Ethyl 4-(2-fluorophenyl)-6-methyl-2-thioxo-1-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The Biginelli reaction is a highly versatile reaction that leads to dihydropyrimidinones/thiones. This scaffold is reported as being a privileged structure due to its ability to interact with biological targets. Synthesis of ethyl 4-(2-fluorophenyl)-6-methyl-2-thioxo-1-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate was achieved through the Biginelli reaction using a functionalized thiourea. In silico studies demonstrated that the compound title showed good potential for interacting with ecto-5’-nucleotidase, which has been considered as a target in designs for anti-cancer drugs.

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Ethyl 4-(2-fluorophenyl)-6-methyl-2-thioxo-1-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

10.20944/preprints201810.0381.v1 ◽

2018 ◽

Author(s):

Itamar Luís Gonçalves ◽

Luciano Porto Kagami ◽

Gustavo Machado das Neves ◽

Liliana Rockenbach ◽

Leonardo Davi ◽

...

Keyword(s):

In Silico ◽

Biginelli Reaction ◽

Cancer Drugs ◽

Biological Targets ◽

In Silico Studies ◽

Anti Cancer ◽

Privileged Structure ◽

Good Potential

The Biginelli reaction is a highly versatile reaction, which leads to dihydropyrimidinones/thiones. This scaffold is reported as being a privileged structure due to its ability to interact with biological targets. Synthesis of ethyl 4-(2-fluorophenyl)-6-methyl-2-thioxo-1-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate was achieved through the Biginelli reaction using a functionalized thiourea. In silico studies demonstrated that the compound title showed good potential for interacting with ecto-5’-nucleotidase, which has been considered as a target in designs for anti-cancer drugs.

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Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies

Journal of Enzyme Inhibition and Medicinal Chemistry ◽

10.1080/14756366.2021.1945591 ◽

2021 ◽

Vol 36 (1) ◽

pp. 1732-1750

Author(s):

Mohammed M. Alanazi ◽

Elwan Alaa ◽

Nawaf A. Alsaif ◽

Ahmad J. Obaidullah ◽

Hamad M. Alkahtani ◽

...

Keyword(s):

In Silico ◽

Design Synthesis ◽

In Silico Studies ◽

Anti Cancer

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Shedding Light on the Interaction of Human Anti-Apoptotic Bcl-2 Protein with Ligands through Biophysical and in Silico Studies

International Journal of Molecular Sciences ◽

10.3390/ijms20040860 ◽

2019 ◽

Vol 20 (4) ◽

pp. 860 ◽

Cited By ~ 2

Author(s):

Joao Ramos ◽

Jayaraman Muthukumaran ◽

Filipe Freire ◽

João Paquete-Ferreira ◽

Ana Otrelo-Cardoso ◽

...

Keyword(s):

Conformational Changes ◽

In Silico ◽

Nucleotide Polymorphisms ◽

Ligand Interaction ◽

Zinc Database ◽

In Silico Studies ◽

Anti Cancer ◽

Binding Groove ◽

The Stability ◽

Dynamics Simulations

Bcl-2 protein is involved in cell apoptosis and is considered an interesting target for anti-cancer therapy. The present study aims to understand the stability and conformational changes of Bcl-2 upon interaction with the inhibitor venetoclax, and to explore other drug-target regions. We combined biophysical and in silico approaches to understand the mechanism of ligand binding to Bcl-2. Thermal shift assay (TSA) and urea electrophoresis showed a significant increase in protein stability upon venetoclax incubation, which is corroborated by molecular docking and molecular dynamics simulations. An 18 °C shift in Bcl-2 melting temperature was observed in the TSA, corresponding to a binding affinity multiple times higher than that of any other reported Bcl-2 inhibitor. This protein-ligand interaction does not implicate alternations in protein conformation, as suggested by SAXS. Additionally, bioinformatics approaches were used to identify deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) of Bcl-2 and their impact on venetoclax binding, suggesting that venetoclax interaction is generally favored against these deleterious nsSNPs. Apart from the BH3 binding groove of Bcl-2, the flexible loop domain (FLD) also plays an important role in regulating the apoptotic process. High-throughput virtual screening (HTVS) identified 5 putative FLD inhibitors from the Zinc database, showing nanomolar affinity toward the FLD of Bcl-2.

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Development of oxopyrrolidine-based anti-cancer compounds: DNA binding, in silico, cell line studies, drug-likeness and mechanism at supra-molecular level

Chemical Papers ◽

10.2478/s11696-013-0486-6 ◽

2014 ◽

Vol 68 (4) ◽

Cited By ~ 9

Author(s):

Imran Ali ◽

Waseem Wani ◽

Kishwar Saleem ◽

Ming-Fa Hsieh

Keyword(s):

