Pyrrolidine Derivatives Research Articles

Improved binding affinities of pyrrolidine derivatives as Mcl-1 inhibitors by modifying amino acid side chains

As an important member of anti-apoptotic Bcl-2 protein, myeloid cell leukemia sequence 1 (Mcl-1) protein is an attractive target for cancer therapy. In this study, a new series of pyrrolidine derivatives as Mcl-1 inhibitors were developed by mainly modifying the amino acid side chain of compound 1. Among them, compound 18 (Ki=0.077μM) exhibited better potent inhibitory activities towards Mcl-1 protein compared to positive control Gossypol (Ki=0.18μM). In addition, compound 40 possessed good antiproliferative activities against PC-3 cells (Ki=8.45μM), which was the same as positive control Gossypol (Ki=7.54μM).

Enantioselective Synthesis of Polysubstituted Benzopyrano[3,4-c]pyrrolidine Frameworks via [3 + 2] Cycloaddition of Azomethine Ylides and Coumarin Derivatives.

An enantioselective synthesis of benzopyrano[3,4-c]pyrrolidine derivatives via organocatalyzed [3 + 2] cycloaddition has been achieved. Cinchona alkaloid-derived organocatalysts as Brønsted bases have been examined for this asymmetric cycloaddition of o-hydroxy aromatic aldimines with 3-substituted coumarins. An unexpected rearrangement of the quaternary acyl moiety in the products resulted in an in situ protection of the o-hydroxy group.

Nitrogen-containing acetals and ketals in the synthesis of pyrrolidine derivatives

This review offers analysis and generalization of data regarding the synthesis of substituted pyrrolidines by using nitrogen-containing acetals and ketals as starting compounds published from year 2000 to 2016. Particular attention has been focused on the synthesis of pyrrolidines that are substituted at position 2. Biological activity data for several pyrrolidine derivatives are reported.

Synthesis, Antimicrobial and In Silico EGFR Inhibitory Activity Evaluation of Sulfonylamino Pyrrolidine Derivatives

A series of novel sulfonylamino pyrrolidine derivatives were synthesized, characterized and evaluated for their antimicrobial activity. All compounds exhibited moderate activity against the microorganisms tested. The compounds were evaluated in silico for their ability to inhibit epidermal growth factor receptor (EGFR). Docking in silico demonstrated that the sulfonylamino pyrrolidine derivatives represent a new class of EGFR inhibitors and bind at the ATP binding pocket of the tyrosine kinase domain of EGFR. The free energy of binding and inhibition constant (k i) of the docked compounds were evaluated.

Enzymatic Ugi Reaction with Amines and Cyclic Imines.

The application of the Ugi reaction to the construction of new peptide scaffolds is an important goal of organic chemistry. To date, there are no examples of the Ugi reaction being performed with a cyclic imine and amine simultaneously. The application of 2-substituted cyclic imines in an enzymatic three-component Ugi-type reaction provides an elegant and attractive synthesis of substituted pyrrolidine and piperidine derivatives in up to 60 % yield. Results on studies of the selection of an enzyme, amount of water, and solvent used in a novel three-component Ugi reaction and the limitations thereof are reported herein. The presented methodology exploiting enzyme promiscuity in the multicomponent reaction fulfills the requirements associated with green chemistry. Several methods, such as isotope labeling and enzyme inhibition, were used to probe the possible mechanism of this complex synthesis. This research is the first example of an enzyme-catalyzed Ugi-type reaction with an imine, amine, and isocyanide.

Ring Expansion of Donor-Acceptor Cyclopropane via Substituent Controlled Selective N-Transfer of Oxaziridine: Synthetic and Mechanistic Insights.

A distinctive N-substituent controlled electrophilic N-transfer of oxaziridines with donor-acceptor cyclopropanes in the presence of MgI2 is reported. Contrary to earlier reports, the oxaziridine having bulkier N-substituents can also give N-transferred product instead of the O-transferred one. Interestingly, the oxaziridines having α-H containing N-substituents lead to the pyrrolidine derivatives through [3 + 2] cycloaddition. A mechanistic reasoning for this divergent reactivity is depicted by density functional theory calculations and validated through energy decomposition analysis.

