scholarly journals Optimisation by Design of Experiment of Benzimidazol-2-One Synthesis under Flow Conditions

Molecules ◽  
2019 ◽  
Vol 24 (13) ◽  
pp. 2447 ◽  
Author(s):  
Serena Mostarda ◽  
Tugçe Gür Maz ◽  
Alessandro Piccinno ◽  
Bruno Cerra ◽  
Erden Banoglu
Keyword(s):  
Drug Discovery ◽  
Design Of Experiment ◽  
Model Reaction ◽  
High Yield ◽  
Flow Conditions ◽  
Inflammatory Drug ◽  
Drug Discovery Program ◽  
Scale Preparation ◽  
Privileged Scaffold ◽  
Set Up

A novel flow-based approach for the preparation of benzimidazol-2-one (1) scaffold by the 1,1′-carbonyldiimidazole (CDI)-promoted cyclocarbonylation of o-phenylenediamine (2) is reported. Starting from a preliminary batch screening, the model reaction was successfully translated under flow conditions and optimised by means of design of experiment (DoE). The method allowed the efficient preparation of this privileged scaffold and to set up a general protocol for the multigram-scale preparation in high yield, purity, and productivity, and was successfully applied for the multigram flow synthesis of N-(2-chlorobenzyl)-5-cyano-benzimidazol-2-one, which is a key synthon for hit-to-lead explorations in our anti-inflammatory drug discovery program.

PEG1000 as a Low Melting and Ecofriendly Solvent for Air Oxidative and Catalyst Free 2,4-Disubstitute Quinazoline Synthesis

2020 ◽  
Vol 17 (9) ◽  
pp. 709-716
Author(s):  
Ebrahim Saeedian Moghadam ◽  
Shahrzad Ghafary ◽  
Mohsen Amini
Keyword(s):  
Melting Point ◽  
High Yield ◽  
Purification Process ◽  
Poly Ethylene Glycol ◽  
Free Condition ◽  
Catalyst Free ◽  
Privileged Scaffold ◽  
Quinazoline Derivatives ◽  
Poly Ethylene ◽  
Work Up

With regard to the importance of quinazoline as a privileged scaffold, herein we report the synthesis of twenty seven 2,4-disubstitute quinazoline derivatives in a new catalyst free condition. In the current work, poly ethylene glycol (PEG1000) as an inexpensive, very simple commercially available, ecofriendly and low melting point solvent was used. Air bubbling, a green oxidant, for oxidation purpose was also used. This is the first report about using PEG1000 as a solvent simultaneously with air bubbling as oxidant in quinazoline synthesis. All of the compounds 1-27 were synthesized in high yield with very simple work up and purification process without using column chromatography. All the structures were confirmed using 1H NMR, 13C NMR, IR, MS and elemental analysis.

Natural Sesquiterpene Lactones in the Prevention and Treatment of Inflammatory Disorders and cancer: A Systematic Study of this Emerging Therapeutic Approach based on Chemical and Pharmacological Aspect

2020 ◽  
Vol 17 (9) ◽  
pp. 1102-1116
Author(s):  
Sudip Kumar Mandal ◽  
Utsab Debnath ◽  
Amresh Kumar ◽  
Sabu Thomas ◽  
Subhash Chandra Mandal ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Biological Activities ◽  
Sesquiterpene Lactones ◽  
Structural Diversity ◽  
Cancer Drug ◽  
Cancer Drug Discovery ◽  
Anti Cancer ◽  
Drug Discovery Program ◽  
Anti Inflammatory ◽  
Family Based

Background and Introduction: Sesquiterpene lactones are a class of secondary metabolite that contains sesquiterpenoids and lactone ring as pharmacophore moiety. A large group of bioactive secondary metabolites such as phytopharmaceuticals belong to this category. From the Asteraceae family-based medicinal plants, more than 5,000 sesquiterpene lactones have been reported so far. Sesquiterpene lactone-based pharmacophore moieties hold promise for broad-spectrum biological activities against cancer, inflammation, parasitic, bacterial, fungal, viral infection and other functional disorders. Moreover, these moiety based phytocompounds have been highlighted with a new dimension in the natural drug discovery program worldwide after the 2015 Medicine Nobel Prize achieved by the Artemisinin researchers. Objective: These bitter substances often contain an α, β-unsaturated-γ-lactone as a major structural backbone, which in recent studies has been explored to be associated with anti-tumor, cytotoxic, and anti-inflammatory action. Recently, the use of sesquiterpene lactones as phytomedicine has been increased. This study will review the prospect of sesquiterpene lactones against inflammation and cancer. Methods: Hence, we emphasized on the different features of this moiety by incorporating its structural diversity on biological activities to explore structure-activity relationships (SAR) against inflammation and cancer. Results: How the dual mode of action such as anti-inflammatory and anti-cancer has been exhibitedby these phytopharmaceuticals will be forecasted in this study. Furthermore, the correlation of anti-inflammatory and anti-cancer activity executed by the sesquiterpene lactones for fruitful phytotherapy will also be revealed in the present review in the milieu of pharmacophore activity relation and pharmacodynamics study as well. Conclusion: So, these metabolites are paramount in phytopharmacological aspects. The present discussion on the future prospect of this moiety based on the reported literature could be a guide for anti-inflammatory and anti-cancer drug discovery programs for the upcoming researchers.

