Piperidine Scaffolds Research Articles

Acridine yellow G as a photo-induced electron transfer catalyzed radical [4 + 2] aza-Diels-Alder annulation of imines

For the preparation of polyfunctionalized piperidine scaffolds, a radical tandem five-condensation domino Knoevenagel-intramolecular [4 + 2] aza-Diels-Alder imin-based reaction was used. Based on acridine yellow G (AYG) as a photo-induced electron transfer (PET) photocatalyst, employing visible light as a renewable source of energy. AYG that is photochemically catalyzed has good yields, as well as outstanding atom economy, and ease of operation. As a result, a diverse set of chemical and environmental parameters can be measured across time. The turnover number (TON) and turnover frequency (TOF) of polyfunctionalized piperidine scaffolds have been computed. Also, gram-scale cyclization can occur, suggesting that the process might find application in industry.

2-(Piperidin-3-yl)phthalimides reduce classical markers of cellular inflammation in LPS-challenged RAW 264.7 cells and also demonstrate potentially relevant sigma and serotonin receptor affinity in membrane preparations

Herein, we report the synthesis of new 4-amino-2-(piperidin-3-yl)isoindoline-1,3-diones and their biological evaluation in a series of in vitro experiments. The synthetic production of these materials was initiated upon the condensation of appropriate nitrophthalic acid derivatives with various 3-aminopiperidines; subsequent reduction provided the final products in moderate to good yields. Readily available chiral pool reagents facilitated entry into optically enriched samples, while the piperidine scaffold furnished a variety of amide and alkylated entries. In total, 16 candidates were produced, and their ensuing treatment in LPS-challenged RAW cells effected slight reductions in secreted TNF-α but provided more robust and dose-dependent declines in nitrite and IL-6 levels relative to basal amounts, all concurrent with maintenance of cellular viability across the concentration ranges screened. The secondary amine cohort including rac-6, (R)-7, and (S)-8 rendered the most pronounced dose-dependent reductions in nitrite and IL-6. When dosed at 30 μM, (R)-7 demonstrated the most compelling effects, with decreases of 32 % and 40 % for nitrite and IL-6, respectively. Notable reductions in the inflammatory markers were also observed for 19 which effected declines in TNF-α (14 %), nitrite (19 %), and IL-6 (11 %) when treated at 30 μM. Additionally, four representative compounds were further evaluated against numerous CNS receptors, channels, and transporters, with 6, 9, and 19 demonstrating varying degrees of nanomolar-to-low-micromolar binding to the σ-1 and σ-2 receptors and also to serotonin receptors 5HT2A, 5HT2B and 5HT3. In this regard, 6 displayed perhaps the most noteworthy affinities, with binding at σ-2 (Ki = 2.2uM), 5HT2B (Ki = 561 nM) and 5HT3 (Ki = 536 nM). Furthermore, no pronounced or dose-dependent Cereblon/DDB1 binding was observed for the screened representative compounds 6, 9, 18 and 19.

Asperinamide A, an anti-inflammatory prenylated indole alkaloid possessing an unprecedented bicyclo[2.2.2]diazaoctane fused with substituted piperidine scaffold from Aspergillus sp. TE-65L

Prenylated indole alkaloids (PIAs) containing a bicyclo[2.2.2]diazaoctane ring have gained extensive attention due to their chemical (especially stereochemical), biosynthetic/synthetic, and bioactive interests. In the present study, An unprecedented PIA (namely asperinamide A, 1), featuring a 6/6/5/6/6/6/5 heptacyclic scaffold fused with bicyclo[2.2.2]diazaoctane and substituted piperidine, hitherto unknown among this family of PIAs, along with its biosynthetic-related analogues sclerotiamide (2) and (+)-stephacidin A (3), were isolated from the Nicotiana tabacum-derived endophytic fungus Aspergillus sp. TE-65L. Their structures were unambiguously determined by detailed NMR, mass spectra, and X-ray crystallographic analysis. A detailed plausible biosynthetic analysis for compounds 1–3 was proposed, which revealed that the unique substituted piperidine ring may be formed through a radical-mediated rearrangement. Compound 1 showed significant anti-inflammatory activity targeting the TLR4-MD2 site in the TLR4/NF-κB signaling pathway.

