of DN. We present the latest meta-analysis that details the combination of PF and irbesartan therapy. METHODS: Before January 31, 2020, we searched various electronic databases for appropriate articles. Our search was not restricted by keyword or language. We then filtered all articles using certain criteria and assessed the quality of the qualified studies. FINDINGS: The meta-analysis included 12 trials that involved 1300 patients (650 in the experimental group and 650 in the control group). The ages of the patients ranged from 30 to 79 years. Compared with irbesartan alone, the total effective rate of PF combined with irbesartan was significantly higher (odds ratio [OR] = 4.95; 95% CI, 3.11-7.58; P < 0.0001). The blood glucose level was controlled by significantly decreasing the fasting plasma glucose level (mean difference [MD] = -1.40; 95% CI, -2.70 to -0.11; P = 0.03) and 2-h plasma glucose level (MD = -1.65; 95% CI, -2.49 to -0.82; P < 0.0001). The combination therapy significantly decreased the levels of serum creatinine (MD = -10.24; 95% CI, -15.25 to -5.23; P < 0.0001), 24-h urinary protein (MD = -0.07; 95% CI, -0.09 to -0.05; P < 0.0001), urinary albumin excretion rate (MD = -22.52; 95% CI, -30.20 to -14.84; P < 0.0001), urinary ß2-microglobulin (MD = -0.15; 95% CI, -0.17 to -0.13; P < 0.0001), and blood urea nitrogen (MD = -1.54; 95% CI, -2.36 to -0.72; P = 0.0002), which was beneficial for improving and protecting renal function. The renal microcirculation was improved by significantly decreasing the whole blood viscosity low shear (MD = -1.41; 95% CI, -1.84 to -0.99; P < 0.0001), whole blood viscosity high shear (MD = -0.54; 95% CI, -0.63 to -0.45; P < 0.0001), whole blood viscosity (MD = -1.31; 95% CI, -1.79 to -0.83; P < 0.0001), whole blood reduction viscosity (MD = -1.42; 95% CI, -1.79 to -1.06; P < 0.0001), platelet aggregation rate (MD = -0.42; 95% CI, -0.50 to -0.35; P < 0.0001), plasma viscosity (MD = -13.02; 95% CI, -15.47 to -10.56; P < 0.0001), and fibrinogen content (MD = -0.25; 95% CI, -0.42 to -0.09; P = 0.003). IMPLICATIONS: PF combined with irbesartan could improve the efficiency in the treatment of DN. However, these results should be handled carefully. These findings should be verified by several rigorous randomized controlled trials.

Synthesis and evaluation of sulfonyl piperazine LpxH inhibitors.

The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is essential in lipid A biosynthesis and has emerged as a promising target for the development of novel antibiotics against multidrug-resistant Gram-negative pathogens. Recently, we reported the crystal structure of Klebsiella pneumoniae LpxH in complex with 1 (AZ1), a sulfonyl piperazine LpxH inhibitor. The analysis of the LpxH-AZ1 co-crystal structure and ligand dynamics led to the design of 2 (JH-LPH-28) and 3 (JH-LPH-33) with enhanced LpxH inhibition. In order to harness our recent findings, we prepared and evaluated a series of sulfonyl piperazine analogs with modifications in the phenyl and N-acetyl groups of 3. Herein, we describe the synthesis and structure-activity relationship of sulfonyl piperazine LpxH inhibitors. We also report the structural analysis of an extended N-acyl chain analog 27b (JH-LPH-41) in complex with K. pneumoniae LpxH, revealing that 27b reaches an untapped polar pocket near the di-manganese cluster in the active site of K. pneumoniae LpxH. We expect that our findings will provide designing principles for new LpxH inhibitors and establish important frameworks for the future development of antibiotics against multidrug-resistant Gram-negative pathogens.

Synthesis and antidepressant effect of novel aralkyl piperazine and piperidine derivatives targeting SSRI/5-HT1A/5-HT7.

A series of novel aralkyl piperazine and piperidine derivatives were synthesized, and evaluated for their serotonin reuptake inhibitory and 5-HT1A/5-HT7 receptors affinities activity. Antidepressant activities in vivo of the selective compound were screened using the forced swimming test (FST) and tail suspension test (TST). The results indicated that compound 19a exhibited high affinities for the 5-HT1A/5-HT7 receptors (5-HT1A, Ki = 12 nM; 5-HT7, Ki = 3.2 nM) coupled with potent serotonin reuptake inhibition (IC50 = 14 nM) and showed a marked antidepressant-like effect in the FST and TST models.

One-pot synthesis of novel tert-butyl-4-substituted phenyl-1H-1,2,3-triazolo piperazine/piperidine carboxylates, potential GPR119 agonists.

