Evaluation of Piperine as Natural Coformer for Eutectics Preparation of Drugs Used in the Treatment of Cardiovascular Diseases.

Piperine (PIP) was evaluated as a natural coformer in the preparation of multicomponent organic materials for enhancing solubility and dissolution rate of the poorly water-soluble drugs: curcumin (CUR), lovastatin (LOV), and irbesartan (IBS). A screening based on liquid assisted grinding technique was performed using 1:1 drug-PIP molar ratio mixtures, followed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) analyses. Three eutectic mixtures (EMs) composed of CUR-PIP, LOV-PIP, and IBS-PIP were obtained. Therefore, binary phase and Tamman's diagrams were constructed for each system to obtain the exact eutectic composition, which was 0.41:0.59, 0.29:0.71, and 0.31:0.69 for CUR-PIP, LOV-PIP, and IBS-PIP, respectively. Further, bulk materials of each system were prepared to characterize them through DSC, PXRD fully, Fourier transform infrared spectroscopy (FT-IR), and solution-state nuclear magnetic resonance (NMR) spectroscopy. In addition, the contact angle, solubility, and dissolution rate of each system were evaluated. The preserved characteristic in the PXRD patterns and FT-IR spectra of the bulk material of each system confirmed the formation of EM mixture without molecular interaction in solid-state. The formation of EM resulted in improved aqueous solubility and dissolution rate associated with the increased wettability observed by the decrease in contact angle. In addition, solution NMR analyses of CUR-PIP, LOV-PIP, and IBS-PIP suggested no significant intermolecular interactions in solution between the components of the EM. Hence, this study concludes that PIP could be an effective coformer to improve the solubility and dissolution rate of CUR, LOV, and IBS.

Angiogenesis-Inhibitory Piperidine Alkaloids from the Leaves of Microcos paniculata.

Eight new 2,6-disubstituted piperidin-3-ol alkaloids (1-8), featuring a C10 unsaturated alkyl side chain, together with three previously reported analogues (9-11) were isolated from the leaves of medicinal plant Microcos paniculata. Their structures and absolute configurations were elucidated unambiguously by means of 1D and 2D NMR spectroscopic data analysis, modified Mosher's method, Snatzke's method, and quantum chemical electronic circular dichroism (ECD) calculations, as well as single-crystal X-ray crystallography. The isolates were evaluated for their antiangiogenic effects on human umbilical vein endothelial cells (HUVECs). Compound 2 displayed an inhibitory effect on tube formation of HUVECs in a concentration-dependent manner.

A Review of Chemistry and Pharmacology of Piperidine Alkaloids of Pinus and Related Genera.

BACKGROUND: Pinus belongs to the family Pinaceae, represented by several species across the globe. Various parts of the plant including needles are rich in biologically active compounds, such as thunbergol, 3-carene, cembrene, α-pinene, quercetin, xanthone. Of all the alkaloids, the piperidine group is one of the important component and holds considerable medicinal importance. METHODS: The group of alkaloids was initially identified from the genus Piper through which a large variety of piperidine molecules have been extracted. The planar structure of this heterocyclic nucleus enables acetamide groups to be added at various ring configurations. RESULTS: Piperidines have gained considerable importance. The broad range of its therapeutic application has paved a way for researchers to implant the nucleus from time to time in diversified pharmacophores and establish new profile. DISCUSSION: Biological functions of piperidine metabolites have been mostly examined on a limited scale, and that most of the findings are preliminary. We have tried to present various clinical applications of piperidine alkaloids in this study that researchers have already attempted to demystify with time. CONCLUSION: We have also illustrated different types of piperidine structures and their sources in different members of the family Pinaceae with special emphasis on Pinus. Given the importance of the piperidine nucleus, the study will enable the researchers to produce scaffolds of highest therapeutic efficacy.

In vivo screening and toxicity studies of indolinone incorporated thiosemicarbazone, thiazole and piperidinosulfonyl moieties as anticonvulsant agents.