Pd(II) based anticancer drug candidates with 1,2-Aminoethyl piperidine scaffold and sulfur donor ancillary: Their in vitro bio-activity, molecular docking and DFT study

A series of Pd(II) complexes Pd-1 to Pd-6; out of these [Pd(PIEAM)(LC)]+; Pd-3, [Pd(PIEAM)(NALC)]; Pd-4, [Pd(PIEAM)(GSH)]; Pd-5 and [Pd(PIEAM)(DL-meth)]2+; Pd-6 have been synthesized from water soluble stable diaqua complex [Pd(PIEAM)(OH2)2](NO3)2; Pd-2. The Pd-2 complex was obtained from hydrolysis of [Pd(PIEAM)Cl2]; Pd-1 (where, PIEAM = 1,2-Aminoethyl piperidine, a bidentate carrier ligand and with ancillary groups like; LC = L-cysteine, NALC = N-acetyl-L-cysteine, GSH = Glutathione, DL-meth = DL-methionine). All these Pd-1-Pd-6 complexes were characterized by different spectroscopic studies, like; UV–Vis, FT-IR, 1H NMR, and ESI Mass analyses. The bioactivity and drug-likeness properties of the complexes were assessed by PASS and ADME prediction software. The bioactivity of the complexes was experimentally investigated on DNA binding properties by gel electrophoresis, electronic, fluorescence, and viscometric methods. The binding constant values of Pd-3 complex with CT DNA bining in both absorption (Kb = 7.50 × 104M−1)and fluorosence titration (KSV = 35.10 × 103 M−1) was found greater than other Pd-1, Pd-2, Pd-4-Pd-6 complexes (Kb = (4.25–0.64) × 104 M−1; KSV = (13.57–1.11) × 103 M−1). The comparison in BSA bining of Pd(II) complexes also suggested the higher binding constant of Pd-3 complex in both spectroscopic method (Kb = 32 × 103M−1; KSV = 2.32 × 104 M−1) than other Pd(II) complexes (Kb = 16–2.4 × 103M−1; KSV = 1.99–1.53 × 104 M−1). A theoretical investigation of the structural property and TD-DFT of the complexes was executed by DFT calculations. The detailed BSA binding activity of the complexes was performed by fluorescence quenching, synchronous, and 3D-fluorescence spectroscopic methods. Molecular docking of the complexes with DNA and BSA was under study for their binding mode and different weak forces. Their cytotoxic behaviors, like; anticancer activity by MTT assay and ROS (Reactive Oxygen Species) generation by NBT (Nitro Blue Tetrazolium) assay, were investigated. The cytotoxicity of the complexes was under investigation on human lung adenocarcinoma cell A549, colorectal carcinoma cell HCT 116, and normal human embryonic kidney cell HEK 293.

Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC.

The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and piperidine scaffolds such as (+)-BNM-III-170 and (S)-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp368 Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the infection of difficult-to-neutralize tier-2 viruses and sensitize infected cells to ADCC mediated by HIV+ plasma. Moreover, the new analogs formed an H-bond with the α-carboxylic acid group of Asp368, opening a new avenue to enlarge the breadth of this family of anti-Env small molecules. Overall, the new structural and biological attributes of these molecules make them good candidates for strategies aimed at the elimination of HIV-1-infected cells.

Application of Chiral Piperidine Scaffolds in Drug Design

Chiral piperidine scaffolds are prevalent as the common cores of a large number of active pharmaceuticals in medical chemistry. This review outlined the diversity of chiral piperidine scaffolds in recently approved drugs, and also covers the scaffolds in leads and drug candidates. The significance of chiral piperidine scaffolds in drug design is also discussed in this article. With the introduction of chiral piperidine scaffolds into small molecules, the exploration of drug-like molecules can be benefitted from the following aspect: (1) modulating the physicochemical properties; (2) enhancing the biological activities and selectivity; (3) improving pharmacokinetic properties; and (4) reducing the cardiac hERG toxicity. Given above, chiral piperidine-based discovery of small molecules will be a promising strategy to enrich our molecules' library to fight against diseases.

