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[Figure not available: see fulltext.] An adequate QSAR model based on the simplex representation of the molecular structure was built in order to optimize the search for new anti-influenza agents. Structural interpretation of the model allowed us to identify molecular fragments that determine the activity of compounds against human influenza viruses. Further virtual screening and targeted synthesis allowed us to select a group of potentially effective compounds, three of which, derivatives of piperidine and isoindoline, turned out to be the most promising.

Sponges of the genus Agelas produce compounds that modulate the activity of voltage-gated sodium ion channels and contribute novel scaffolds for the development of compounds with activity against a plethora of biological targets. In particular, clathrodin and dibromosceptrin were reported to decrease the average maximum amplitude of inward sodium currents in isolated chick embryo sympathetic ganglia cells; we envisaged these compounds as a starting point to design novel Nav channel modulators. This endeavor was part of our long-term goal of designing a comprehensive library of Agelas alkaloid analogs that would cover a broader chemical space and allow us to examine the activity of such compounds on Nav channels. Our series of compounds was designed by maintaining the terminal structural features found in clathrodin while rigidizing the central part of the molecule and replacing the 3-aminopropene linker with a 4-methylenepiperazine moiety. Synthesised compounds were screened for inhibitory action against the human voltage-gated sodium channel isoforms Nav 1.3, Nav 1.4, cardiac Nav 1.5, and Nav 1.7 using an automated patch clamp electrophysiology technique. The results demonstrate that we have obtained a series of compounds with a modest but selective inhibitory activity against the Nav 1.3 channel isoform. The most potent compound showed selective activity against the Nav 1.3 channel isoform with an IC50 of 19 μM and is a suitable starting point for further development of selective Nav 1.3 channel modulators. Such compounds could prove to be beneficial as a pharmacological tool towards the development of novel therapeutically useful compounds in the treatment of pain.

Efficient methodologies for the preparation of pentacyclo[5.4.0.02,6 .03,10.05,9]undecane (PCU) amine derivatives are described via microwave-assisted synthesis. The obtained results revealed that microwave-assisted synthetic procedures under controlled conditions (power, temperature and time) are very convenient, high yielding, efficient and low-cost methods for the preparation of PCU amine derivatives. The new methods show several advantages including operational simplicity, good performance, significant reduction in reaction time, less by-product formation and easier purification.

Isoprenoid biosynthesis is an important area for anti-infective drug development. One isoprenoid target is (E)-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate (HMBPP) reductase (IspH), which forms isopentenyl diphosphate and dimethylallyl diphosphate from HMBPP in a 2H+/2e? reduction. IspH contains a 4 Fe?4 S cluster, and in this work, we first investigated how small molecules bound to the cluster by using HYSCORE and NRVS spectroscopies. The results of these, as well as other structural and spectroscopic investigations, led to the conclusion that, in most cases, ligands bound to IspH 4 Fe?4 S clusters by η1 coordination, forming tetrahedral geometries at the unique fourth Fe, ligand side chains preventing further ligand (e.g., H2O, O2) binding. Based on these ideas, we used in silico methods to find drug-like inhibitors that might occupy the HMBPP substrate binding pocket and bind to Fe, leading to the discovery of a barbituric acid analogue with a Ki value of ≈500 nm against Pseudomonas aeruginosa IspH.

ERK1/2 inhibitors have attracted special attention concerning the ability of circumventing cases of innate or log-term acquired resistance to RAF and MEK kinase inhibitors. Based on the 4-aminoquinazoline pharmacophore of kinases, herein we describe the synthesis of 4-aminoquinazoline derivatives bearing a 1,2,3-triazole stable core to bridge different aromatic and heterocyclic rings using copper-catalysed azide-alkyne cycloaddition reaction (CuAAC) as a Click Chemistry strategy. The initial screening of twelve derivatives in tumoral cells (CAL-27, HN13, HGC-27, and BT-20) revealed that the most active in BT-20 cells (25a, IC50 24.6 μM and a SI of 3.25) contains a more polar side chain (sulfone). Furthermore, compound 25a promoted a significant release of lactate dehydrogenase (LDH), suggesting the induction of cell death by necrosis. In addition, this compound induced G0/G1 stalling in BT-20 cells, which was accompanied by a decrease in the S phase. Western blot analysis of the levels of p-STAT3, p-ERK, PARP, p53 and cleaved caspase-3 revealed p-ERK1/2 and p-STA3 were drastically decreased in BT-20 cells under 25a incubation, suggesting the involvement of these two kinases in the mechanisms underlying 25a-induced cell cycle arrest, besides loss of proliferation and viability of the breast cancer cell. Molecular docking simulations using the ERK-ulixertinib crystallographic complex showed compound 25a could potentially compete with ATP for binding to ERK in a slightly higher affinity than the reference ERK1/2 inhibitor. Further in silico analyses showed comparable toxicity and pharmacokinetic profiles for compound 25a in relation to ulixertinib.