Based on the biological importance of the thiazole nucleus, we decided to prepare and evaluate the biological activity of some new isatin derivatives containing thiazole moiety. The 5-(piperidin-1-ylsulfonyl)indoline-2,3-dione (1) was prepared and used as a starting material in the synthesis of many isatin derivatives for anticonvulsant evaluation. All the newly synthesized thiazlidino/thiosemicarbazide-indolin-2-one derivatives screened in vivo for their anticonvulsant activity against pentylenetetrazole-induced convulsions in mice. The results were compared with phenobarbitone sodium as a standard anticonvulsant drug. Most of the tested compounds exhibited anticonvulsant activity with relative potency ranging from 0.02 to 0.2 in comparison to standard drug phenobarbitone. The most active compounds 3, 6a, 6c and 8, were exposed to further investigations in rats to evaluate the effect of most active derivatives on the haematological, liver, kidney functions as well as histopathological studies of the liver and kidney tissues. Finally, the most potent compounds 3, 6a, 6c and 8 observed good toxic properties for both liver and kidney function with mild variability changes on RBCs, WBCs, Platelets, Hb, AST, ALT, and creatinine level, as well as kidney and liver tissue and these good results obtained rather than used low dose from phenobarbitone.

The piperine derivative HJ105 inhibits Aß1-42-induced neuroinflammation and oxidative damage via the Keap1-Nrf2-TXNIP axis.

BACKGROUND: Piperine is a great lead compound, as a phytopharmaceutical with reported neuroprotective effects in neurodegenerative diseases. HJ105, a piperine derivative with high affinity to Keap1 receptor, attracts increasing attention in Alzheimer's disease (AD) treatment. PURPOSE: This work mainly aimed to study HJ105's therapeutic effects on Aß1-42-associated AD and the underpinning mechanisms. METHODS: In the in vivo part, a rat model of AD was established by bilateral intra-hippocampal administration of aggregated Aß1-42, followed by a month of intragastric HJ105 or donepezil administration. Spatial and learning memories were detected by the Morris water maze assay, passive avoidance learning as well as Y-maze test. The morphology of hippocampal neurons was assessed by hematoxylin-eosin (H&E) staining. In addition, the amounts of the IL-1ß and TNF-α were obtained with specific ELISA kits. More importantly, apoptosis-related proteins and factors involved in Nrf2/TXNIP/NLPR3 pathways were detected by Western blot, while the interaction between Keap1 and Nrf2 was assessed by co-immunoprecipitation. In the in vitro part, human neuroblastoma (SH-SY5Y) cells were applied to evaluate the role of HJ105 on Aß1-42-induced neuronal damage. RESULTS: Treatment of HJ105 not only reversed memory impairment, but also protected neurons in the hippocampus by inhibiting Bax/Bcl2 ratio increase. HJ105 decreased TXNIP expression, suppressing NLRP3 inflammasome activation in the hippocampus, which in turn counteracted the upregulation of IL-1ß and TNF-α. Notably, HJ105 exerted an inhibitory effect on Keap1-Nrf2 interaction and upregulated nuclear Nrf2, which conversely increased the expression levels of superoxide dismutase, catalase and glutathione peroxidase and downregulated malondialdehyde. Additionally, neurotoxicity induced by Aß1-42 in SH-SY5Y cells was alleviated by HJ105. CONCLUSION: Overall, HJ105 exerts neuroprotective effects in SH-SY5Y cells induced by Aß1-42 as well as in experimental rats with AD by decreasing apoptosis, oxidative stress and neuroinflammation, partly via suppression of Keap1-Nrf2 complex generation. HJ105 might represent a promising compound for AD treatment.

Nucleotide analogues containing a pyrrolidine, piperidine or piperazine ring: Synthesis and evaluation of inhibition of plasmodial and human 6-oxopurine phosphoribosyltransferases and in vitro antimalarial activity.

