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

2021 ◽  
Vol 379 (5) ◽  
Author(s):  
Giovanna Li Petri ◽  
Maria Valeria Raimondi ◽  
Virginia Spanò ◽  
Ralph Holl ◽  
Paola Barraja ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Binding Mode ◽  
Biologically Active ◽  
Bioactive Molecules ◽  
Biological Profile ◽  
Pyrrolidine Ring ◽  
Reaction Conditions ◽  
Drug Candidates ◽  
Steric Factors ◽  
Proline Derivatives

AbstractThe 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.

scholarly journals Machine Learning to Identify Flexibility Signatures of Class A GPCR Inhibition

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 454 ◽  
Author(s):  
Joseph Bemister-Buffington ◽  
Alex J. Wolf ◽  
Sebastian Raschka ◽  
Leslie A. Kuhn
Keyword(s):  
Machine Learning ◽  
Ligand Binding ◽  
Binding Site ◽  
Nearest Neighbor ◽  
Three Dimensional ◽  
Binding Mode ◽  
Biologically Active ◽  
Ligand Binding Site ◽  
K Nearest Neighbor ◽  
Class A

We show that machine learning can pinpoint features distinguishing inactive from active states in proteins, in particular identifying key ligand binding site flexibility transitions in GPCRs that are triggered by biologically active ligands. Our analysis was performed on the helical segments and loops in 18 inactive and 9 active class A G protein-coupled receptors (GPCRs). These three-dimensional (3D) structures were determined in complex with ligands. However, considering the flexible versus rigid state identified by graph-theoretic ProFlex rigidity analysis for each helix and loop segment with the ligand removed, followed by feature selection and k-nearest neighbor classification, was sufficient to identify four segments surrounding the ligand binding site whose flexibility/rigidity accurately predicts whether a GPCR is in an active or inactive state. GPCRs bound to inhibitors were similar in their pattern of flexible versus rigid regions, whereas agonist-bound GPCRs were more flexible and diverse. This new ligand-proximal flexibility signature of GPCR activity was identified without knowledge of the ligand binding mode or previously defined switch regions, while being adjacent to the known transmission switch. Following this proof of concept, the ProFlex flexibility analysis coupled with pattern recognition and activity classification may be useful for predicting whether newly designed ligands behave as activators or inhibitors in protein families in general, based on the pattern of flexibility they induce in the protein.

Characterization of photosystem II with the atomic-force microscope

1992 ◽  
Vol 50 (2) ◽  
pp. 1146-1147
Author(s):  
Kathleen M. Marr ◽  
Mary K. Lyon
Keyword(s):  
Photosystem Ii ◽  
Atomic Force Microscope ◽  
Three Dimensional ◽  
Biologically Active ◽  
Atomic Force ◽  
Freeze Etching ◽  
Image Averaging ◽  
Oxygen Evolving ◽  
Averaging Techniques

Photosystem II (PSII) is different from all other reaction centers in that it splits water to evolve oxygen and hydrogen ions. This unique ability to evolve oxygen is partly due to three oxygen evolving polypeptides (OEPs) associated with the PSII complex. Freeze etching on grana derived insideout membranes revealed that the OEPs contribute to the observed tetrameric nature of the PSIl particle; when the OEPs are removed, a distinct dimer emerges. Thus, the surface of the PSII complex changes dramatically upon removal of these polypeptides. The atomic force microscope (AFM) is ideal for examining surface topography. The instrument provides a topographical view of individual PSII complexes, giving relatively high resolution three-dimensional information without image averaging techniques. In addition, the use of a fluid cell allows a biologically active sample to be maintained under fully hydrated and physiologically buffered conditions. The OEPs associated with PSII may be sequentially removed, thereby changing the surface of the complex by one polypeptide at a time.

Privileged Structures in the Design of Potential Drug Candidates for Neglected Diseases

2019 ◽  
Vol 26 (23) ◽  
pp. 4323-4354 ◽  
Author(s):  
Ana Cristina Lima Leite ◽  
José Wanderlan Pontes Espíndola ◽  
Marcos Veríssimo de Oliveira Cardoso ◽  
Gevanio Bezerra de Oliveira Filho
Keyword(s):  
Biologically Active ◽  
Neglected Diseases ◽  
Financial Return ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Wide Range ◽  
Methods Of Synthesis ◽  
Current Therapies ◽  
Resistant Strains ◽  
Privileged Structures