From dopamine 4 to sigma 1: Synthesis, SAR and biological characterization of a piperidine scaffold of σ1 modulators

The sigma 1 receptor is a multifunctional receptor with wide distribution in the nervous system and its function has been implicated with a number of neurological disorders including dementia and Alzheimer's disease (AD) and other neurodegenerative disorders. In addition, modulators of σ1 have been advanced into clinical trials for the treatment of pain. Starting from our previously disclosed piperidine scaffold, we have identified a class of potent sigma 1 modulators. This work highlights the key SAR components that lead to the divergence in D4 and σ1 activity. In addition, we further profile lead compounds in a panel of off-target receptors, in vitro and in vivo pharmacokinetic studies. This has culminated in the discovery of multiple σ1 receptor modulators with properties that will allow for study in animal models.

Synthesis of Aminoethyl-Substituted Piperidine Derivatives as σ1 Receptor Ligands with Antiproliferative Properties.

A series of novel σ1 receptor ligands with a 4‐(2‐aminoethyl)piperidine scaffold was prepared and biologically evaluated. The underlying concept of our project was the improvement of the lipophilic ligand efficiency of previously synthesized potent σ1 ligands. The key steps of the synthesis comprise the conjugate addition of phenylboronic acid at dihydropyridin‐4(1H)‐ones 7, homologation of the ketones 8 and introduction of diverse amino moieties and piperidine N‐substituents. 1‐Methylpiperidines showed particular high σ1 receptor affinity and selectivity over the σ2 subtype, whilst piperidines with a proton, a tosyl moiety or an ethyl moiety exhibited considerably lower σ1 affinity. Molecular dynamics simulations with per‐residue binding free energy deconvolution demonstrated that different interactions of the basic piperidine‐N‐atom and its substituents (or the cyclohexane ring) with the lipophilic binding pocket consisting of Leu105, Thr181, Leu182, Ala185, Leu186, Thr202 and Tyr206 are responsible for the different σ1 receptor affinities. Recorded logD7.4 and calculated clogP values of 4a and 18a indicate low lipophilicity and thus high lipophilic ligand efficiency. Piperidine 4a inhibited the growth of human non‐small cell lung cancer cells A427 to a similar extent as the σ1 antagonist haloperidol. 1‐Methylpiperidines 20a, 21a and 22a showed stronger antiproliferative effects on androgen negative human prostate cancer cells DU145 than the σ1 ligands NE100 and S1RA.

Oxidative Fragmentation of Cytisine as an Entry to the Bis(piperidine) Scaffold of Virgidivarine

Oxidative Fragmentation of Cytisine as an Entry to the Bis(piperidine) Scaffold of Virgidivarine

Formal Synthesis of (-)-Quinagolide: Diastereoselective Ring Expansion via a Bicyclic Aziridinium Ion Strategy to Access the Octahydrobenzo[g]quinoline Architecture.

The diastereoselective formal synthesis of (-)-quinagolide, a D2 receptor agonist, has been achieved. The synthesis started from l-pyroglutamic acid and relied on utilization of (a) a stereospecific catalytic hydrogenation and diastereoselective Horner-Emmons-Michael cascade to obtain functionalized prolinate, (b) a Lewis acid mediated Pummerer cyclization to construct a tricyclic fused ring system, and (c) a diastereoselective ring expansion via a bicyclic aziridinium intermediate to access the required 3-substituted piperidine scaffold.

Heterocyclic group transfer reactions with I(iii) N-HVI reagents: access to N-alkyl(heteroaryl)onium salts via olefin aminolactonization.