Parasites of the Plasmodium genus are unable to produce purine nucleotides de novo and depend completely on the salvage pathway. This fact makes plasmodial hypoxanthine-guanine-(xanthine) phosphoribosyltransferase [HG(X)PRT] a valuable target for development of antimalarial agents. A series of nucleotide analogues was designed, synthesized and evaluated as potential inhibitors of Plasmodium falciparum HGXPRT, P. vivax HGPRT and human HGPRT. These novel nucleoside phosphonates have a pyrrolidine, piperidine or piperazine ring incorporated into the linker connecting the purine base to a phosphonate group(s) and exhibited a broad range of Ki values between 0.15 and 72 µM. The corresponding phosphoramidate prodrugs, able to cross cell membranes, have been synthesized and evaluated in a P. falciparum infected human erythrocyte assay. Of the eight prodrugs evaluated seven exhibited in vitro antimalarial activity with IC50 values within the range of 2.5-12.1 µM. The bis-phosphoramidate prodrug 13a with a mean (SD) IC50 of 2.5 ± 0.7 µM against the chloroquine-resistant P. falciparum W2 strain exhibited low cytotoxicity in the human hepatocellular liver carcinoma (HepG2) and normal human dermal fibroblasts (NHDF) cell lines at a concentration of 100 µM suggesting good selectivity for further structure-activity relationship investigations.

Preparative separation of two isomeric antimalaria alkaloids febrifugine and isofebrifugine from Dichroa febrifuga roots by countercurrent chromatography.

Two antimalaria alkaloids, febrifugine and isofebrifugine, were successfully separated from total alkaloids of Dichroa febrifuga roots by one-step preparative countercurrent chromatography with a selected biphasic solvent system. The selected biphasic solvent system was composed of chloroform: methanol: water (2:1:1, v/v) according to partition performance of the two target components. Selection of biphasic solvent system was conducted by high performance liquid chromatography combined with high performance thin layer chromatography, which greatly assisted the screening procedure for biphasic solvent system. Totally, 50 mg of total alkaloid was separated by one-step preparative countercurrent chromatography, yielding 12 mg of febrifugine and 9 mg of isofebrifugine with more than 98.0% purity, respectively.

Discovery of an Allosteric Ligand Binding Site in SMYD3 Lysine Methyltransferase.

SMYD3 is a multifunctional epigenetic enzyme with lysine methyltransferase activity and various interaction partners. It is implicated in the pathophysiology of cancers but with an unclear mechanism. To discover tool compounds for clarifying its biochemistry and potential as a therapeutic target, a set of drug-like compounds was screened in a biosensor-based competition assay. Diperodon was identified as an allosteric ligand; its R and S enantiomers were isolated, and their affinities to SMYD3 were determined (KD =42 and 84 µM, respectively). Co-crystallization revealed that both enantiomers bind to a previously unidentified allosteric site in the C-terminal protein binding domain, consistent with its weak inhibitory effect. No competition between diperodon and HSP90 (a known SMYD3 interaction partner) was observed although SMYD3-HSP90 binding was confirmed (KD =13 µM). Diperodon clearly represents a novel starting point for the design of tool compounds interacting with a druggable allosteric site, suitable for the exploration of noncatalytic SMYD3 functions and therapeutics with new mechanisms of action.

Pharmacokinetics and Pharmacodynamic Herb-Drug Interaction of Piperine with Atorvastatin in Rats.