Identification of fused bicyclic derivatives of pyrrolidine and imidazolidinone as dengue virus-2 NS2B-NS3 protease inhibitors

A series of fused ring derivatives of pyrrolidine and imidazolidinone were designed, synthesized, characterized and assayed against the DENV-2 NS2B-NS3 protease and wild-type DENV-2 virus. The linear dipeptide compound 1 and the non-peptidic fused ring compound 2 show comparable activities against DENV-2 NS2B-NS3 protease and wild-type DENV-2 virus in a viral replication assay. The preliminary SAR reveals that a substituent and its stereochemistry at C-3 position, substitution (X) at N-2 arene and a linker (Y) between C-3 position and its attached arene are important for the fused-ring scaffold of pyrrolidino [1,2-c]imidazolidinone to block the active site of NS2B-NS3 protease. This promising structural core will facilitate the discovery of non-peptidic, potent NS2B-NS3 protease inhibitors to stop dengue virus infections.

Straightforward and Highly Stereoselective Synthesis of 3,3,4‐Trifluoropyrrolidines Involving 1,3‐Dipolar Cycloaddition with 2,3,3‐Trifluoroacrylate

The reactions of benzyl 2,3,3‐trifluoroacrylate with azomethine ylides, generated by the treatment of imino esters with lithium diisopropylamide, took place smoothly to give the corresponding 1,3‐dipolar cycloadducts, fluorine‐containing pyrrolidines, in good yields and with high diastereoselectivities (>95:<5). When the fluorinated acrylate bore a chiral auxiliary as a substituent, for instance (l)‐(–)‐menthyl ester, the 1,3‐dipolar cycloaddition reaction was found to give the corresponding fluorinated pyrrolidine derivatives in not only a diastereoselective but also an enantioselective manner.

Asymmetric Organocatalysis in the Synthesis of Pyrrolidine Derivatives­ Bearing a Benzofuran-3(2H)-one Scaffold

A new enantio- and diastereoselective approach to pyrrolidine derivatives bearing a benzofuran-3(2<i>H</i>)-one scaffold is reported. The approach, based on the [3+2] cycloaddition between 2-arylidenebenzofuran-3(2<i>H</i>)-ones and imines derived from salicylaldehyde and diethyl aminomalonates, benefits from broad substrate scope, high chemical and stereochemical efficiency, and operational simplicity. Notably, simple and readily available quinine is employed as the catalyst of the reaction. Target products bearing two biologically relevant heterocyclic moieties and three adjacent stereogenic centers with one being quaternary have been obtained in excellent yields and in a highly stereoselective manner.

Access to Fluoropyrrolidines by Intramolecular Aza-Michael Addition Reaction

Study of the intramolecular aza-Michael addition reaction from an aminofluorovinylsulfone opens a new route for the synthesis of pyrrolidine derivatives. An unexpected diastereoselective cyclization reaction was observed, leading preferentially to the anti-N-benzylpyrrolidine sulfone. The resulting sulfone was reacted with aldehydes to access β-substituted α-fluoroalkenyl pyrrolidines in one step.

Directing Group in Decarboxylative Cross-Coupling: Copper-Catalyzed Site-Selective C-N Bond Formation from Nonactivated Aliphatic Carboxylic Acids.

Copper-catalyzed directed decarboxylative amination of nonactivated aliphatic carboxylic acids is described. This intramolecular C-N bond formation reaction provides efficient access to the synthesis of pyrrolidine and piperidine derivatives as well as the modification of complex natural products. Moreover, this reaction presents excellent site-selectivity in the C-N bond formation step through the use of directing group. Our work can be considered as a big step toward controllable radical decarboxylative carbon-heteroatom cross-coupling.

Pyrrolidinone and pyrrolidine derivatives: Evaluation as inhibitors of InhA and Mycobacterium tuberculosis

A series of GEQ analogues bearing pyrrolidinone or pyrrolidine cores were synthesized and evaluated against InhA, essential target for Mycobacterium tuberculosis (M.tb) survival. The compounds were also evaluated against M.tb H37Rv growth. Interestingly, some of the compounds, not efficient as InhA inhibitors, are active against M.tb with MICs up to 1.4 μM. In particular, compound 4b was screened with different M.tb mutated strains in order to identify the cellular target, but without success, suggesting a new possible mode of action.

First investigation of modified poly(2-vinyl-4,4-dimethylazlactone)s as kinetic hydrate inhibitors

A series of polymers of 2-vinyl-4,4-dimethylazlactone (VDMA) of varying molecular weights modified with small organic amines have been synthesized. Their performance as kinetic hydrate inhibitors (KHIs) has been investigated in high pressure steel rocking cells using a Structure II-forming synthetic hydrocarbon gas mixture. It was found that the PVDMA polymer with the lowest molecular weight (Mn=1845g/mole by 1H NMR) performed the best. It was also found that the n-propylamine derivative performed the best of the amine derivatives. The cloud point of this polymer derivative was found to be lower than ambient temperature, which is considered too low for practical oilfield applications. However, high cloud point PVDMA derivatives such as the ethylamine or pyrrolidine derivatives still gave reasonable KHI performance. The KHI performance of the n-propylamine derivative of PVDMA-I was tested at different concentrations in the range 1000–7000ppm. It was found that the performance improved as the polymer concentration was increased.