scholarly journals Achieving selectivity in porphyrin bromination through a DoE-driven optimization under continuous flow conditions

2020 ◽  
Author(s):  
Paolo Zardi ◽  
Michele Maggini ◽  
Tommaso Carofiglio
Keyword(s):  
Reaction Time ◽  
Design Of Experiment ◽  
Continuous Flow ◽  
Optimization Process ◽  
Porphyrin Ring ◽  
Flow Conditions ◽  
Reaction Parameters ◽  
Synthetic Procedure ◽  
Relevant Factors ◽  
Post Functionalization

AbstractThe post-functionalization of porphyrins through the bromination in β position of the pyrrolic rings is a relevant transformation because the resulting bromoderivatives are useful synthons to covalently link a variety of chemical architectures to a porphyrin ring. However, single bromination of porphyrins is a challenging reaction for the abundancy of reactive β-pyrrolic positions in the aromatic macrocycle. We herein report a synthetic procedure for the efficient preparation of 2-bromo-5,10,15,20-tetraphenylporphyrin (1) under continuous flow conditions. The use of flow technology allows to reach an accurate control over critical reaction parameters such as temperature and reaction time. Furthermore, by performing the optimization process through a statistical DoE (Design of Experiment) approach, these parameters could be properly adjusted with a limited number of experiments. This process led us to a better understanding of the relevant factors that govern porphyrins monobromination and to obtain compound 1 with an unprecedent 80% yield.

Triazol: a privileged scaffold for proteolysis targeting chimeras

2019 ◽  
Vol 11 (22) ◽  
pp. 2919-2973 ◽  
Author(s):  
Li-Wen Xia ◽  
Meng-Yu Ba ◽  
Wei Liu ◽  
Weyland Cheng ◽  
Chao-Ping Hu ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Anticancer Activity ◽  
Mode Of Action ◽  
Critical Analysis ◽  
Enzyme Inhibitors ◽  
Structure Activity Relationship ◽  
Target Protein ◽  
Activity Relationship ◽  
Structure Activity ◽  
Privileged Scaffold

Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer activity. This review provides an overview of PROTACs with a triazole scaffold and discusses its structure–activity relationship. Important milestones in the development of PROTACs are addressed and a critical analysis of this drug discovery strategy is also presented.

A New Approach to Drug Discovery

2012 ◽  
Vol 17 (4) ◽  
pp. 542-549 ◽  
Author(s):  
Maria Cândida Monteiro ◽  
Mercedes de la Cruz ◽  
Juan Cantizani ◽  
Catalina Moreno ◽  
José R. Tormo ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Antifungal Activity ◽  
High Throughput Screening ◽  
Low Cost ◽  
Pharmacological Action ◽  
Natural Extracts ◽  
Microbial Extracts ◽  
Set Up ◽  
Microtiter Assay ◽  
Selection Of

Natural products are an inexhaustible source for drug discovery. However, the validation and selection of primary screening assays are vital to guarantee a selection of extracts or molecules with relevant pharmacological action and worthy of following up. The assay must be rapid, simple, easy to implement, and produce quick results and preferably at a low cost. In this work, we developed and validated a colorimetric microtiter assay using the resazurin viability dye. The parameters of the resazurin method for high-throughput screening (HTS) using natural extracts against Aspergillus fumigatus were optimized and set up. The extracts plus RPMI-1640 modified medium containing the spores and 0.002% resazurin were added per well. The fluorescence was read after 24 to 30 h of incubation. The resazurin proved to be as suitable as Alamar Blue for determining the minimal inhibitory concentration of different antifungals against A. fumigatus and effective to analyze fungicidal and fungistatic compounds. An HTS of 12 000 microbial extracts was carried out against two A. fumigatus strains, and 2.7% of the extracts displayed antifungal activity. Our group has been the first to use this methodology for screening a collection of natural extracts to identify compounds with antifungal activity against the medically important human pathogen A. fumigatus.