Herbals that are widely consumed as therapeutic alternatives to conventional drugs for cardiovascular diseases, may lead to herb-drug interactions (HDIs). Atorvastatin (ATR) is drug of choice for hyperlipidemia and is extensively metabolized through CYP3A4 enzyme. Thus, we postulate that concomitant administration of ATR with piperine (PIP, potent inhibitor of CYP3A4 enzyme)/ridayarishta (RID, cardiotonic herbal formulations containing PIP) may lead to potential HDI. A simple, accurate, sensitive high-performance liquid chromatography-photodiode array detection method using Kromasil-100 C18 column, mobile phase acetonitrile: 30 mM phosphate buffer (55:45 v/v) pH 4.5 with flow rate gradient programming was developed to study the potential HDI in rats. Method was found to be linear (2-100 ng/mL) with Lower Limit of Detection (LLOD) 2 ng/mL. The precision (%CV < 15%), accuracy (-1.0 to -10% R.E) with recoveries above 90% from rat plasma of ATR and IS were obtained. The pharmacokinetic (PK) interactions studies on co-administration of ATR (8.4 mg/kg, p.o.) with PIP (35 mg/kg, p.o.), demonstrated a threefold increase in Cmax of ATR (P < 0.01) with significant increase in AUC0-t/AUC0-∞ compared to ATR alone indicating potential PK-HDI. However co-administration of RID (4.2 mL/kg, p.o.) showed less significant changes (P > 0.05) indicating low HDI. The pharmacodynamic effects/interactions study (TritonX-100 induced hyperlipidemic model in rats) suggested no significant alterations in the lipid profile on co-administration of PIP/RID with ATR, indicating that there may be no significant pharmacodynamic interactions.

Effects of Desilication in NaOH/Piperidine Medium and Phosphorus Modification on the Catalytic Activity of HZSM-5 Catalyst in Methanol to Propylene Conversion.

BACKGROUND: Propylene is one of the main petrochemical building blocks applied as a feedstock for various chemical and polymer intermediates. The methanol-to-propylene (MTP) processes are reliable options for propylene production from non-petroleum resources. The highsilica ZSM-5 zeolite is found to be a reliable candidate for the methanol to propylene catalysis. OBJECTIVE: In this study, the mesoporosity was first introduced into a high silica ZSM-5 zeolite via an alkaline treatment by NaOH solution with piperidine to decrease the diffusion limitation, and then the structure of zeolite was stabilized by phosphorus modification to improve the acidic properties and to enhance the catalyst stability. METHODS: High-silica H-ZSM-5 catalysts (Si/Al = 200) were successfully prepared through microwave-assisted hydrothermal technique in the presence of tetrapropyl ammonium hydroxide (TPAOH) structure-directing agent. The mesoporosity was efficiently introduced into the ZSM-5 crystals via desilication derived from alkaline NaOH/piperidine solution. Then, the acidity of the desilicated ZSM-5 samples was improved using phosphorus modification. The catalysts were subjected to XRD, ICP-OES, FE-SEM, BET, TGA, FT-IR and NH3-TPD analysis. RESULTS: The catalytic performance of the prepared catalysts in the methanol to propylene (MTP) reaction was examined in a fixed-bed reactor at 475 °C, atmospheric pressure and methanol WHSV of 0.9 h-1. The results showed that the alkaline treatment in NaOH/piperidine solution created uniform mesoporosity with no severe damage in the crystal structure. Similarly, phosphorus modification developed the acidic features and led to the optimal catalytic efficiency in terms of the maximum propylene selectivity (49.16%) and P/E ratio (5.97) as well as the catalyst lifetime. CONCLUSION: The results showed an excellent catalytic activity in terms of 99.21% methanol conversion, good propylene selectivity up to 49.16%, a high ratio of P/E of 5.97 and a low selectivity to C5 + hydrocarbons of 11.57% for ZS-D-PI-P sample.

Overcoming vincristine resistance in cancer: Computational design and discovery of piperine-inspired P-glycoprotein inhibitors.

