Benzoxazole-appended piperidine derivatives as novel anticancer candidates against breast cancer.

Novel series of benzoxazole-appended piperidine derivatives were planned, synthesized and screened against two breast cancer cell lines. Considerable antiproliferative activity was observed for screened compounds (IC50 = 33.32 ± 0.2 µM to 7.31 ± 0.43 µM and 1.66 ± 0.08 µM to 12.10 ± 0.57 µM) against MCF-7 and MDA-MB-231 cell lines respectively being more potent than doxorubicin (IC50 = 8.20 ± 0.39 µM and 13.34 ± 0.63 µM respectively). Active compounds were submitted for enzyme inhibition assays when 4d and 7h demonstrated potent EGFR inhibition (0.08 ± 0.002 µM and 0.09 ± 0.002 µM respectively) compared to erlotinib (0.11 ± 0.003 µM). However, no one compound displayed effective ARO inhibition activity as tested compounds were less active than letrozole. Apoptosis inducing ability results implied that apoptosis was provoked by significant stimulation of caspase-9 protein levels (4.25-7.04-fold) upon treatment of MCF-7 cells with 4a, 7h, 9, 12e and 12f. Alternatively, MDA-MB-231 cells treated with 4d, 7a, 12b and 12c considerably increased caspase-9 levels (2.32-4.06-fold). Cell cycle arrest and annexin-V/Propidium iodide assays further confirmed apoptosis when tested compounds arrested cell cycle at various phases and demonstrated high annexin V binding affinity. Docking outcomes proved valuable binding affinities for compounds 4d and 7h to EGFR enzyme while compounds 4a and 12e, upon docking into the active site of ARO, failed to interact with heme, suggesting their inabilities to act as AIs. Therefore, these benzoxazoles can act as promising candidates exhibiting EGFR inhibition and apoptosis-promoting properties.

Piperidine Derivatives: Recent Advances in Synthesis and Pharmacological Applications.

Piperidines are among the most important synthetic fragments for designing drugs and play a significant role in the pharmaceutical industry. Their derivatives are present in more than twenty classes of pharmaceuticals, as well as alkaloids. The current review summarizes recent scientific literature on intra- and intermolecular reactions leading to the formation of various piperidine derivatives: substituted piperidines, spiropiperidines, condensed piperidines, and piperidinones. Moreover, the pharmaceutical applications of synthetic and natural piperidines were covered, as well as the latest scientific advances in the discovery and biological evaluation of potential drugs containing piperidine moiety. This review is designed to help both novice researchers taking their first steps in this field and experienced scientists looking for suitable substrates for the synthesis of biologically active piperidines.

Palladium-Catalyzed Arylation of Endocyclic 1-Azaallyl Anions: Concise Synthesis of Unprotected Enantioenriched cis-2,3-Diarylpiperidines.

Unprotected cis-2,3-diarylpiperidines are synthesized through an unprecedented palladium-catalyzed cross-coupling reaction between aryl halides and elusive endocyclic 1-azaallyl anions. These intermediates are generated in situ by the deprotonation of 2-aryl-1-piperideines, precursors that are readily prepared in two operations from simple piperidines. An asymmetric version of this reaction with (2R, 3R)-iPr-BI-DIME as the ligand provides products in moderate to good yields and enantioselectivities. This study significantly expands the synthetic utility of endocyclic 1-azaallyl anions.

Characterization of Queen Supergene Pheromone in the Red Imported Fire Ant Using Worker Discrimination Assays.