Surface Tubing Temperature Transducers Reduce Damage to Downhole Equipment Following a Downhole Gauge Failure

2021 ◽  
Author(s):  
Livia Zihlmann ◽  
Mike Parker ◽  
Luke Malsam
Keyword(s):  
Flow Pattern ◽  
Single Phase ◽  
Small Difference ◽  
Load Condition ◽  
Flow Conditions ◽  
Root Cause ◽  
Ground Conditions ◽  
Set Up ◽  
Phase Sensor ◽  
Downhole Sensors

Abstract Downhole sensors gather vital data for the health of an ESP system. Not only do the sensor readings help indicate the flow pattern; they also help indicate further issues such as plugging and degradation of the ESP system. Once a system has grounded on a single phase, sensor readings are lost, and operators must rely on current and frequency for the system to operate efficiently. In unconventional applications of ESP, operators see a small difference between no load, no flow and gas locking conditions. This small difference is due to the de-rating of motors used in order to get the fluid to surface in the severe applications. When the sensor readings typically are lost, operators are no longer able to accurately diagnose the reason for a shutdown. Adding the Tubing Temperature Transducers (TTT's) helps regain an indication of motor temperature along with load on the system. When operators have a drop in the tubing temperature this indicates the system is not able to get as much fluid to surface either indicating gas locking or a no-load condition which results in heating of the downhole system, particularly the motor. All these possible scenarios cause degradation of the ESP equipment and can cause pre-mature failure. If the system is set up with TTT's operators can shut-in the well to avoid extended periods of excessive heating caused by either gas locking or no flow conditions. Single phase to ground conditions occur frequently, however this paper does not address the root cause of a single-phase grounds, rather it addresses what the operator can do to operate efficiently when a unit has grounded out a single phase.

An Efficient Palladium-Catalyzed α-Arylation of Acetone Below its Boiling Point

Synlett ◽  
2020 ◽  
Vol 31 (15) ◽  
pp. 1532-1536
Author(s):  
Jeffery Richardson ◽  
Simon P. Mutton ◽  
Fionna M. Martin ◽  
Lesley Walton ◽  
Andrew J. Ledgard
Keyword(s):  
Drug Discovery ◽  
Boiling Point ◽  
Aryl Halide ◽  
Ambient Temperatures ◽  
Drug Discovery Program ◽  
Palladium Catalyzed ◽  
Discovery Program

The monoarylation of acetone is a powerful transformation, but is typically performed at temperatures significantly in excess of its boiling point. Conditions described for performing the reaction at ambient temperatures led to significant dehalogenation when applied to a complex aryl halide. We describe our attempts to overcome both issues in the context of our drug-discovery program.

Leveraging Automation toward Development of a High-Throughput Gene Expression Profiling Platform

2020 ◽  
pp. 247255522095659
Author(s):  
Jing Chen ◽  
Alan Futran ◽  
Austin Crithary ◽  
Sha Li ◽  
Alex Wolicki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Discovery ◽  
High Throughput ◽  
Screening Strategy ◽  
Qrt Pcr ◽  
Reverse Transcription Pcr ◽  
Expression Platform ◽  
Program Support ◽  
Drug Discovery Program ◽  
One Step

We previously developed a panel of one-step real-time quantitative reverse transcription PCR (one-step qRT-PCR; hereafter referred to as qRT-PCR) assays to assess compound efficacy. However, these high-cost, conventional qRT-PCR manual assays are not amenable to high-throughput screen (HTS) analysis in a time-sensitive and complex drug discovery process. Here, we report the establishment of an automated gene expression platform using in-house lysis conditions that allows the study of various cell lines, including primary T cells. This process innovation provides the opportunity to perform genotypic profiling in both immunology and oncology therapeutic areas with quantitative studies as part of routine drug discovery program support. This newly instituted platform also enables a panel screening strategy to efficiently connect HTS, lead identification, and lead optimization in parallel.

scholarly journals Mining the Information for Structure Based Drug Designing by Relational Database Management Notion

2009 ◽  
Vol 6 (4) ◽  
pp. 1047-1054
Author(s):  
R. Balajee ◽  
M. S. Dhanarajan
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Three Dimensional ◽  
Chemical Properties ◽  
Structure Based Drug Design ◽  
Molecular Systems ◽  
Drug Discovery Program ◽  
And Behavior

Structure based drug design is a technique that is used in the initial stages of a drug discovery program. The role of various computational methods in the characterization of the chemical properties and behavior of molecular systems is discussed. The field of bioinformatics has become a major part of the drug discovery pipeline playing a key role for validating drug targets. By integrating data from many inter-related yet heterogeneous resources, informatics can help in our understanding of complex biological processes and help improve drug discovery. The determination of the three dimensional properties of small molecules and macromolecular receptor structures is a core activity in the efforts towards a better understanding of structure-activity relationships.

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