P-glycoprotein (P-gp)/MDR-1 plays a major role in the development of multidrug resistance (MDR) by pumping the chemotherapeutic drugs out of the cancer cells and reducing their efficacy. A number of P-gp inhibitors were reported to reverse the MDR when co-administered with chemotherapeutic drugs. Unfortunately, none has approved for clinical use due to toxicity issues. Some of the P-gp inhibitors tested in the clinics are reported to have cross-reactivity with CYP450 drug-metabolizing enzymes, resulting in unpredictable pharmacokinetics and toxicity of co-administered chemotherapeutic drugs. In this study, two piperine analogs (3 and 4) having lower cross-reactivity with CYP3A4 drug-metabolizing enzyme are identified as P-glycoprotein (P-gp) inhibitors through computational design, followed by synthesis and testing in MDR cancer cell lines over-expressing P-gp (KB ChR 8-5, SW480-VCR, and HCT-15). Both the analogs significantly increased the vincristine efficacy in MDR cancer cell lines at low micromole concentrations. Specifically, 3 caused complete reversal of vincristine resistance in KB ChR 8-5 cells and found to act as competitive inhibitor of P-gp as well as potentiated the vincristine-induced NF-KB-mediated apoptosis. Therefore, 3 ((2E,4E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-(4-hydroxy-3-methoxyphenyl)penta-2,4-dien-1-one) can serve as a potential P-gp inhibitor for in vivo investigations, to reverse multidrug resistance in cancer.

Discovery of the Potent, Selective, Orally Available CXCR7 Antagonist ACT-1004-1239.

The chemokine receptor CXCR7, also known as ACKR3, is a seven-transmembrane G-protein-coupled receptor (GPCR) involved in various pathologies such as neurological diseases, autoimmune diseases, and cancers. By binding and scavenging the chemokines CXCL11 and CXCL12, CXCR7 regulates their extracellular levels. From an original high-throughput screening campaign emerged hit 3 among others. The hit-to-lead optimization led to the discovery of a novel chemotype series exemplified by the trans racemic compound 11i. This series provided CXCR7 antagonists that block CXCL11- and CXCL12-induced ß-arrestin recruitment. Further structural modifications on the trisubstituted piperidine scaffold of 11i yielded compounds with high CXCR7 antagonistic activities and balanced ADMET properties. The effort described herein culminated in the discovery of ACT-1004-1239 (28f). Biological characterization of ACT-1004-1239 demonstrated that it is a potent, insurmountable antagonist. Oral administration of ACT-1004-1239 in mice up to 100 mg/kg led to a dose-dependent increase of plasma CXCL12 concentration.

Hydroxypropyl-ß-cyclodextrin as an effective carrier of curcumin - piperine nutraceutical system with improved enzyme inhibition properties.

The nutraceutical system of curcumin-piperine in 2-hydroxypropyl-ß-cyclodextrin was prepared by using the kneading technique. Interactions between the components of the system were defined by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR). Application of hydroxypropyl-ß-cyclodextrin as a carrier-solubiliser improved solubility of the curcumin-piperine system, its permeability through biological membranes (gastrointestinal tract, blood-brain barrier) as well as the antioxidant, antimicrobial and enzyme inhibitory activities against acetylcholinesterase and butyrylcholinesterase.

Iron and Physical Activity: Bioavailability Enhancers, Properties of Black Pepper (Bioperine®) and Potential Applications.

Black pepper (Piper nigrum L.) has been employed in medicine (epilepsy, headaches, and diabetes), where its effects are mainly attributed to a nitrogen alkaloid called piperidine (1-(1-[1,3-benzodioxol-5-yl]-1-oxo-2,4 pentenyl) piperidine). Piperine co-administered with vitamins and minerals has improved its absorption. Therefore, this study aimed to describe the impact of the joint administration of iron (Fe) plus black pepper in physically active healthy individuals. Fe is a micronutrient that aids athletic performance by influencing the physiological functions involved in endurance sports by improving the transport, storage, and utilization of oxygen. Consequently, athletes have risk factors for Fe depletion, Fe deficiency, and eventually, anemia, mainly from mechanical hemolysis, gastrointestinal disturbances, and loss of Fe through excessive sweating. Declines in Fe stores have been reported to negatively alter physical capacities such as aerobic capacity, strength, and skeletal muscle recovery in elite athletes. Thus, there is a need to maintain Fe storage, even if Fe intake meets the recommended daily allowance (RDA), and Fe supplementation may be justified in physically active individuals, in states of Fe deficiency, with or without anemia. Females, in particular, should monitor their Fe hematological profile. The recommended oral Fe supplements are ferrous or ferric salts, sulfate, fumarate, and gluconate. These preparations constitute the first line of treatment; however, the high doses administered have gastrointestinal side effects that reduce tolerance and adherence to treatment. Thus, a strategy to counteract these adverse effects is to improve the bioavailability of Fe. Therefore, piperine may benefit the absorption of Fe through its bioavailability enhancement properties. Three research studies of Fe associated with black pepper have reported improvements in parameters related to the metabolism of Fe, without adverse effects. Although more research is needed, this could represent an advance in oral Fe supplementation for physically active individuals.