Organophosphonium salts containing C(sp3)?+P bonds are among the most utilized reagents in organic synthesis for constructing C?C double bonds. However, their use as C-selective electrophilic groups is rare. Here, we explore an efficient and general transition-metal-free method for sequential chemo- and regioselective C?H and C(sp3)?+P bond functionalizations. In the present study, C?H alkylation resulting in the synthesis of benzhydryl triarylphosphonium salts was achieved by one-pot, four-component cross-coupling reactions of simple and commercially available starting materials. The utility of the resulting phosphonium salt building blocks was demonstrated by the chemoselective post-functionalization of benzylic C(sp3)?+PPh3 groups to achieve aminations, thiolations, and arylations. In this way, benzhydrylamines, benzhydrylthioethers, and triarylmethanes, structural motifs that are present in many pharmaceuticals and agrochemicals, are readily accessed. These include the synthesis of two anticancer agents from simple materials in only two to three steps. Additionally, a protocol for late-stage functionalization of bioactive drugs has been developed using benzhydrylphosphonium salts. This new approach should provide novel transformations for application in both academic and pharmaceutical research.

An efficient ruthenium-catalyzed method has been developed for the direct N-alkylation of sulfur-containing amines with alcohols, for the first time, by a step-economical and environmentally friendly hydrogen borrowing strategy. The present methodology features base-free conditions and broad substrate scope, with water being the only by-product. Moreover, this protocol has been applied to the synthesis of the pharmaceutical drug Quetiapine.

The present invention provides, in one aspect, bifunctional compounds that can be used to promote or enhance degradation of certain circulating proteins. In another aspect, the present invention provides bifunctional compounds that can be used to promote or enhance degradation of certain autoantibodies. In certain embodiments, treatment or management of a disease and/or disorder requires degradation, removal, or reduction in concentration of the circulating protein or the autoantibody in the subject. Thus, in certain embodiments, administration of a compound of the invention to the subject removes or reduces the circulation concentration of the circulating protein or the autoantibody, thus treating, ameliorating, or preventing the disease and/or disorder. In certain embodiments, the circulating protein is TNF.

Neuropeptide S modulates important neurobiological functions including locomotion, anxiety, and drug abuse through interaction with its G protein-coupled receptor known as neuropeptide S receptor (NPSR). NPSR antagonists are potentially useful for the treatment of substance abuse disorders against which there is an urgent need for new effective therapeutic approaches. Potent NPSR antagonists in vitro have been discovered which, however, require further optimization of their in vivo pharmacological profile. This work describes a new series of NPSR antagonists of the oxazolo[3,4-a]pyrazine class. The guanidine derivative 16 exhibited nanomolar activity in vitro and 5-fold improved potency in vivo compared to SHA-68, a reference pharmacological tool in this field. Compound 16 can be considered a new tool for research studies on the translational potential of the NPSergic system. An in-depth molecular modeling investigation was also performed to gain new insights into the observed structure-activity relationships and provide an updated model of ligand/NPSR interactions.

Background: The bromodomain and extra-terminal proteins (BET), in particular BRD4, has recently emerged as a potential therapeutic target for the treatment of many human disorders such as cancer, inflammation, obesity and cardiovascular disease, which draw more and more attention to discover potent BRD4 inhibitors in the past years. In this article, we described the discovery process of an entirely new chemotype of BRD4 inhibitors. Methods: A fragment-based drug discovery strategy was employed in attempting to find a novel chemotype of BRD4 inhibitors. Thus, the potential hits were firstly identified by docking study with KAc binding pocket and AlphaScreen assay. Then the elected hit was further structurally optimized based on the interaction revealed by the docking study and the Structure-Activity Relationship (SAR). Results: A 1-(2-hydroxyphenyl)ethan-1-one fragment was first identified as an efficient hit to BRD4 with a weak inhibition activity and high ligand efficiency (IC50 = 8.9 μM，LE > 0.5) based on virtual screening and biochemical assay. Then, two-rounds optimization of the hit by a fragment-based drug discovery approach enabled the discovery of a potent BRD4 inhibitor 9, which exhibit nanomolar potency in biochemical assays (IC50 = 0.18 μM). Conclusion: The title compounds displayed potent inhibitory activity to BRD4, implying acetophenone core is an effective KAc residue mimic, suggesting acetophenone derivatives as a new chemotype may be promising for developing novel BRD4 inhibitors. 9.