Background: Privileged motifs are recurring in a wide range of biologically active compounds that reach different pharmaceutical targets and pathways and could represent a suitable start point to access potential candidates in the neglected diseases field. The current therapies to treat these diseases are based in drugs that lack of the desired effectiveness, affordable methods of synthesis and allow a way to emergence of resistant strains. Due the lack of financial return, only few pharmaceutical companies have been investing in research for new therapeutics for neglected diseases (ND). Methods: Based on the literature search from 2002 to 2016, we discuss how six privileged motifs, focusing phthalimide, isatin, indole, thiosemicarbazone, thiazole, and thiazolidinone are particularly recurrent in compounds active against some of neglected diseases. Results: It was observed that attention was paid particularly for Chagas disease, malaria, tuberculosis, schistosomiasis, leishmaniasis, dengue, African sleeping sickness (Human African Trypanosomiasis - HAT) and toxoplasmosis. It was possible to verify that, among the ND, antitrypanosomal and antiplasmodial activities were between the most searched. Besides, thiosemicarbazone moiety seems to be the most versatile and frequently explored scaffold. As well, phthalimide, isatin, thiazole, and thiazolidone nucleus have been also explored in the ND field. Conclusion: Some described compounds, appear to be promising drug candidates, while others could represent a valuable inspiration in the research for new lead compounds.

Naturally Occurring Organic Acid-catalyzed Facile Diastereoselective Synthesis of Biologically Active (E)-3-(arylimino)indolin-2-one Derivatives in Water at Room Temperature

2019 ◽  
Vol 23 (16) ◽  
pp. 1778-1788 ◽  
Author(s):  
Gurpreet Kaur ◽  
Arvind Singh ◽  
Kiran Bala ◽  
Mamta Devi ◽  
Anjana Kumari ◽  
...  
Keyword(s):  
Room Temperature ◽  
Biologically Active ◽  
Environmentally Benign ◽  
Diastereoselective Synthesis ◽  
Substituted Anilines ◽  
Reaction Conditions ◽  
Naturally Occurring ◽  
Acid Catalyzed ◽  
Reaction Media ◽  
Column Chromatographic

A simple, straightforward and efficient method has been developed for the synthesis of (E)-3-(arylimino)indolin-2-one derivatives and (E)-2-((4-methoxyphenyl)imino)- acenaphthylen-1(2H)-one. The synthesis of these biologically-significant scaffolds was achieved from the reactions of various substituted anilines and isatins or acenaphthaquinone, respectively, using commercially available, environmentally benign and naturally occurring organic acids such as mandelic acid or itaconic acid as catalyst in aqueous medium at room temperature. Mild reaction conditions, energy efficiency, good to excellent yields, environmentally benign conditions, easy isolation of products, no need of column chromatographic separation and the reusability of reaction media are some of the significant features of the present protocol.

Synthesis and Biological Activity of Quaternary Quinolinium Salts: A Review

2020 ◽  
Vol 23 (21) ◽  
pp. 2271-2294 ◽  
Author(s):  
Divya Utreja ◽  
Shivali Sharma ◽  
Akhil Goyal ◽  
Komalpreet Kaur ◽  
Sonia Kaushal
Keyword(s):  
Tyrosine Kinases ◽  
Biological Activities ◽  
Polymeric Materials ◽  
Tubulin Polymerization ◽  
Quinoline Derivatives ◽  
Heterocyclic Chemistry ◽  
Biological Profile ◽  
Drug Candidates ◽  
Anti Hiv ◽  
Quinolinium Salts

Heterocyclic chemistry is the only branch of chemistry that has applications in varied areas such as dyes, photosensitizers, coordination compounds, polymeric materials, biological, and many other fields. Quinoline and its derivatives have always engrossed both synthetic chemists and biologists because of their diverse chemical and pharmacological properties as these ring systems can be easily found in various natural products, especially in alkaloids. Among alkaloids, quinoline derivatives i.e. quinolinium salts have attracted much attention nowadays owing to their diverse biological profile such as antimicrobial, antitumor, antifungal, hypotensive, anti-HIV, analgesics and anti-inflammatory, etc. Quinoline and its analogs have recently been examined for their modes of function in the inhibition of tyrosine kinases, proteasome, tubulin polymerization, topoisomerase, and DNA repair. These observations have been guiding scientists for the expansion of new quinoline derivatives with improved and varied biological activities. Quinolinium salts have immense possibilities and scope to investigate these compounds as potential drug candidates. Therefore, we shall present a concise compilation of this work to aid in present knowledge and to help researchers explore an interesting quinoline class having medicinal potential.