Pyridinium and related N-alkyl(heteroaryl)onium salts are versatile synthetic intermediates in organic chemistry, with applications ranging from ring functionalizations to provide diverse piperidine scaffolds to their recent emergence as radical precursors in deaminative cross couplings. Despite their ever-expanding applications, methods for their synthesis have seen little innovation, continuing to rely on a limited set of decades old transformations and a limited subset of coupling partners. Herein, we leverage (bis)cationic nitrogen-ligated I(iii) hypervalent iodine reagents, or N-HVIs, as “heterocyclic group transfer reagents” to provide access to a broad scope of N-alkyl(heteroaryl)onium salts via the aminolactonization of alkenoic acids, the first example of engaging an olefin to directly generate these salts. The reactions proceed in excellent yields, under mild conditions, and are capable of incorporating a broad scope of sterically and electronically diverse aromatic heterocycles. The N-HVI reagents can be generated in situ, the products isolated via simple trituration, and subsequent derivatizations demonstrate the power of this platform for diversity-oriented synthesis of 6-membered nitrogen heterocycles.

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.

Discovery of a Chiral DNA‐Targeted Platinum–Acridine Agent with Potent Enantioselective Anticancer Activity

AbstractA structure–activity relationship study was performed for a set of rigidified platinum–acridine anticancer agents containing linkers derived from chiral pyrrolidine and piperidine scaffolds. Screening a library of microscale reactions and selected resynthesized compounds in non‐small‐cell lung cancer (NSCLC) cells showed that cytotoxicities varied by more than three orders of magnitude. A potent hit compound was discovered containing a (R)‐N‐(piperidin‐3‐yl) linker (P2‐6R), which killed NCI‐H460 and A549 lung cancer cells 100 times more effectively than the S enantiomer (P2‐6S). P2‐6R accumulated in A549 cells significantly faster and produced 50‐fold higher DNA adduct levels than P2‐6S. Ligand similarity analysis suggests that only module 6R may be compatible with strainless monofunctional intercalative binding. NCI‐60 screening and COMPARE analysis highlights the spectrum of activity and potential utility of P2‐6R for treating NSCLC and other solid tumors.

Discovery of a Chiral DNA-Targeted Platinum-Acridine Agent with Potent Enantioselective Anticancer Activity.

A structure-activity relationship study was performed for a set of rigidified platinum-acridine anticancer agents containing linkers derived from chiral pyrrolidine and piperidine scaffolds. Screening a library of microscale reactions and selected resynthesized compounds in non-small-cell lung cancer (NSCLC) cells showed that cytotoxicities varied by more than three orders of magnitude. A potent hit compound was discovered containing a (R)-N-(piperidin-3-yl) linker (P2-6R), which killed NCI-H460 and A549 lung cancer cells 100 times more effectively than the S enantiomer (P2-6S). P2-6R accumulated in A549 cells significantly faster and produced 50-fold higher DNA adduct levels than P2-6S. Ligand similarity analysis suggests that only module 6R may be compatible with strainless monofunctional intercalative binding. NCI-60 screening and COMPARE analysis highlights the spectrum of activity and potential utility of P2-6R for treating NSCLC and other solid tumors.

Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study.

A series of potent HIV-1 protease inhibitors, containing diverse piperidine analogues as the P2-ligands, 4-substituted phenylsulfonamides as the P2’-ligands and a hydrophobic cyclopropyl group as the P1’-ligand, were designed, synthesized and evaluated in this work. Among these twenty-four target compounds, many of them exhibited excellent activity against HIV-1 protease with half maximal inhibitory concentration (IC50) values below 20 nM. Particularly, compound 22a containing a (R)-piperidine-3-carboxamide as the P2-ligand and a 4-methoxylphenylsulfonamide as the P2’-ligand exhibited the most effective inhibitory activity with an IC50 value of 3.61 nM. More importantly, 22a exhibited activity with inhibition of 42% and 26% against wild-type and Darunavir (DRV)-resistant HIV-1 variants, respectively. Additionally, the molecular docking of 22a with HIV-1 protease provided insight into the ligand-binding properties, which was of great value for further study.

Multicomponent reaction for the synthesis of highly functionalized piperidine scaffolds catalyzed by TMSI

An efficient method for the synthesis of highly functionalized piperidines via one-pot domino reaction of β-ketoesters, aromatic aldehydes, and aromatic amines was reported. This multicomponent coupling was catalyzed by TMSI in methanol at room temperature, giving desired substituted pyridines in moderate to good yields.