The development of nanoparticles-based heterogeneous catalysts continues to be of scientific and industrial interest for the advancement of sustainable chemical processes. Notably, up-scaling the production of catalysts to sustain unique structural features, activities and selectivities is highly important and remains challenging. Herein, we report the expedient synthesis of Pd-nanoparticles as amination catalysts by the reduction of simple palladium salt on commercial silica using molecular hydrogen. The resulting Pd-nanoparticles constitute stable and reusable catalysts for the synthesis of various N-alkyl amines using borrowing hydrogen technology without the use of any base or additive. By applying this Pd-based catalyst, functionalized and structurally diverse N-alkylated amines as well as some selected drug molecules were synthesized in good to excellent yields. Practical and synthetic utility of this Pd-based amination protocol has been demonstrated by upscaling catalyst preparation and amination reactions to several grams-scales as well as recycling of catalyst. Noteworthy, this Pd-catalyst preparation has been up-scaled to kilogram scale and catalysts prepared in both small (1 g) and large-scale (kg) exhibited similar structural features and activity.

The present invention relates to a compound of formula (I), or one of its pharmaceutically acceptable salts: wherein R1, R2 and -X-Y- have specific definitions. It also relates to the use of such a compound as reactivator of acetylcholinesterase for treating organophosphorous nerve agents poisoning; and to a process for preparing it.

Recent research points to the Sigma Receptor (σR) as a possible neuromodulatory system with multi-functional action and σ1Rs have been suggested as a drug target for a number of CNS conditions. Hexacyclododecylamines have shown σ1R activity and provide an advantageous scaffold for drug design that can improve the blood-brain barrier permeability of privileged structures. A series of oxa-and aza-hexaxcyclododecylamines were synthesised and evaluated for sigma-1 receptor activity and voltage-gated calcium channel blocking ability to determine the effect of inclusion of amine containing heterocycles. The compounds had promising σ1R activities (Ki = 0.067 – 11.86 μM) with the aza-hexacyclododecylamines 12, 24 and 27 showing some of the highest affinities (Ki = 0.067 μM, 0.215 μM and 0.496 μM respectively). This confirms, as observed in previous studies, that the aza compounds are more favourable for σ1R binding than their oxa counterparts. The addition of the amine heterocycle showed affinities similar to that of related structures with only two lipophilic binding regions. This indicates that the inclusion of an amine heterocycle into these structures is a viable option in the design of new σ1R ligands. Significant voltage-gated calcium channel blocking ability was also observed for 12, 24 and 27, suggesting a link between σ1R activity and intracellular calcium levels.

Twenty-two novel genipin derivatives have been designed, synthesized, and evaluated for their inhibitory activity against acetylcholinesterase (AChE). As a result, compound 13a bearing ligustrazine moiety displayed the most potent AChE inhibitory activity in this series with IC50 value of 218?nm. Besides, MTT assay was performed to investigate the neuroprotection of these compounds against PC12 cells injured by Amyloid β-protein 1–42 (Aβ1–42). Among them, 8a showed higher inhibition rate (%Inhibition?=?22.29) than the positive reference Donepezil (%Inhibition?=?17.65).

A novel series of gardenamide A derivatives was synthesized as potential anti-Alzheimer's disease agents. The neuroprotective effects of these multifunctional agents against oxygen-glucose deprivation (OGD)-induced neurotoxicity in rat cortical neurons, and hydrogen peroxide (H2O2)- A nd amyloid-β1-42 (Aβ1-42)-induced neurotoxicity in rat hippocampal neurons were evaluated. In vitro studies revealed that these compounds demonstrated moderate to good multifunctional neuroprotective activity. Among the entire series, compounds 10e, 10j, 10n and 10p appeared to be the most active multifunctional neuroprotective agents. Studies indicate that compounds 10e, 10f, 10h, 10i, 10j, 10n and 10p exhibit significant activities against OGD-induced neurotoxicity in rat cortical neurons, and 10e, 10j, 10n and 10p show prominent activities against H2O2- A nd Aβ1-42-induced neurotoxicity in rat hippocampal neurons. Moreover, these derivatives did not exert conspicuous neurotoxicity in rat cortical neurons. Thus, the present study evidently shows that 10e, 10j, 10n and 10p are potent multifunctional neuroprotective agents, which may serve as promising lead candidates for anti-Alzheimer's disease drug development.