Ants use chemical signals to communicate for various purposes related to colony function. Social organization in the red imported fire ant, Solenopsis invicta, is determined by the Sb supergene, with colonies of the monogyne (single-queen) form lacking the element and colonies of the polygyne (multiple-queen) form possessing it. Polygyne workers accept new reproductive queens in their nest, but only those carrying Sb; young winged queens lacking this genetic element are executed as they mature sexually in their natal nest or as they attempt to enter a foreign nest to initiate reproduction after mating and shedding their wings. It has been suggested that queen supergene genotype status is signaled to workers by unsaturated cuticular hydrocarbons, while queen reproductive status is signaled by piperidines (venom alkaloids). We used high-throughput behavioral assays to study worker acceptance of paper dummies dosed with fractions of extracts of polygyne queens, or blends of synthetic counterparts of queen cuticular compounds. We show that the queen supergene pheromone comprises a blend of monoene and diene unsaturated hydrocarbons. Our assays also reveal that unsaturated hydrocarbons elicit discrimination by polygyne workers only when associated with additional compounds that signal queen fertility. This synergistic effect was obtained with a polar fraction of queen extracts, but not by the piperidine alkaloids, suggesting that the chemical(s) indicating queen reproductive status are compounds more polar than cuticular hydrocarbons but are not the piperidine alkaloids. Our results advance understanding of the role of chemical signaling that is central to the regulation of social organization in an important invasive pest and model ant species.

Exploration of Spirocyclic Derivatives of Ciprofloxacin as Antibacterial Agents.

The previously reported as well as newly synthesized derivatives of the 1-oxa-9-azaspiro[5.5]undecane were employed in the synthesis of thirty-six derivatives of ciprofloxacin using commercially available 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and the literature protocol involving the preparation of boron chelate complex to facilitate nucleophilic aromatic substitution. All new fluoroquinolone derivatives were tested against two gram-positive as well as three gram-negative strains of bacteria. With the activity spectrum of the new derivatives being substantially narrower than that of ciprofloxacin, compounds were distinctly active against two of the five strains: gram-negative Acinetobacter baumannii 987® and gram-positive Bacillus cereus 138®. Towards these two strains, a large group of compounds displayed equal or higher potency than ciprofloxacin.

Gene regulation by morpholines and piperidines in the cardiac embryonic stem cell test.

The cardiac embryonic stem cell test (ESTc) is an in vitro embryotoxicity screen which uses cardiomyocyte formation as the main differentiation route. Studies are ongoing into whether an improved specification of the biological domain can broaden the applicability of the test, e.g. to discriminate between structurally similar chemicals by measuring expression of dedicated gene transcript biomarkers. We explored this with two chemical classes: morpholines (tridemorph; fenpropimorph) and piperidines (fenpropidin; spiroxamine). These compounds cause embryotoxicity in rat such as cleft palate. This malformation can be linked to interference with retinoic acid balance, neural crest (NC) cell migration, or cholesterol biosynthesis. Also neural differentiation within the ESTc was explored in relation to these compounds. Gene transcript expression of related biomarkers were measured at low and high concentrations on differentiation day 4 (DD4) and DD10. All compounds showed stimulating effects on the cholesterol biosynthesis related marker Msmo1 after 24 h exposure and tridemorph showed inhibition of Cyp26a1 which codes for one of the enzymes that metabolises retinoic acid. A longer exposure duration enhanced expression levels for differentiation markers for cardiomyocytes (Nkx2-5; Myh6) and neural cells (Tubb3) on DD10. This readout gave additional mechanistic insight which enabled previously unavailable in vitro discrimination between the compounds, showing the practical utility of specifying the biological domain of the ESTc.

Synthesis and Characterization of Novel Methyl (3)5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates.

Series of methyl 3- and 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates were developed and regioselectively synthesized as novel heterocyclic amino acids in their N-Boc protected ester form for achiral and chiral building blocks. In the first stage of the synthesis, piperidine-4-carboxylic and (R)- and (S)-piperidine-3-carboxylic acids were converted to the corresponding ß-keto esters, which were then treated with N,N-dimethylformamide dimethyl acetal. The subsequent reaction of ß-enamine diketones with various N-mono-substituted hydrazines afforded the target 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates as major products, and tautomeric NH-pyrazoles prepared from hydrazine hydrate were further N-alkylated with alkyl halides to give 3-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates. The structures of the novel heterocyclic compounds were confirmed by 1H-, 13C-, and 15N-NMR spectroscopy and HRMS investigation.