Solubility Data of the Bioactive Compound Piperine in (Transcutol + Water) Mixtures: Computational Modeling, Hansen Solubility Parameters and Mixing Thermodynamic Parameters.

The solubility values and thermodynamic parameters of a natural phytomedicine/nutrient piperine (PPN) in Transcutol-HP (THP) + water combinations were determined. The mole fraction solubilities (xe) of PPN in THP + water combinations were recorded at T = 298.2-318.2 K and p = 0.1 MPa by the shake flask method. Hansen solubility parameters (HSPs) of PPN, pure THP, pure water and THP + water mixtures free of PPN were also computed. The xe values of PPN were correlated well with "Apelblat, Van't Hoff, Yalkowsky-Roseman, Jouyban-Acree and Jouyban-Acree-Van't Hoff" models with root mean square deviations of < 2.0%. The maximum and minimum xe value of PPN was found in pure THP (9.10 × 10-2 at T = 318.2 K) and pure water (1.03 × 10-5 at T = 298.2 K), respectively. In addition, HSP of PPN was observed more closed with that of pure THP. The thermodynamic parameters of PPN were obtained using the activity coefficient model. The results showed an endothermic dissolution of PPN at m = 0.6-1.0 in comparison to other THP + water combinations studied. In addition, PPN dissolution was recorded as entropy-driven at m = 0.8-1.0 compared with other THP + water mixtures evaluated.

The role of Piper chaba Hunt. and its pure compound, piperine, on TRPV1 activation and adjuvant effect.

BACKGROUND: Piper chaba Hunt. is used as an ingredient in Thai traditional preparation for arthritis. Its isolated compound is piperine which shows anti-inflammatory activity. Piperine produces a burning sensation because it activates TRPV1 receptor. The TRPV1 activation involved with the analgesic and adjuvant effect. P. chaba Hunt. has not been reported about TRPV1 activation and adjuvant effect. The aim of this study was to investigate the effect of P. chaba extract and piperine on TRPV1 receptor, which is considered as a target for analgesic and their adjuvant effects to support the development of an analgesic drug from herbal medicine. METHODS: The effect of P. chaba extract and piperine on HEK cells expressing TRPV1 channel was examined by calcium imaging assay. Adjuvant effects of P. chaba extract and piperine were investigated by a fluorescein isothiocyanate (FITC)-induced contact hypersensitivity (CHS) model in mice. RESULTS: P. chaba extract induced calcium influx with EC50 value of 0.67 µg/ml. Piperine induced calcium influx with EC50 value of 0.31 µg/ml or 1.08 µM. For mouse CHS model, we found that 1% piperine, 5% piperine, 1% P. chaba extract and 5% P. chaba extract significantly enhanced sensitization to FITC as revealed by ear swelling responses. CONCLUSION: P. chaba extract and piperine activated TRPV1 channel and enhanced contact sensitization to FITC.

Discovery and structure-activity relationships study of positive allosteric modulators of the M3 muscarinic acetylcholine receptor.