An Update on Recent Advances in Cubosome: A Novel Drug Delivery System

2021 ◽  
Vol 21 ◽  
Author(s):  
Madhukar Garg ◽  
Anju Goyal ◽  
Sapna Kumari
Keyword(s):  
Drug Delivery ◽  
Drug Delivery System ◽  
Lipid Bilayers ◽  
Delivery System ◽  
Liquid Crystalline ◽  
Three Dimensional ◽  
Biologically Active ◽  
Potential Applications ◽  
Health Related ◽  
Novel Drug

: Cubosomes are highly stable nanostructured liquid crystalline dosage delivery form derived from amphiphilic lipids and polymer-based stabilizers converting it in a form of effective biocompatible carrier for the drug delivery. The delivery form comprised of bicontinuous lipid bilayers arranged in three dimensional honeycombs like structure provided with two internal aqueous channels for incorporation of number of biologically active ingredients. In contrast liposomes they provide large surface area for incorporation of different types of ingredients. Due to the distinct advantages of biocompatibility and thermodynamic stability, cubosomes have remained the first preference as method of choice in the sustained release, controlled release and targeted release dosage forms as new drug delivery system for the better release of the drugs. As lot of advancement in the new form of dosage form has bring the novel avenues in drug delivery mechanisms so it was matter of worth to compile the latest updates on the various aspects of mentioned therapeutic delivery system including its structure, routes of applications along with the potential applications to encapsulate variety drugs to serve health related benefits.

Synthesis of Phosphonates via Michaelis-Arbuzov Reaction

2017 ◽  
Vol 14 (6) ◽  
pp. 883-903 ◽  
Author(s):  
Boppudi Hari Babu ◽  
Gandavaram Syam Prasad ◽  
Chamarthi Naga Raju ◽  
Mandava Venkata Basaveswara Rao
Keyword(s):  
Reaction Times ◽  
Biologically Active ◽  
Fine Tuning ◽  
Arbuzov Reaction ◽  
Reaction Conditions ◽  
Solvent Type ◽  
Potential Applications ◽  
Synthetic Methodologies ◽  
Optimal Reaction ◽  
The Arbuzov Reaction

Background: Michaelis–Arbuzov reaction has played a key role for the synthesis of dialkyl or diaryl phosphonates by reacting various alkyl or aryl halides with trialkyl or triaryl phosphite. This reaction is very versatile in the formation of P-C bond from the reaction of aliphatic halides with phosphinites or phosphites to yield phosphonates, phosphinates, phosphine oxides. The Arbuzov reaction developed some methodologies, possible mechanistic pathways, selectivity, potential applications and biologically active various phosphonates. Objective: The synthesis of phosphonates via Michaelis–Arbuzov reaction with many new and fascinating methodologies were developed and disclosed in the literature, and these are explored in this review. Conclusion: This review has discussed past developments and vast potential applications of Arbuzov reaction in the synthesis of organophosphonates. As presented in this review, various synthetic methodologies were developed to prepare a large variety of phosphonates. Improvements in the reaction conditions of Lewis-acid mediated Arbuzov rearrangement as well as the development of MW-assisted Arbuzov rearrangement were discussed. Finally, to achieve high selectivities and yields, fine-tuning of reaction conditions including solvent type, temperature, and optimal reaction times to be considered.

Pd Catalyzed N1/N4 Arylation of Piperazine for Synthesis of Drugs, Biological and Pharmaceutical Targets: An Overview of Buchwald Hartwig Amination Reaction of Piperazine in Drug Synthesis

2018 ◽  
Vol 15 (2) ◽  
pp. 208-220 ◽  
Author(s):  
Vaibhav Mishra ◽  
Tejpal Singh Chundawat
Keyword(s):  
Bond Formation ◽  
Catalyst Design ◽  
Biologically Active ◽  
Reaction Conditions ◽  
Biological Targets ◽  
Amination Reaction ◽  
Drug Synthesis ◽  
Substituted Piperazine ◽  
Approved Drugs ◽  
Fda Approved Drugs