Stereoselective Allylic Alkylations of Amino Ketones and Their Application in the Synthesis of Highly Functionalized Piperidines.

Chelated ketone enolates are excellent nucleophiles for allylic alkylations. Electron-withdrawing groups on the allyl moiety allow subsequent intramolecular Michael additions giving rise to piperidines with up to five stereogenic centers.

Understanding the Conformational Behavior of Fluorinated Piperidines: The Origin of the Axial-F Preference.

Gaining an understanding of the conformational behavior of fluorinated compounds would allow for expansion of the current molecular design toolbox. In order to facilitate drug discovery efforts, a systematic survey of a series of diversely substituted and protected fluorinated piperidine derivatives has been carried out using NMR spectroscopy. Computational investigations reveal that, in addition to established delocalization forces such as charge-dipole interactions and hyperconjugation, solvation and solvent polarity play a major role. This work codifies a new design principle for conformationally rigid molecular scaffolds.

Functionalization of Piperidine Derivatives for the Site-Selective and Stereoselective Synthesis of Positional Analogues of Methylphenidate.

Rhodium-catalyzed C-H insertions and cyclopropanations of donor/acceptor carbenes have been used for the synthesis of positional analogues of methylphenidate. The site selectivity is controlled by the catalyst and the amine protecting group. C-H functionalization of N-Boc-piperidine using Rh2 (R-TCPTAD)4 , or N-brosyl-piperidine using Rh2 (R-TPPTTL)4 generated 2-substitited analogues. In contrast, when N-α-oxoarylacetyl-piperidines were used in combination with Rh2 (S-2-Cl-5-BrTPCP)4 , the C-H functionalization produced 4-susbstiuted analogues. Finally, the 3-substituted analogues were prepared indirectly by cyclopropanation of N-Boc-tetrahydropyridine followed by reductive regio- and stereoselective ring-opening of the cyclopropanes.

Transition-Metal-Free Multiple Functionalization of Piperidines to 4-Substituted and 3,4-Disubstituted 2-Piperidinones.

Remote and multiple functionalization of piperidines without the use of transition-metal catalysts and elaborate directing groups is one of the major challenges in organic synthesis. Herein is reported an unprecedented two-step protocol that enables the multiple functionalization of piperidines to either 4-substituted or trans-3,4-disubstituted 2-piperidones. First, by exploiting the duality of TEMPO reactivity, which under oxidative and thermal conditions fluctuates between cationic and persistent-radical form, a novel multiple C(sp3 )-H oxidation of piperidines to α,ß-unsaturated 2-piperidones was developed. Second, the intrinsic low reactivity of the unsaturated piperidones toward conjugated Grignard additions was overcome by using trimethylsilyl chloride (TMSCl) as Lewis acid. Subsequently, conjugated Grignard addition/electrophilic trapping protocol provided substituted 2-piperidone intermediates, some of which were then transformed into pharmaceutical alkaloids.

Efficacy of different dose of dexmedetomidine combined with remifentanil in colonoscopy: a randomized controlled trial.