Dna Binding ◽

In Silico ◽

Binding Constants ◽

Sodium Hydride ◽

Nitrogen Atmosphere ◽

In Silico Studies ◽

Anti Cancer ◽

Increasing Demand ◽

Good Oral Bioavailability ◽

Mcf 7

AbstractDue to an increasing demand for effective anti-cancer drugs, an oxopyrrolidine-based ligand, sodium 1-(3-(2-aminoethylamino)propyl)-5-oxopyrrolidine-2-carboxylate, was synthesised by the sodium hydride-assisted coupling of pyroglutamic acid with 1,3-diiodopropane under a nitrogen atmosphere. The intermediate thus formed was allowed to react with ethylenediamine in acetonitrile. The ligand formed individual complexes with Cu(II) and Ni(II) metal ions, respectively. The complexes were relatively resistant to degradation in PBS at physiological pH. The DNA-binding constants (K b) for the ligand, copper and nickel complexes were 2.09 × 104 M-1, 2.37 × 104 M-1 and 2.11 × 104 M-1, respectively, revealing the strong binding of these complexes with DNA. Haemolysis assays indicated that the ligand and its complexes were less toxic to rabbit RBCs than doxorubicin. Lipinski’s parameters calculated for the reported compounds indicated their good oral bioavailability. All the compounds exhibited good activities towards MCF-7 (wild type) cancer cell lines. The results of in silico studies, DNA-binding and anti-cancer activities indicated that the reported compounds might be interacting with DNA as one of their possible mechanisms of action.

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Computational Drug Designing and Prediction Of Important Parameters Using in silico Methods- A Review

Current Computer - Aided Drug Design ◽

10.2174/1573399815666190326120006 ◽

2019 ◽

Vol 15 (5) ◽

pp. 384-397

Author(s):

Tahmeena Khan ◽

Alfred J. Lawrence ◽

Iqbal Azad ◽

Saman Raza ◽

Seema Joshi ◽

...

Keyword(s):

In Silico ◽

Docking Studies ◽

Drug Uptake ◽

Drug Candidate ◽

Potential Drug ◽

Toxicological Assessment ◽

Biological Targets ◽

In Silico Studies ◽

Drug Designing

Background:: Computational or in silico studies are undertaken to assess the drug like properties of lead compounds. These studies help in fast prediction of relevant properties. Objective: : Through this review, an effort is made to encapsulate some of the important parameters which should be met by a compound for it to be considered as a potential drug candidate along with an overview of automated softwares which can be used for making various predictions. Methods:: Drug uptake, its absorption, evacuation and associated hazardous effects are important factors for consideration in drug designing and should be known in early stages of drug development. Several important physicochemical properties like molecular weight, polar surface area (PSA), molecular flexibility etc. have to be taken into consideration in drug designing. Toxicological assessment is another important aspect of drug discovery which predicts the safety and adverse effects of a drug. Results: : Additionally, bioactivity scores of probable drug leads against various human receptors can also be predicted to evaluate the probability of them to act as a potential drug candidate. The in vivo biological targets of a molecule can also be efficiently predicted by molecular docking studies. Conclusion:: Some important software like iGEMDOCK, AutoDock, OSIRIS property explorer, Molinspiration, MetaPrint2D, admetSAR and their working methodology and principle of working have been summarized in this review.

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Safe and Effective Kinase Inhibitors for the Treatment of Gynecological Cancers: In Silico Approach

Current Drug Metabolism ◽

10.2174/1389200222666210331125421 ◽

2021 ◽

Vol 22 ◽

Author(s):

Vaishali M. Patil ◽

Abhishek Kumar ◽

Vaishali Anand ◽

Priya Bansal ◽

Neeraj Masand

Keyword(s):

Mortality Rate ◽

Anticancer Agents ◽

In Silico ◽

Kinase Inhibitors ◽

Developmental Toxicity ◽

Reproductive Toxicity ◽

Cancer Therapeutics ◽

Cancer Drugs ◽

Gynecological Cancers ◽

Anti Cancer

Aims: To study various types of gynecological cancers and the available therapeutics to investigate safe and effective drugs. Background: Cancer is the most common cause of mortality throughout the world. When the statistics is considered for gynecological cancers, ovarian, cervical and uterine cancers are among the most prevalent types. They have worst prognosis and the highest mortality rate and by the year 2040 significant increase in mortality rate is predicted. Objective: The major limitation with development of anti-cancer therapeutics for the gynecological cancers are safety of the therapeutics for the developing fetus as well as the mother. Various medicinal classes of natural to synthetic therapeutics have been reported including kinase inhibitors as the most promising category of anti-cancer drugs. Method: A dataset of kinase inhibitory clinically approved anticancer agents was derived through literature review. A QSAR based approach i.e. VEGAQSAR has been applied to evaluate the reproductive and developmental toxicity for the selected class of kinase inhibitors. Result: In the present work, the promising category of anticancer kinase inhibitors has been investigated for its toxicity potential with the help of in silico approach. The anti-cancer kinase inhibitors were categorized based on the found non-toxic or toxic properties towards reproductive and developmental toxicity. Conclusion: Early prediction of the available or proposed anti-cancer therapeutics for their contribution towards developmental and reproductive toxicity is an important criterion for their use in pregnancy associated cancers. The investigation of toxicity profile of available anti-cancer kinase therapeutics will be helpful to design and develop novel and safe anti-cancer drugs in the near future. Other: The study outcomes will benefit the current anticancer drug development efforts.

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