The present invention is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte. In additional embodiments, the (CRBM) is a moiety which binds to a receptor of other cells which can degrade proteins, such as a LRP1, LDLR, FcyRI, FcRN, Transferrin or Macrophage Scavenger receptor. Pharmaceutical compositions based upon these bifunctional small molecules represent an additional aspect of the present invention. These compounds and/or compositions may be used to treat disease states and conditions by removing circulating proteins through degradation in the hepatocytes or macrophages of a patient or subject in need of therapy. Methods of treating disease states and/or conditions in which circulating proteins are associated with the disease state and/or condition are also described herein.

Compound of formula (I′) or (I′′) or a pharmaceutically acceptable salt thereof. The compound is an inhibitor of mammalian kinase enzyme activity, including ROR1 tyrosine kinase activity and may be used in the treatment of disorders associated with such activity.

The invention relates to the field of medicinal chemistry, in particular to a gardenia amide A derivative (I), a preparation method and a medicine composition containing the derivative. Pharmacodynamic experiments prove that the compound has the function of serving as a nerve cell injury protector and can be used for treating neurodegenerative diseases, particularly treating or preventing senile dementia.

Given the widespread importance of piperazines as building blocks for the production of pharmaceuticals, an efficient and selective synthesis is highly desirable. Here we show the direct synthesis of piperazines from 1,2-dicarbonyl and 1,2-diamine substrates using the R-selective imine reductase from Myxococcus stipitatus as biocatalyst. Various N- and C-substituted piperazines with high activity and excellent enantioselectivity were obtained under mild reaction conditions reaching up to 8.1 g per liter.

The present invention relates to novel betulinic substituted amide compounds of formula (I); and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, X, Y, Z1, Z2, Z3 and are Formula (II) as defined herein. The invention novel betulinic substituted amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.

Signaling pathway inhibition of VEGFR-II is visualized as valuable tool in cancer management. In the current study, the synthesis of novel 1-4-(7-chloroquinolin-4-yl)piperazin-1-yl)-2-(N-substituted-amino)-ethanone derivatives (4a–t) was achieved through the amination of 2-chloro-1-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)ethanone (3) with different secondary amines. The structures of the target compounds were confirmed by IR, 1H-NMR, 13C-NMR, HRMS, and microanalysis. Compounds 4a–t were subjected to in vitro anticancer screening against human breast cancer (MCF-7) and prostate cancer (PC3) cell lines. The highest cytotoxicty against both cell lines was displayed by 2-(4-(4-bromobenzyl)piperazin-1-yl)-1-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)ethanone (4q), with IC50 values of 6.502 and 11.751 μM against MCF-7 and PC3 cells, respectively, compared with the standard drug doxorubicin (MCF-7: 6.774 μM, PC3: 7.7316 μM). Due to its notable activity toward MCF-7 cells, 4q was further evaluated as VEGFR-II inhibitor, showing an IC50 of 1.38 μM compared to sorafenib (0.33 μM). The docking study proved that 4q has a binding mode akin to that of VEGFR-II inhibitors.

A series of novel dimethylpyrazole and piperazine-containing (bis)1,2,4-triazole derivatives have been conveniently synthesized via Mannich reaction in good yields. Their structures were identified by IR,1H NMR,13C NMR, and elemental analysis. The preliminary bioassays showed that among 14 new compounds, the trifluoromethyl-containing compounds exhibited superior activity than the methyl-containing ones; some of the compounds displayed significant in vitro and in vivo fungicidal activity against several plant fungi and were comparable with the control Triadimefon; several compounds exhibited certain herbicidal activity against Brassica campestris; several compounds possessed favorable KARI inhibitory activity, especially 8D could be a promising KARI inhibitor for further study. The research results will provide useful information for the design and discovery of new agrochemicals with novel heterocyclic Mannich base structures containing piperazine moiety.

PROBLEM TO BE SOLVED: To provide a purification method of N-alkyl piperazines, capable of providing high purity N-alkyl piperazines with low cost and having a high recovery rate.SOLUTION: A mixture of N-alkyl piperazines and a piperazine is distilled in the presence of a polar organic solvent having a higher boiling point than that of the piperazine.