BACKGROUND: Dexmedetomidine has advantages during colonoscopy as it allows the patient to cooperate during the procedure. Few studies examined the dexmedetomidine-remifentanil combination. This study was to evaluate the effects of different doses of the dexmedetomidine-remifentanil combination in colonoscopy. METHODS: This was a prospective trial carried out at the Fourth Hospital of Hebei Medical University between 02/2018 and 10/2018. The patients were randomized: group I (dexmedetomidine 0.2 µg·kg- 1), group II (dexmedetomidine 0.3 µg·kg- 1), and group III (dexmedetomidine 0.4 µg·kg- 1), all combined with remifentanil. The primary outcomes were the patient's body movements during the procedure and adverse events. RESULTS: Compared with at admission (T0), the SBP, HR, and RR at immediately after giving DEX (T1), at the beginning of the examination (T2), 5 min after the beginning of the examination (T3), 10 min after the beginning of the examination (T4), and at the end of the examination (T5) in the three groups were all reduced (all P < 0.05), but all were within the clinically normal range. SpO2 remained > 98% in all patients during the examination. Compared with T0, the BIS values of the three groups were decreased at T1 and T2 (all P < 0.05). There were no significant differences in BIS among the three groups (all P > 0.05). The minimum BIS value in group III was lower than in groups I and II (P < 0.05). The degree of satisfaction with the anesthesia effect was higher in groups II and III that in group I (P < 0.05). No hypotension occurred, seven patients had bradycardia, and four patients had nausea/vomiting. CONCLUSIONS: Dexmedetomidine 0.3 µg·kg- 1 combined with remifentanil was effective for colonoscopy and had few adverse reactions. Chinese Clinical Trial Registry: ChiCTR2000029105 , Registered 13 January 2020 - Retrospectively registered.

Nitroso Diels-Alder Cycloadducts Derived From N-Acyl-1,2-dihydropyridines as a New Platform to Molecular Diversity.

This review focuses upon the use of nitroso Diels-Alder reactions as a structural complexity generating reaction that has been so far a quite scarcely treated topic, despite its potential. In particular, the use of N-acyl-1,2-dihydropyridines as a non-symmetrical diene component in nitroso Diels-Alder reactions encompasses an initial diversification of pathways giving rise to different cycloadducts (direct and inverse). Selective elaborations of these cycloadducts, basically using a reagent-based approach, deliver a discrete number of structurally diverse compounds, including some original heterobicyclic scaffolds and functionalized heterocycles. This forward synthetic planning allowed the individuation of a new biologically active compound based on a novel oxadiaza-bicyclic-[3.3.1]-nonene scaffold which is still under preclinical evaluation.

Enantioselective Palladium(II)-Catalyzed Oxidative Aminofluorination of Unactivated Alkenes with Et4 NF⋠3 HF as a Fluoride Source.

The first asymmetric PdII -catalyzed aminofluorination of unactivated alkenes using chiral quinoline-oxazolines (Quox) as ligands has been developed. This reaction provides easy access to a wide array of enantiomerically enriched ß-fluoropiperidines in good yields and with excellent enantioselectivity. Notably, Et4 NF⋅3 HF as a readily accessible nucleophilic fluoride source was found to play an essential role in the enantioselective control, and CsOCF3 also acts a key additive to improve the excellent ee value of products.

Direct Regio- and Diastereoselective Synthesis of δ-Lactams from Acrylamides and Unactivated Alkenes Initiated by RhIII -Catalyzed C-H Activation.

We report a RhIII -catalyzed regio- and diastereoselective synthesis of δ-lactams from readily available acrylamide derivatives and unactivated alkenes. The reaction provides a rapid route to a diverse set of δ-lactams in good yield and stereoselectivity, which serve as useful building blocks for substituted piperidines. The regioselectivity of the reaction with unactivated terminal alkene is significantly improved by using Cpt ligand on the RhIII catalyst. The synthetic utility of the reaction is demonstrated by the preparation of a potential drug candidate containing a trisubstituted piperidine moiety. Mechanistic studies show that the reversibility of the C-H activation depends on the choice of Cp ligand on the RhIII catalyst. The irreversible C-H activation is observed and becomes turnover-limiting with [Cpt RhCl2 ]2 as catalyst.

Discovery of a new family of heterocyclic amine linked plastoquinone analogs for antimicrobial evaluation.