We have synthesized a new series of 1,2,3-triazolo piperazine and piperidine carboxylate derivatives using a simple and one-pot click chemistry with significantly reduced reaction times (~5 min) and enhanced reaction yields (~95-98%). The fourteen novel compounds thus synthesized were tested for ability to target GPR119, a G-protein coupled target receptor that plays critical role in regulation of type-2 diabetes mellitus. Four analogs (3e, 3g, 5e and 5g) demonstrated similar or better EC50 values over previously reported AR231453 activity towards GPR119.

Novel Piperazino-Enaminones Decrease Pro-inflammatory Cytokines Following Hemarthrosis in a Hemophilia Mouse Model.

Hemarthrosis is the primary cause of hemophiliac arthropathy (HA). Pro-inflammatory cytokines are thought to play an important role in the pathogenesis of HA, and thus, anti-cytokine approaches may be used as an adjuvant therapy. A novel series of enaminone compounds (JODI), that contain the N-aryl piperazino motif, have been shown in vitro to reduce pro-inflammatory cytokines and thus may be efficacious in vivo. In this report, we will assess whether JODI can suppress multiple cytokines which might be potentially responsible for joint inflammation in a mouse model of hemarthrosis. The results showed that JODI significantly improved the survival after LPS treatment, and most pro-inflammatory cytokines/chemokines were decreased significantly after JODI administration. In the hemophilia mouse model, hemarthrosis resulted in local cytokine/chemokine changes, represented by elevated pro-inflammatory (IL-6, MCP-1, MIP-1α, MIP-1ß) and pro-angiogenic (VEGF and IL-33) cytokines, and decreased anti-pro-inflammatory cytokines IL-4 and IL-10. The changes were reversed by administration of JODI, which can be used as a novel approach to manage hemophilia arthropathy.

The Discovery of LML134, a Histamine H3 Receptor Inverse Agonist for the Clinical Treatment of Excessive Sleep Disorders.

Histamine H3 receptor (H3R) inverse agonists that have been in clinical trials for the treatment of excessive sleep disorders, have been plagued with insomnia as a mechanism-based side effect. We focused on the identification of compounds that achieve high receptor occupancy within a short time, followed by rapid disengagement from the receptor, a target profile that could provide therapeutic benefits without the undesired side effect of insomnia. This article describes the optimization work that led to the discovery of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate (18 b, LML134).

Activity-Based Protein Profiling Delivers Selective Drug Candidate ABX-1431, a Monoacylglycerol Lipase Inhibitor, To Control Lipid Metabolism in Neurological Disorders.

Monoacylglycerol lipase (MGLL or MAGL) is a critical point of regulation of both endocannabinoid and eicosanoid signaling pathways in the brain, thereby providing novel therapeutic opportunities for neurological and neurodegenerative diseases. In this issue Cisar et al. disclose the discovery, optimization, and initial preclinical profiling of ABX-1431, a covalent, irreversible MGLL inhibitor. Activity-based protein profiling was key to the discovery of ABX-1431. ABX-1431 is a first-in-class experimental drug that was well-tolerated and safe in phase 1 clinical studies. Data from an exploratory phase 1b study indicate that it has the potential to treat symptoms of adult patients with syndrome of Gilles de la Tourette. ABX-1431 is currently entering clinical phase 2 studies for this neurological disorder as well as for other indications, such as neuromyeltis optica and multiple sclerosis.

Identification of ABX-1431, a Selective Inhibitor of Monoacylglycerol Lipase and Clinical Candidate for Treatment of Neurological Disorders.

The serine hydrolase monoacylglycerol lipase (MGLL) converts the endogenous cannabinoid receptor agonist 2-arachidonoylglycerol (2-AG) and other monoacylglycerols into fatty acids and glycerol. Genetic or pharmacological inactivation of MGLL leads to elevation in 2-AG in the central nervous system and corresponding reductions in arachidonic acid and eicosanoids, producing antinociceptive, anxiolytic, and antineuroinflammatory effects without inducing the full spectrum of psychoactive effects of direct cannabinoid receptor agonists. Here, we report the optimization of hexafluoroisopropyl carbamate-based irreversible inhibitors of MGLL, culminating in a highly potent, selective, and orally available, CNS-penetrant MGLL inhibitor, 28 (ABX-1431). Activity-based protein profiling experiments verify the exquisite selectivity of 28 for MGLL versus other members of the serine hydrolase class. In vivo, 28 inhibits MGLL activity in rodent brain (ED50 = 0.5-1.4 mg/kg), increases brain 2-AG concentrations, and suppresses pain behavior in the rat formalin pain model. ABX-1431 (28) is currently under evaluation in human clinical trials.