The title compound was readily prepared from 2, 3, 4, 5-tetramethoxytoluene via the Blanc reaction, oxidation, and alkylation. The described method provides a good yield of the heterocyclic substitute at the C-5 position of the Coenzyme Q homologue and is suitable for the synthesis of other homologues.

Metal homoenolates, produced via C-C bond cleavage of cyclopropanols, have been extensively investigated as nucleophiles for the synthesis of β-substituted carbonyl derivatives. Herein, we demonstrate that zinc homoenolates can react as carbonyl-electrophiles in the presence of nucleophilic amines to yield highly valuable trans-cyclopropylamines in good yields and high diastereoselectivities. GSK2879552, a lysine demethylase 1 inhibitor currently in clinical trials for the treatment of small cell lung carcinoma, was synthesized using this strategy.

Monoamine transporters regulate the concentration of monoamine neurotransmitters, which are essential for vital physiological processes, and their dysfunction can cause several central nervous system diseases. Monoamine transporters currently appear to be the potential target in the management of these disorders. In this study, homologation and bioisosterism techniques have been used in the designing of new 1,4-disubstituted piperazines and piperidines. These derivatives were synthesized and evaluated as potential triple reuptake inhibitors for studying the structure-activity relationships. The most advanced compound, 1-(4-(5-benzhydryl-1H-tetrazol-1-yl)butyl)-4-(3-phenylpropyl)piperazine (2i), was able to inhibit monoamine neurotransmitter reuptake in an in vitro test (IC50?=?158.7?nM for 5-HT, 99?nM for NE and 97.5?nM for DA). These novel potent triple reuptake inhibitor-based 1,4-disubstituted piperazine and piperidine scaffolds deserve further systematic optimization and pharmacological evaluation.

PROBLEM TO BE SOLVED: To provide a method for producing N-alkyl piperazines in high yield by selectively alkylating one amino group.SOLUTION: In the method for producing N-alkyl piperazines, piperazines represented by general formula (1) are reacted with a specific alkylating agent in the presence of an acid. In the formula: R-Rare each independently a hydrogen atom, a methyl group, an ethyl group, a 3-8C linear alkyl group or the like, a hydroxyethyl group, a hydroxypropyl group, a dihydroxypropyl group, a methoxy group, an ethoxy group, a phenyl group, a benzyl group, a 2-phenylethyl group, or the like.

The invention discloses a preparing method of an N-monosubstituted piperazine compound shown in the formula (6). Piperazine monohydrochloride (1) and RX or RCl react in solvent to prepare monosubstituted piperazine dihydrochloride (4) or (5), alkali is added for neutralizing, and the product (6) is obtained through rectification steaming.

An efficient two-step route was developed for the synthesis of 1-aralkyl-4-benzylpiperazine derivatives by a Blanc reaction and alkylation. The key intermediate, N-benzylpiperazine, was prepared in an excellent yield by direct benzylation of commercially available piperazine under metal-free conditions.

The present invention relates to a compound having a cardiotonic activating function and a pharmaceutical composition containing the same. The composition comprising the compound according to the present invention is effective in preventing or treating heart failure. In addition, the compound is represented by chemical formula 2 or is pharmaceutically acceptable salt thereof.COPYRIGHT KIPO 2016

A simplified Boc deprotection using a high-temperature flow reactor is described. The system afforded the qualitative yield of a wide variety of deprotected substrates within minutes using acetonitrile as the solvent and without the use of acidic conditions or additional workups. Highly efficient, multistep reaction sequences in flow are also demonstrated wherein no extraction or isolation was required between steps.

A series of novel phthalimide derivatives related to benzylpiperazine were synthesized and evaluated as cholinesterase inhibitors. The results showed that all compounds were able to inhibit acetylcholinesterase (AChE), with two of them dramatically inhibiting butyrylcholinesterase (BuChE). Most compounds exhibited potent anti-AChE activity in the range of nM concentrations. In particular, compounds 7aIII and 10a showed the most potent activity with the IC50 values of 18.44 nM and 13.58 nM, respectively. To understand the excellent activity of these compounds, the structure-activity relationship was further examined. The protein-ligand docking study demonstrated that the target compounds have special binding modes and these results are in agreement with the kinetic study.