A series of aminobenzoquinones, denoted as PQ analogs (PQ1-13), were synthesized by employing a green methodology approach using water as solvent developed by Tandon et al. Subsequently, in vitro antimicrobial potential of all PQ analogs was evaluated in a panel of seven bacterial strains (three gram positive and four gram negative bacteria) and three fungi. The antifungal profile of all PQ analogs indicated that four analogs (while PQ2, PQ9, and PQ10 were effective against Candida tropicalis, PQ11 is effective against Candida albicans) have potent antifungal activity. The results revealed that PQ9 showed similar antibacterial activity against Staphylococcus epidermidis compared clinically prevalent antibacterial drugs cefuroxime. PQ11 exhibited the highest antibacterial activity against S. epidermidis, which was about fourfold better than that of cefuroxime. Owing to their outstanding activities, PQ9 and PQ11 were chosen for a further investigation for biofilm and cytotoxicity evaluation. Based on the tests performed, there was a significant positive correlation between inhibition of the biofilm attachment and time. In addition, PQ9 and PQ11 showed cytotoxic effects at high concentrations on Balb/3T3, HaCaT, HUVEC, and NRK-52E cells (>24 and >18 µg/mL, respectively). Thus, two analogs (PQ9 and PQ11) were identified as the hits with the strong antibacterial efficiency against the S. epidermidis with low MIC values.

Transition-Metal-Free Deconstructive Lactamization of Piperidines.

One of the major challenges in organic synthesis is the activation or deconstructive functionalization of unreactive C(sp3 )-C(sp3 ) bonds, which requires using transition or precious metal catalysts. We present here an alternative: the deconstructive lactamization of piperidines without using transition metal catalysts. To this end, we use 3-alkoxyamino-2-piperidones, which were prepared from piperidines through a dual C(sp3 )-H oxidation, as transitory intermediates. Experimental and theoretical studies confirm that this unprecedented lactamization occurs in a tandem manner involving an oxidative deamination of 3-alkoxyamino-2-piperidones to 3-keto-2-piperidones, followed by a regioselective Baeyer-Villiger oxidation to give N-carboxyanhydride intermediates, which finally undergo a spontaneous and concerted decarboxylative intramolecular translactamization.

Palladium(II)-Catalyzed Enantioselective Aminotrifluoromethoxylation of Unactivated Alkenes using CsOCF3 as a Trifluoromethoxide Source.

Asymmetric PdII -catalyzed intramolecular aminotrifluoromethoxylation of unactivated alkenes using readily accessible and stable CsOCF3 as a trifluoromethoxide source has been developed, which affords a wide variety of enantiomerically enriched ß-substituted OCF3 -containing piperidines in good yields. Introducing a sterically bulky group into pyridine-oxazoline (Pyox) ligands is crucial to increasing both reactivity and enantioselectivity for the reaction. Additionally, the reaction features good functional group compatibility and mild reaction conditions.

Design and synthesis of bridged piperidine and piperazine isosteres.

We have developed versatile methods toward the synthesis of a variety of piperidine/piperazine bridged isosteres of pridopidine. The compounds were assessed against the D2 receptor in agonist and antagonist modes and against the D4 receptor in agonist mode. hERG Binding and the ADME profiles were studied.

In vitro modulatory effects of functionalized pyrimidines and piperidine derivatives on Aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR) activities.

The development of biologically active molecules based on molecular recognition is an attractive and challenging task in medicinal chemistry and the molecules that can activate/deactivate certain receptors are of great medical interest. In this contribution, selected pyrimidine/piperidine derivatives were synthesized and tested for the ability to activate/deactivate Aryl hydrocarbon receptor (AhR) and Glucocorticoid receptor (GR). Tested compounds are shown to activate the receptors but to much lesser extent than positive controls, dioxin and dexamethasone for Ahr and GR, respectively. However, some of them antagonized the positive controls action. Although further in vivo studies are needed to fully characterize the bioactivities of these compounds, the reported in vitro evidences demonstrate that they might be used as the modulators of AhR and GR activities.