Spiropiperidine Derivatives Research Articles

Spiro heterocycles bearing piperidine moiety as potential scaffold for antileishmanial activity: synthesis, biological evaluation, and in silico studies

New spiro-piperidine derivatives were synthesised via the eco-friendly ionic liquids in a one-pot fashion. The in vitro antileishmanial activity against Leishmania major promastigote and amastigote forms highlighted promising antileishmanial activity for most of the derivatives, with superior activity compared to miltefosine. The most active compounds 8a and 9a exhibited sub-micromolar range of activity, with IC50 values of 0.89 µM and 0.50 µM, respectively, compared to 8.08 µM of miltefosine. Furthermore, the antileishmanial activity reversal of these compounds via folic and folinic acids displayed comparable results to the positive control trimethoprim. This emphasises that their antileishmanial activity is through the antifolate mechanism via targeting DHFR and PTR1. The most active compounds showed superior selectivity and safety profile compared to miltefosine against VERO cells. Moreover, the docking experiments of 8a and 9a against Lm-PTR1 rationalised the observed in vitro activities. Molecular dynamics simulations confirmed a stable and high potential binding to Lm-PTR1.

Rhodium(III)-Catalyzed Synthesis of Spiropiperidine Derivatives via C-H Activation.

Spiropiperidine derivatives, an important class of bioactive molecules, were synthesized under mild conditions by rhodium(III)-catalyzed intramolecular ArC-H activation. This reaction provides a novel route to highly substituted tricyclic spiropiperidines in good to excellent yields. Under acidic conditions the resulting enamines reacted with pendant amides to afford spiropiperidines derivatives possessing an original tetracyclic structure.

Polymer-anchored [Fe(III)Azo] complex: An efficient reusable catalyst for oxidative bromination and multi-components reaction for the synthesis of spiropiperidine derivatives

A heterogeneous catalyst was prepared by attaching Fe(III) into organically modified chloromethylated polytstyrene and characterized by AAS, IR, PXRD, TG-DTA, UV–Vis, and SEM studies. In presence of H2O2 and KBr as bromine source, the catalyst showed remarkably high conversion with para-selectivity towards the oxidative bromination reaction in acetic acid medium. The catalyst was also very active and highly efficient for the production of spiropiperidine derivatives through multi-component reaction in isopropyl alcohol at room temperature. The catalyst was not leached during the catalytic reactions, moreover, after five cycles the catalytic activity and selectivity of the catalyst were not decreased very significantly.

Ugi-Type Reactions of Spirocyclic Indolenines as a Platform for Compound Library Generation

A simple and efficient method for the synthesis of highly substituted spiroindoline derivatives is presented. A Fischer indolization is combined with Ugi-type reactions to explore the chemical space concerning this privileged structure. Moreover, spiropiperidine derivatives could be postmodified for the production of a small-molecule library that will be part of the Joint European Compound Library of the European Lead Factory.

Cerium Supported Chitosan as an Efficient and Recyclable Heterogeneous Catalyst for Sustainable Synthesis of Spiropiperidine Derivatives

A new Ce/chitosan catalyst has been prepared and used for the highly efficient synthesis of diverse range of spiropiperidine derivatives via multicomponent reaction of substituted anilines, formaldehyde and different cyclic active methylene compounds at room temperature in PEG-200. The catalyst could be reused for five consecutive cycles without appreciable loss in catalytic activity. The structure of the catalyst was determined by IR, XRD, EDX, TEM and ICP-AES techniques. The present green protocol has advantages such as novel products, energy sustainability, short reaction times, high yield of products, economic viability and recyclability of the catalyst.

Tandem Prins Strategy for the Synthesis of Spiropyrrolidine and Spiropiperidine Derivatives

AbstractCascade cyclization of a 3‐[(3‐methylbut‐2‐enylamino)methyl]but‐3‐en‐1‐ol derivative with aldehydes in the presence of TMSOTf at 0 °C under mild conditions provides the corresponding spiropyrrolidine scaffolds in good yields. Similar cyclization of a 3‐[(4‐methylpent‐3‐enylamino)methyl]but‐3‐en‐1‐ol derivative with aldehydes affords the correponding spiropiperidine compounds. This is a new approach for the construction of biologically relevant spirocycles in a single‐step process.

Titanium-Mediated Spirocyclization Reactions of 4-Alkylpyridines

Pyridines substituted at the 4-position with alkyl tethers containing beta-dicarbonyl moieties were converted to spirocyclic 4,4-disubstituted dihydropyridines. Optimal conditions for these transformations involved N-acylation of the pyridine substrate with a chloroformate electrophile in the presence of Ti(O(i)Pr)(4). Cyclization products could be easily converted into spiro-piperidine derivatives or elaborated into more complex heterocyclic frameworks via Au-catalyzed cycloisomerization.

Discovery of novel spiro-piperidine derivatives as highly potent and selective melanin-concentrating hormone 1 receptor antagonists

Optimization of high-throughput screening hit 1a led to the identification of a novel spiro-piperidine class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Compound 3c was identified as a highly potent and selective MCH-1R antagonist, which has an IC50 value of 0.09nM at hMCH-1R. The synthesis and structure–activity relationships of the novel spiro-piperidine MCH-1R antagonists are described.

Spiro[1,2,4‐benzotriazine‐3(4H),4′‐(1‐substituted)piperidines] and Related Compounds as Ligands for Sigma Receptors.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Spiro[1,2,4-benzotriazine-3(4H),4′-(1′-substituted)piperidines] and related compounds as ligands for sigma receptors

As analogues of some conformationally restricted spiropiperidine derivatives which are endowed with high affinity for σ1 receptor, a set of 16 spiro[1,2,4-benzotriazine-3(4H),4′-(1′-substituted)piperidines] and congeneric compounds was prepared and tested for affinity to σ1 receptor subtype. All N-arylalkyl substituted derivatives exhibited high affinity for the relevant receptor, with Ki in the low nanomolar range. Affinity for σ2 subtype (assayed only for a few representative compounds) was from one to three order of magnitude lower. Spiro[1,2,4-benzotriazine-3(4H),4′-(1′-benzyl)piperidine] (2), with a ratio Kiσ2/Kiσ1=7000 should represent the most selective σ1 ligand so far described.

Synthesis of new piperidine and cyclohexylamino-spiro derivatives as potential anticalcium agents

The spiropiperidine derivatives have considerable importance in pharmaceutical chemistry due to their effects on different biological systems [...]

Asymmetric synthesis. XXXIV. Synthesis of spiro-piperidine derivatives via the CN(R,S) method

5-Aza-spiro-[3,5] nonane and 6-aza-spiro-[4,5] decane derivatives 5 and 9 have been prepared from 2-cyano-6-phenyloxazolopiperidine synthon 2b via alkylation followed by cyclisation of the resulting halogeno aminonitrile under dissolving metal conditions.