A series of novel 1,2,4-triazole thione derivatives containing 1,2,3-triazole and substituted piperazine moieties were synthesized via the Mannich reaction of 1,2,3-triazole-containing 1,2,4-triazole thiol intermediates with various substituted piperazines and formaldehyde in high yields. The structures of 14 title compounds were confirmed by melting points, IR, 1H NMR, 13C NMR, and elemental analysis. The bioassay results showed that some of the title compounds exhibit significant fungicidal activities against several plant fungi at 50 μg/mL, especially trifluoromethyl-containing triazole thione derivative 9g showed broad activities and could be made further structural optimization for novel fungicides innovation research.

A series of novel carboxamide compounds 19a-19j, 20a-20j and 22a-22d containing piperazine and arylsulfonyl moieties have been synthesized. The bioassay results showed that some compounds exhibited favorable herbicidal activities against dicotyledonous plants and many of them possessed excellent antifungal activities. Among 24 novel compounds, some showed superiority over the commercial fungicides Chlorothalonil, Dimethomorph, Thiophanate-methyl, Iprodione, and Zhongshengmycin at 500 mg/L concentration. Some compounds also exhibited high KARI inhibitory activity at 100 γ1/4g/mL concentration and could be used as new KARI lead inhibitors for further studies. Moreover, SAR of these new compounds were comprehensively investigated using different computational methods in which 3D-QSAR model obtained provided useful information for further structural optimization for the discovery of new fungicides. The results of this research will contribute to explore comprehensive biological activities of piperazine-containing compounds in different areas of chemistry.

A series of novel 1,2,4-triazole thione and bis(1,2,4-triazole thione) derivatives containing phenylpyrazole and substituted piperazine moieties have been conveniently synthesized via Mannich reaction using various 1,2,4-triazole thiols, substituted piperazines, and formaldehyde at room temperature in short time. Their structures were confirmed by IR, 1H NMR, 13C NMR and elemental analysis. The preliminary bioassays for 27 new title compounds have shown that some of them possess certain herbicidal activities against Echinochloa crusgalli at 100 μg/mL concentration. Some of the compounds exhibited significant in vitro fungicidal activities, especially against Cercospora arachidicola and Rhizoctonia cerealis at the concentration of 50 μg/mL, and were comparable with that of control Triadimefon. Meanwhile, IXp held the control efficacy of 60% against Puccinia sorghi Schw. at 200 μg/mL concentration in the in vivo test. The SAR analysis has indicated that compounds with two CF3 groups both on triazole and pyrazole rings are more effective than compounds with one CF3 group or two CH3 groups according to their fungicidal activity data. On the whole, compounds VIIIg, IXi, IXo and IXp could be used as novel lead structures for the design and discovery of new fungicides.

Cinnarizine, cyclizine, buclizine, and meclizine belong to a family of antihistamines that resemble each other in terms of a 1-diphenylmethylpiperazine moiety. We present the development of a four-step continuous process to generate the final antihistamines from bulk alcohols as the starting compounds. HCl is used to synthesize the intermediate chlorides in a short reaction time and excellent yields. This methodology offers an excellent way to synthesize intermediates to be used in drug synthesis. Inline separation allows the collection of pure products and their immediate consumption in the following steps. Overall isolated yields for cinnarizine, cyclizine, and a buclizine derivative are 82, 94, and 87 %, respectively. The total residence time for the four steps is 90 min with a productivity of 2 mmol h-1. The incredible bulk: Bulk alcohols are converted continuously into chlorides using HCl in a microflow. A reaction network that consists of four steps and two inline separations leads to the continuous preparation of cinnarizine, cyclizine, and a buclizine derivative with yields of 82, 94, and 87 %, respectively. The total residence time for the four steps is 90 min with a productivity of 2 mmol h-1.

A new strategy for the efficient synthesis of C-5 heterocyclyl substituted Coenzyme Q analogues was developed by N-alkylation of bromomethylated quinone 11 with a series of amines 12 under metal-free conditions. In vitro antioxidant activities of these Coenzyme Q analogues were evaluated and compared with commercial antioxidant Coenzyme Q10 by employing DPPH assay. All these N-heterocyclyl substituted Coenzyme Q analogues are found to be exhibiting good antioxidant properties and may be used as potent antioxidants for combating oxidative stress.