REGIOSPECIFIC SYNTHESIS AND RATIONALIZATION OF THE REGIODIVERGENCE SOME SPIROOXINDOLES AS EXPECTED ANTIOXIDANT AGENTS

The spirooxindolo pyrrolidine frameworks form core units of many naturally occurring molecules possess significant pharmacological activities. The [3+2] cycloaddition reactions of azomethine ylides has been realized through multi-component reaction (MCR) affording regiospecific spiroindoline-3, 2’-pyrrolidine derivatives. The reactivity of the spiroindoline (increase EHOMO value) has been depended upon electron repelling and attracting groups. The behavior of spiroindoline towards carbon electrophile and nitrogen nucleophile can be investigated. All compound structures are fully supported by spectroscopic data and elemental analysis.The antioxidant activity for these synthesized compounds could be expected that highly antioxidant activity was with compounds which proved to possess high HOMO values

ChemInform Abstract: Chain Walking as a Strategy for Carbon—Carbon Bond Formation at Unreactive Sites in Organic Synthesis: Catalytic Cycloisomerization of Various 1,n‐Dienes

Abstract20 examples

ChemInform Abstract: Enantioselective Synthesis of Fused Heterocycles with Contiguous Stereogenic Centers by Chiral Phosphoric Acid Catalyzed Symmetry Breaking.

Described herein is a highly enantioselective synthesis of fused piperidine and pyrrolidine derivatives with all-carbon stereogenic centers. The enantioselective reductive amination from Cs-symmetric 1,3-dione derivatives proceeded in a highly stereoselective manner by taking advantage of the desymmetrization approach to afford fused heterocycles with contiguous stereogenic centers in good to excellent enantioselectivities (up to 98% ee).

Discovery of novel S1P2 antagonists, part 3: Improving the oral bioavailability of a series of 1,3-bis(aryloxy)benzene derivatives.

The structure of the S1P2 antagonist 1 has been modified with the aim of improving its oral bioavailability. The chemical modification of the alkyl chain and carboxylic acid moieties of 1 led to significant improvements in the oral exposure of compounds belonging to this series. The optimization of the ring size of the urea portion of these molecules also led to remarkable improvements in the oral exposure. Based on these changes, the pyrrolidine derivative 16 was identified as a suitable candidate compound and showed excellent pharmacokinetic profiles in rat and dog, while maintaining high levels of potency and selective antagonistic activity toward S1P2.

Use of Diverse Chemometric and Validation Methods to Accurately Predict Human Urotensin-II Receptor Antagonist Activity.

Despite being identified as the most potent receptor related to vasoconstriction, human urotensin-II receptor (hUT) has not been fully explored as a target for the treatment of cardiovascular diseases. In view of this and with an aim to identify precise structural requirements for binding of hUT antagonists, we endeavoured to develop, for the first time, multivariate QSAR models using chemometric methods like partial least squares (PLS) and feed-forward neural network (FFNN). A set of 48 pyrrolidine derivatives having hUT binding affinity was used for multivariate model development. The accuracy and predictability of the developed models was evaluated using crossvalidation. The PLS model showed good correlation between selected descriptors and Ki values (r(2) =0.745 and r(2) (CV) =0.773). However, the predictive performance of FFNN was better than the PLS technique with r(2) =0.810. The study clearly suggests the role of lipophilic and steric descriptors in the ligand-hUT interactions. The QSAR models generated can be successfully extended to predict the binding affinities and for the effective design of novel hUT antagonists.

Diastereoselective synthesis of novel tetra-and pentacyclic annulated coumarino-δ-sultam pyrrolidine, pyrrolizidine, pyrrolothiazole and isoxazolidine derivatives via intramolecular 1,3-dipolar cycloadditions

A facile and efficient strategy towards the novel tetra- and pentacyclic annulated coumarino-δ-sultam pyrrolidine, pyrrolizidine, pyrrolothiazole and isoxazolidine via intramolecular 1,3-dipolar cycloadditions of is described.

ChemInform Abstract: Palladium‐Catalyzed Radical Cascade Iododifluoromethylation/Cyclization of 1,6‐Enynes with Ethyl Difluoroiodoacetate.

AbstractThe title reaction proceeds under mild reaction conditions to give pyrrolidine derivatives with high stereoselectivity.