The synthesis of 3-azabicyclo[4.3.0]nonane scaffolds from brefeldin A

Brefeldin A (BFA) is a fungal metabolite that displays a wide range of biological activities making it an attractive target for drug discovery. To explore the biological potential of the BFA scaffold an amine-macrocycle target 3 was proposed. To access, we dissembled BFA into smaller building blocks in preparation for regenerating the macro-lactone. These entities can then be used to synthesise new brefeldin analogues with various new structural features for biological testing. To overcome supply issues a scaled fermentation process of Penicillium camemberti was employed generating 4.5 kg of BFA. Novel N-BFA type derivatives were generated and herein we describe the synthesis of two new scaffolds 12 and 14 from BFA over six steps in 24% and 17% yield, respectively. A trans-fused bicyclic cyclopentanoid piperidine scaffold 16 can be generated from 12 that may serve as a valuable new scaffold for the synthesis of novel natural product-like compounds.

Design, synthesis, biological evaluation and molecular docking study of arylcarboxamido piperidine and piperazine-based hydroxamates as potential HDAC8 inhibitors with promising anticancer activity

HDAC8 has been established as one of the vital targets as far as the cancer is concerned. Different compounds having potential HDAC inhibitory activity have been approved by USFDA. However, none of these compounds are selective towards specific HDAC isoform. In this current study, some new hydroxamate derivatives with alkylpiperidine and alkylpiperazine linker moieties have been designed, synthesized and biologically evaluated. All these compounds are effective HDAC8 inhibitors comprising more or less similar cytotoxic potential against different cancer cell lines. It is observed that the piperazine scaffold containing compound is more active than the compound with piperidine scaffold for exerting HDAC8 inhibitory activity. Moreover, the 4-quinolyl cap group is better than the biphenyl group which is better than the benzyl group for producing higher HDAC8 inhibition as well as cytotoxicity. These compounds displayed selective HDAC8 inhibition over HDAC3. Moreover, these compounds showed an increased caspase3/7 activity suggesting their anticancer potential through modulation of apoptotic pathways. Molecular docking study with three potent compounds was performed with both HDAC3 and HDAC8 enzymes to understand the selectivity profile of these compounds. Compound containing 4-quinolyl cap group with alkyl piperazinyl urea linker moiety has been emerged out as the lead molecule that may be further modified to design more effective and selective HDAC8 inhibitors in future.

Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis, Structure-Activity Relationships, and Sleep-Promoting Properties in Rats.

The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts toward a novel DORA. We started our investigation with rac-[3-(5-chloro-benzooxazol-2-ylamino)piperidin-1-yl]-(5-methyl-2-[1,2,3]triazol-2-ylphenyl)methanone (3), a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine scaffold was essential to improve potency at the orexin 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-ylphenyl)-{(S)-2-[5-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]pyrrolidin-1-yl}methanone (51), a potent, brain-penetrating DORA with in vivo efficacy similar to that of suvorexant in rats.

The formation of all-cis-(multi)fluorinated piperidines by a dearomatization-hydrogenation process.

Piperidines and fluorine substituents are both independently indispensable components in pharmaceuticals, agrochemicals and materials. Logically, the incorporation of fluorine atoms into piperidine scaffolds is therefore an area of tremendous potential. However, synthetic approaches towards the formation of these architectures are often impractical. The diastereoselective synthesis of substituted monofluorinated piperidines often requires substrates with pre-defined stereochemistry. That of multifluorinated piperidines is even more challenging, and often needs to be carried out in multistep syntheses. In this report, we describe a straightforward process for the one-pot rhodium-catalysed dearomatization-hydrogenation of fluoropyridine precursors. This strategy enables the formation of a plethora of substituted all-cis-(multi)fluorinated piperidines in a highly diastereoselective fashion through pyridine dearomatization followed by complete saturation of the resulting intermediates by hydrogenation. Fluorinated piperidines with defined axial/equatorial orientation of fluorine substituents were successfully applied in the preparation of commercial drugs analogues. Additionally, fluorinated PipPhos as well as fluorinated ionic liquids were obtained by this dearomatization-hydrogenation process.