CdS-1 (nanosphers) and CdS-2 (nanocapsule), were synthesized via green synthetic route without using any toxic surfactants by thermolysis of bis(4-benzhydrylpiperazine-1-carbodithioate-κ2 S, S?)cadmium(II) (1) and bis (4-benzylpipera-zine-1-carbodithioate-κ2 S, S?)cadmium(II) (2), respectively in the presence of ethylenediamine as a solvent. The nanoparticles were characterized by TEM, XRD, SEM, FT-IR UV–Visible and Fluorescence spectroscopy. The TEM results showed the formation of nanospheres (CdS-1) and nanocapsules (CdS-2) from complexes 1 and 2, respectively. Both CdS nanoparticles (NPs) have hexagonal crystal phase and a band gap value in the visible region as confirmed by the XRD and UV–Visible spectra, respectively. The photoluminescence (PL) data revealed that CdS-2 has longer recombination time of photo-injected electron hole pairs than CdS-1. The similar FT-IR spectra for both CdS NPs, and different HOMO-LUMO gap values for complexes {4.8187?eV (1) and CdS-2 4.7504?eV (2)} as predicted by DFT calculations suggest that stability of complexes play a key role in controlling morphology. Furthermore, the visible light driven photocatalytic degradation of Congo red dye was observed higher for nanocapsules than nanospheres due to a longer recombination time of photo-injected electron hole pairs.

A series of chromones, bearing substituted amino groups or N-substituted carboxamide moieties in position 2, was synthesized and characterized in cellular assays for modulation of the ABC transporters ABCC1 (MDCKII-MRP1 cells), ABCB1 (Kb-V1 cells) and ABCG2 (MCF-7/Topo cells). The most potent ABCC1 modulators identified among these flavonoid-type compounds were comparable to the reference compound reversan regarding potency, but superior in terms of selectivity concerning ABCB1 and ABCG2 (2-[4-(Benzo[c][1,2,5]oxadiazol-5-ylmethyl)piperazin-1-yl]-5,7-dimethoxy-4H-chromen-4-one (51): ABCC1, IC50 11.3-1/4M; inactive at ABCB1 and ABCG2). Compound 51 was as effective as reversan in reverting ABCC1-mediated resistance to cytostatics in MDCKII-MRP1 cells and proved to be stable in mouse plasma and cell culture medium. Modulators, such as compound 51, are of potential value as pharmacological tools for the investigation of the (patho)physiological role of ABCC1.

Disclosed are a compound having cardiotonic activity and a pharmaceutical composition containing the same, and the composition containing the compound, according to the present invention, is useful for preventing and treating heart failure.COPYRIGHT KIPO 2016

Series of novel furan/thiophene and piperazine-containing 1,2,4-triazole Mannich bases and bis(1,2,4-triazole) Mannich bases have been conveniently synthesized via Mannich reaction with triazole Schiff bases, various piperazine derivatives, and formaldehyde as intermediates in good yields. Their structures were characterized by melting points, 1H NMR, 13C NMR, IR and elemental analysis. The preliminary bioassay showed that most compounds exhibited significant in vitro and in vivo fungicidal activity against several test plant fungi. Among 32 new compounds, the trifluoromethyl-containing compounds showed superior activity than the methyl-containing ones. Several compounds, such as F8, F9, F10, G5, H7, H8, I3 and I4, were comparable with some commercial fungicides against different fungi during the present study and could be further structurally optimized. Meanwhile, several compounds showed good herbicidal activity against Brassica campestris at 100 μg/mL and KARI inhibitory activity at 200 μg/mL. However, compounds exhibited poor insecticidal activity against oriental armyworm at 200 μg/mL in the preliminary studies. The research results will provide useful information for the design and discovery of new agrochemicals with novel heterocyclic structures.

(A.H.); Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder characterized by memory loss, language impairment, personality changes and intellectual decline. Taking into account the key pathological features of AD, such as low levels of acetylcholine, beta-amyloid (Aβ) aggregation, oxidative stress and dyshomeostasis of biometals, a new series of paeonol derivatives 5a-5d merging three different functions, i.e., antioxidant, anti-acetylcholinesterase (AChE) activity, metal chelating agents for AD treatment have been synthesized and characterized. Biological assays revealed that compared with paeonol (309.7 μM), 5a-5d had a lower DPPH IC50 value (142.8-191.6 μM). 5a-5d could significantly inhibit hydrogen peroxide-induced neuronal PC12 cell death assessed by MTT assay in the concentration range of 5-40 μM. AChE activity was effectively inhibited by 5a-5d, with IC50 values in the range of 0.61-7.04 μM. 5a-5d also exhibited good metal-chelating ability. All the above results suggested that paeonol derivatives may be promising multifunctional agents for AD treatment.

