Synthesis of novel 2-pyrrolidinone and pyrrolidine derivatives and study of their inhibitory activity against autotaxin enzyme

Gerokonstantis, Dimitrios Triantafyllos; Nikolaou, Aikaterini; Magkrioti, Christiana; Afantitis, Antreas; Aidinis, Vassilis; Kokotos, George; Moutevelis‐Minakakis, Panagiota

doi:10.1016/j.bmc.2019.115216

Cited by 15 publications

(18 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In 2020, Gerokonstantis et al [ 67 ] synthesized compounds 89a–e and 90 (Fig. 20 ), which are potent inhibitors of autotaxin (ATX), a glycoprotein responsible for the hydrolysis of lysophosphatidylcholine (LPC) into bioactive lipid lysophosphatidic acid (LPA), whose upregulation is involved in pathological inflammatory conditions.…”

Section: Pyrrolidine Derivatives From Commercial Building Blocksmentioning

confidence: 99%

Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds

et al. 2021

View full text Add to dashboard Cite

The five-membered pyrrolidine ring is one of the nitrogen heterocycles used widely by medicinal chemists to obtain compounds for the treatment of human diseases. The great interest in this saturated scaffold is enhanced by (1) the possibility to efficiently explore the pharmacophore space due to sp3-hybridization, (2) the contribution to the stereochemistry of the molecule, (3) and the increased three-dimensional (3D) coverage due to the non-planarity of the ring—a phenomenon called “pseudorotation”. In this review, we report bioactive molecules with target selectivity characterized by the pyrrolidine ring and its derivatives, including pyrrolizines, pyrrolidine-2-one, pyrrolidine-2,5-diones and prolinol described in the literature from 2015 to date. After a comparison of the physicochemical parameters of pyrrolidine with the parent aromatic pyrrole and cyclopentane, we investigate the influence of steric factors on biological activity, also describing the structure–activity relationship (SAR) of the studied compounds. To aid the reader’s approach to reading the manuscript, we have planned the review on the basis of the synthetic strategies used: (1) ring construction from different cyclic or acyclic precursors, reporting the synthesis and the reaction conditions, or (2) functionalization of preformed pyrrolidine rings, e.g., proline derivatives. Since one of the most significant features of the pyrrolidine ring is the stereogenicity of carbons, we highlight how the different stereoisomers and the spatial orientation of substituents can lead to a different biological profile of drug candidates, due to the different binding mode to enantioselective proteins. We believe that this work can guide medicinal chemists to the best approach in the design of new pyrrolidine compounds with different biological profiles.

show abstract

Section: Pyrrolidine Derivatives From Commercial Building Blocksmentioning

confidence: 99%

Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds

et al. 2021

View full text Add to dashboard Cite

show abstract

“…[27,28] In addition to these heterocyclic aromatic compounds, aliphatic heterocyclic compounds such as morpholine, piperidine, and pyrrolidine are other examples of bioactive compounds used in many fields and pharmaceutical chemistry in particular. [29][30][31][32][33] In light of the significant literature data mentioned above, the main purpose of this study is to synthesize 2,6-disubstituted and 2,5,6-trisubstituted imidazo [2,1-b] [1,3,4]thiadiazole derivatives, to characterize these compounds using various spectroscopic methods, and to investigate their antimicrobial activity.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to these heterocyclic aromatic compounds, aliphatic heterocyclic compounds such as morpholine, piperidine, and pyrrolidine are other examples of bioactive compounds used in many fields and pharmaceutical chemistry in particular …”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization, Antimicrobial Evaluation, and Computational Investigation of Substituted Imidazo[2,1‐b][1,3,4]Thiadiazole Derivatives

Dagli

Karakurt

et al. 2020

ChemistrySelect

View full text Add to dashboard Cite

In this study, a novel series of 2,6-disubstituted and 2,5,6trisubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized starting from 2-amino-1,3,4-thiadiazole derivatives. Structures of the synthesized compounds were characterized using various analysis techniques. Then, in vitro biological activity tests were carried out for all synthesized compounds and they were found to show moderate to good activity against all bacteria and fungi tested. Next, molecular docking simulations were performed to observe the inhibition effect of the synthesized compounds on the 3R9C receptor and support their biological activity results. Finally, the pharmacokinetic, ADME and toxicity properties of all compounds were examined using FAF-Drugs and ProTox webservers and it was concluded that they had acceptable toxicity and ADME properties.

show abstract

“…The crucial role of ATX in the onset and progress of a multitude of severe disorders has attracted the interest of both the academic and industrial community towards the development of potent ATX inhibitors as drug-targets. Accordingly, several series of ATX inhibitors have been developed in the last decade ( Figure 1 ) [ 27 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Some of them were discovered by performing high-throughput screening methods while others by rational design, using the solved crystal structure of ATX co-crystallized with inhibitors [ 24 , 25 , 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors

Magkrioti

Kaffe

Stylianaki

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

Autotaxin (ATX) is a secreted glycoprotein, widely present in biological fluids, largely responsible for extracellular lysophosphatidic acid (LPA) production. LPA is a bioactive growth-factor-like lysophospholipid that exerts pleiotropic effects in almost all cell types, exerted through at least six G-protein-coupled receptors (LPAR1-6). Increased ATX expression has been detected in different chronic inflammatory diseases, while genetic or pharmacological studies have established ATX as a promising therapeutic target, exemplified by the ongoing phase III clinical trial for idiopathic pulmonary fibrosis. In this report, we employed an in silico drug discovery workflow, aiming at the identification of structurally novel series of ATX inhibitors that would be amenable to further optimization. Towards this end, a virtual screening protocol was applied involving the search into molecular databases for new small molecules potentially binding to ATX. The crystal structure of ATX in complex with a known inhibitor (HA-155) was used as a molecular model docking reference, yielding a priority list of 30 small molecule ATX inhibitors, validated by a well-established enzymatic assay of ATX activity. The two most potent, novel and structurally different compounds were further structurally optimized by deploying further in silico tools, resulting to the overall identification of six new ATX inhibitors that belong to distinct chemical classes than existing inhibitors, expanding the arsenal of chemical scaffolds and allowing further rational design.

show abstract

Synthesis of novel 2-pyrrolidinone and pyrrolidine derivatives and study of their inhibitory activity against autotaxin enzyme

Cited by 15 publications

References 63 publications

Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds

Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds

Synthesis, Characterization, Antimicrobial Evaluation, and Computational Investigation of Substituted Imidazo[2,1‐b][1,3,4]Thiadiazole Derivatives

Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors

Contact Info

Product

Resources

About