The M3 muscarinic acetylcholine receptor (mAChR) is a member of the family of mAChRs, which are associated with a variety of physiological functions including the contraction of various smooth muscle tissues, stimulation of glandular secretion, and regulation of a range of cholinergic processes in the central nerve system. We report here the discovery and a comprehensive structure--activity relationships (SARs) study of novel positive allosteric modulators (PAMs) of the M3 mAChR through a high throughput screening (HTS) campaign. Compound 9 exhibited potent in vitro PAM activity towards the M3 mAChR and significant enhancement of muscle contraction in a concentration-dependent manner when applied to isolated smooth muscle strips of rat bladder. Compound 9 also showed excellent subtype selectivity over other subtypes of mAChRs including M1, M2, and M4 mAChRs, and moderate selectivity over the M5 mAChR, indicating that compound 9 is an M3-preferring M3/M5 dual PAM. Moreover, compound 9 displayed acceptable pharmacokinetics profiles after oral dosing to rats. These results suggest that compound 9 may be a promising chemical probe for the M3 mAChR for further investigation of its pharmacological function both in vitro and in vivo.

Discovery of Aryl Formyl Piperidine Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase Inhibitors.

Most of the current monoacylglycerol lipase (MAGL) inhibitors function by an irreversible mechanism of action, causing a series of side effects. Herein, starting from irreversible inhibitors, 25 compounds were synthesized and evaluated in vitro for MAGL inhibition, among which, compound 36 showed the most potent inhibitory activity (IC50 = 15 nM). Crucially, docking studies demonstrated that the m-chlorine-substituted aniline fragment occupied a hydrophobic subpocket enclosed by side chains of Val191, Tyr194, Val270, and Lys273, which creatively identify a new key anchoring point for the development of new MAGL inhibitors. Furthermore, in vivo evaluation innovatively revealed that this reversible inhibitor 36 significantly ameliorated depressive-like behaviors induced by reserpine. To the best of our knowledge, this is the first time that reversible inhibitors of MAGL were developed to support MAGL as a potential therapeutic target for depression.

Total Synthesis of (-)-Anaferine: A Further Ramification in a Diversity-Oriented Approach.

The piperidine ring is a widespread motif in several natural bioactive alkaloids of both vegetal and marine origin. In the last years, a diversity-oriented synthetic (DOS) approach, aimed at the generation of a library of piperidine-based derivatives, was developed in our research group, employing commercially available 2-piperidine ethanol as a versatile precursor. Here, we report the exploration of another ramification of our DOS approach, that led us to the stereoselective total synthesis of (-)-anaferine, a bis-piperidine alkaloid present in Withania somnifera extract. This natural product was obtained in 9% overall yield over 13 steps, starting from a key homoallylic alcohol previously synthesised in our laboratory. Therefore, the collection of piperidine-derivatives accessible from 2-piperidine ethanol was enriched with a new, diverse scaffold.

Cassane Diterpenoids from the Aerial Parts of Caesalpinia pulcherrima and Their Antifeedant and Insecticidal Activities against Mythimna separate and Plutella xylostella.

Ten new cassane diterpenoids, caesalpulcherrins A-J (1-10), together with 11 known analogues (11-21) were isolated from the aerial parts of Caesalpinia pulcherrima. Their structures and relative stereochemistry were elucidated by spectrometric and spectroscopic methods, including one-dimensional (1D) and two-dimensional (2D) NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and single-crystal X-ray diffraction analysis. Compounds 1-4 represent the first examples of 2,5-dimethoxyfuranocassane diterpenoids. Results of the antifeedant activity indicated that isovouacapenol C (12) and pulcherrin N (14) exhibited remarkable antifeedant activity against Mythimna separate with EC50 values of 3.43 and 4.20 µg/cm2, respectively. Meanwhile, pulcherrimin C (13) and 12-demethyl neocaesalpin F (18) exerted significant antifeedant activity against Plutella xylostella with an EC50 data of 4.00 and 3.05 µg/cm2, respectively. Some of the compounds showed obvious toxic activity against the plant-feeding generalist insect herbivores, M. separate and P. xylostella, at 0.8 mg/mL (800 ppm). Furthermore, the structure-activity relationships of antifeedant and insecticidal activities are also discussed in the article.