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The catalytic activity of Al grafted MCM-41 (Al-MS) was explored for solvent free acid catalysed direct N-alkylation of amines using alcohols as green alkylating agent to establish a clean method for synthesis of N-alkylated amines. The study revealed that acidity of Al-MS catalyst, reaction conditions and substrate's (amines and alcohols) nature are important factors influencing the N-alkylation reaction. The Al grafted MCM-41 with Si/Al molar ratio of 5 showed excellent activity for N-alkylation of amines with alcohols. The reusability of spent catalyst regenerated by simple washing with acetone was demonstrated for subsequent four reaction cycles.

New Co-Schiff base complexes that incorporate a sterically hindered ligand and an intramolecular bulky piperazine base in close proximity to the Co center are synthesized. Their utility as catalysts for the oxidation of para-substituted lignin model phenols with molecular oxygen is examined. Syringyl and guaiacyl alcohol, as models of S and G units in lignin, are oxidized in good yield using a catalyst bearing an N-benzylpiperazinyl substituent, with the catalysts displaying improved reactivity for G oxidation. Computational evaluation of the catalysts shows that the piperazinyl substituent is within bonding distance of the Co center. The increased steric interference is suggested as the source of increased G reactivity. This journal is the Partner Organisations 2014.

An efficient, one-pot, two-step reductive amination of alkenes through tandem ozonolysis using ammonia-borane as a reducing agent is described. The reaction has been carried out in water. This is a highly efficient and mild procedure that is applicable to a wide variety of amine substrates. In particular, this is the first successful manifestation that this type of reaction can be carried out in water with ammonia-borane.

This study presents the synthesis and biological evaluation of a new series of arylalkyl/arylalkylsulfonyl piperazine and piperidine-based derivatives as sigma receptor ligands. It was found that a number of halogen substituted sulfonamides display relatively high and low affinities to σ1 and σ2 receptors, respectively. The σ1 affinities and subtype selectivities of four piperidine derivatives were also found to be generally comparable to those of piperazine analogues. Compared to σ1-Rs compounds with n = 0 and 2, those with n = 1 proved to have optimal length of carbon chain by exhibiting higher affinities. Within this series, the 4-benzyl-1-(3-iodobenzylsulfonyl)piperidine sigma ligand was identified with 96-fold σ1/σ2 selectivity ratio (Kiσ1 = 0.96 ± 0.05 nM and K iσ2 = 91.8 ± 8.1 nM).

Phenolic lignin model monomers and dimers representing the primary substructural units of lignin were successfully oxidized to benzoquinones in high yield with molecular oxygen using new Co-Schiff base catalysts bearing a bulky heterocyclic nitrogen base as a substituent. This is the first example of a catalytic system able to convert both S and G lignin model phenols in high yield, a process necessary for effective use of lignin as a chemical feedstock.

A compound represented by the following general formula (I): [wherein R1 and R2 represent a C1-6 alkyl group; R3, R4 and R5 represent hydrogen atom, a C1-6 alkyl group, or an aryl group; Y1 and Y2 represent —O—, —S—, —Se—, —CH═CH—, —C(R6)(R7)—, or —N(R8)— (wherein R6, R7 and R8 represent hydrogen atom or a C1-6 alkyl group); A represents a C1-3 alkylene group; n and n′ represent 0, 1 or 2; Z1 and Z2 represent a nonmetallic atom group required to form a benzo-condensed ring or a naphtho-condensed ring; L1 to L7 represent a methine group; and M? represents a counter ion in a number required for neutralizing electrical charge], which is useful as a fluorescent probe of which optical characteristics change depending on pH change.

A series of novel 1,4-disubstituted piperidine/piperazine derivatives were designed, synthesized and evaluated for their in vitro activities against HIV-1 Bal (R5) infection in CEMX174 5.25M7 cells. A majority of these compounds showed potent anti-HIV-1 activities with IC50 at nanomolar levels. N-(4-Fluoro-benzyl)piperazine analog B07 hydrochloride exhibited potency against HIV-1 activity similar to that of TAK-220 hydrochloride, but it had much better water solubility (25 mg/ml in phosphate sodium buffer at 25 °C) and oral bioavailability (56%) than TAK-220 hydrochloride (a solubility of 2 mg/ml and oral bioavailability of 1.4%). These results suggest that B07 hydrochloride may serve as a better lead for the development of new anti-HIV-1 therapies or microbicides for treatment and prevent of HIV-1 infection.