Background: Substituted piperazine heterocycles are among the most significant structural components of pharmaceuticals. N1/N4 substituted piperazine containing drugs and biological targets are ranked 3rd in the top most frequent nitrogen heterocycles in U.S. FDA approved drugs. The high demand of N1/N4 substituted piperazine containing biologically active compounds and U.S. FDA approved drugs, has prompted the development of Pd catalyzed C-N bond formation reactions for their synthesis. Buchwald-Hartwig reaction is the key tool for the synthesis of these compounds. Objective: This review provides strategies for Pd catalyzed C-N bond formation at N1/N4 of piperazine in the synthesis of drugs and biological targets with diverse use of catalyst-ligand system and reaction parameters. Conclusion: It is clear from the review that a vast amount of work has been done in the synthesis of N1/N4 substituted piperazine containing targets under the Pd catalyzed Buchwald-Hartwig amination of aryl halides by using different catalyst-ligand systems. These methods have become increasingly versatile as a result of innovation in catalyst design and improvements in reaction conditions. This review gives an overview of recent utilization of Buchwald-Hartwig amination reaction in drug/target synthesis.

3D-QSAR Studies of S-DABO Derivatives as Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

2019 ◽  
Vol 16 (8) ◽  
pp. 868-881
Author(s):  
Yueping Wang ◽  
Jie Chang ◽  
Jiangyuan Wang ◽  
Peng Zhong ◽  
Yufang Zhang ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Three Dimensional ◽  
Predictive Ability ◽  
3D Qsar ◽  
Binding Mode ◽  
Quantitative Structure Activity Relationship ◽  
Field Analysis ◽  
Reverse Transcriptase Inhibitors ◽  
Qsar Studies ◽  
Hiv 1

Background: S-dihydro-alkyloxy-benzyl-oxopyrimidines (S-DABOs) as non-nucleoside reverse transcriptase inhibitors have received considerable attention during the last decade due to their high potency against HIV-1. Methods: In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) of a series of 38 S-DABO analogues developed in our lab was studied using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The Docking/MMFF94s computational protocol based on the co-crystallized complex (PDB ID: 1RT2) was used to determine the most probable binding mode and to obtain reliable conformations for molecular alignment. Statistically significant CoMFA (q2=0.766 and r2=0.949) and CoMSIA (q2=0.827 and r2=0.974) models were generated using the training set of 30 compounds on the basis of hybrid docking-based and ligand-based alignment. Results: The predictive ability of CoMFA and CoMSIA models was further validated using a test set of eight compounds with predictive r2 pred values of 0.843 and 0.723, respectively. Conclusion: The information obtained from the 3D contour maps can be used in designing new SDABO derivatives with improved HIV-1 inhibitory activity.

scholarly journals A Novel Pseudomonas geniculata AGE Family Epimerase/Isomerase and Its Application in d-Mannose Synthesis

Foods ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1809
Author(s):  
Zhanzhi Liu ◽  
Ying Li ◽  
Jing Wu ◽  
Sheng Chen
Keyword(s):  
3D Structure ◽  
Three Dimensional ◽  
Optimal Temperature ◽  
Reaction Conditions ◽  
Enzymatic Production ◽  
Physiological Properties ◽  
Potential Applications ◽  
Kinetics Of ◽  
Optimal Reaction ◽  
Gene Age

d-mannose has exhibited excellent physiological properties in the food, pharmaceutical, and feed industries. Therefore, emerging attention has been applied to enzymatic production of d-mannose due to its advantage over chemical synthesis. The gene age of N-acetyl-d-glucosamine 2-epimerase family epimerase/isomerase (AGEase) derived from Pseudomonas geniculata was amplified, and the recombinant P. geniculata AGEase was characterized. The optimal temperature and pH of P. geniculata AGEase were 60 °C and 7.5, respectively. The Km, kcat, and kcat/Km of P. geniculata AGEase for d-mannose were 49.2 ± 8.5 mM, 476.3 ± 4.0 s−1, and 9.7 ± 0.5 s−1·mM−1, respectively. The recombinant P. geniculata AGEase was classified into the YihS enzyme subfamily in the AGE enzyme family by analyzing its substrate specificity and active center of the three-dimensional (3D) structure. Further studies on the kinetics of different substrates showed that the P. geniculata AGEase belongs to the d-mannose isomerase of the YihS enzyme. The P. geniculata AGEase catalyzed the synthesis of d-mannose with d-fructose as a substrate, and the conversion rate was as high as 39.3% with the d-mannose yield of 78.6 g·L−1 under optimal reaction conditions of 200 g·L−1d-fructose and 2.5 U·mL−1P. geniculata AGEase. This novel P. geniculata AGEase has potential applications in the industrial production of d-mannose.

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