Synthesis, antimicrobial, anti-cancer and in silico studies of new urea derivatives

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

Molbank ◽

10.3390/m1029 ◽

2018 ◽

Vol 2018 (4) ◽

pp. M1029 ◽

Cited By ~ 1

Author(s):

Itamar 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 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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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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Design, synthesis, anti-cancer activity and in-silico studies of some novel 4,5-dihydroisoxazole-5-carboxamide derivatives

Synthetic Communications ◽

10.1080/00397911.2021.1974041 ◽

2021 ◽

pp. 1-11

Author(s):

Srinivas Endoori ◽

Kali Charan Gulipalli ◽

Srinu Bodige ◽

Arbaz Sujat Shaikh ◽

Divya Vemula ◽

...

Keyword(s):

In Silico ◽

Design Synthesis ◽

In Silico Studies ◽

Anti Cancer ◽

Cancer Activity

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Design, Synthesis, Anti-Cancer Activity, and in silico Studies of Novel Imidazo[1,2-a]pyridine Derivatives

Russian Journal of General Chemistry ◽

10.1134/s1070363220090212 ◽

2020 ◽

Vol 90 (9) ◽

pp. 1727-1736

Author(s):

S. Endoori ◽

K. C. Gulipalli ◽

S. Bodige ◽

J. N. Narendra Sharath Chandra ◽

N. Seelam

Keyword(s):

In Silico ◽

Pyridine Derivatives ◽

Design Synthesis ◽

In Silico Studies ◽

Anti Cancer ◽

Cancer Activity

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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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1,3-Disubstituted urea derivatives: Synthesis, antimicrobial activity evaluation and in silico studies

Bioorganic Chemistry ◽

10.1016/j.bioorg.2020.104104 ◽

2020 ◽

Vol 102 ◽

pp. 104104 ◽

Cited By ~ 1

Author(s):

Miyase Gözde Gündüz ◽

Sümeyye Buran Uğur ◽

Funda Güney ◽

Ceren Özkul ◽

Vagolu Siva Krishna ◽

...

Keyword(s):

Antimicrobial Activity ◽

In Silico ◽

Urea Derivatives ◽

Activity Evaluation ◽

In Silico Studies

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Potential Anti-Cancer Flavonoids Isolated From Caesalpinia bonduc Young Twigs and Leaves: Molecular Docking and In Silico Studies

Bioinformatics and Biology Insights ◽

10.1177/1177932218821371 ◽

2019 ◽

Vol 13 ◽

pp. 117793221882137 ◽

Cited By ~ 4

Author(s):

Franklyn Nonso Iheagwam ◽

Olubanke Olujoke Ogunlana ◽

Oluseyi Ebenezer Ogunlana ◽

Itunuoluwa Isewon ◽

Jelili Oyelade

Keyword(s):

Molecular Docking ◽

In Silico ◽

Strong Interactions ◽

Cytotoxic Activities ◽

Target Proteins ◽

Lead Compounds ◽

In Silico Studies ◽

Anti Cancer ◽

Therapeutic Molecules ◽

Endothelial Growth Factor

Tyrosine kinase (TK), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP) are important cancer therapeutic target proteins. Based on reported anti-cancer and cytotoxic activities of Caesalpinia bonduc, this study isolated phytochemicals from young twigs and leaves of C bonduc and identified the interaction between them and cancer target proteins (TK, VEGF, and MMP) in silico. AutoDock Vina, iGEMDOCK, and analysis of pharmacokinetic and pharmacodynamic properties of the isolated bioactives as therapeutic molecules were performed. Seven phytochemicals (7-hydroxy-4′-methoxy-3,11-dehydrohomoisoflavanone, 4,4′-dihydroxy-2’-methoxy-chalcone, 7,4′-dihydroxy-3,11-dehydrohomoisoflavanone, luteolin, quercetin-3-methyl, kaempferol-3-O-β-d-xylopyranoside and kaempferol-3-O-α-l-rhamnopyranosyl-(1 → 2)-β-D-xylopyranoside) were isolated. Molecular docking analysis showed that the phytochemicals displayed strong interactions with the proteins compared with their respective drug inhibitors. Pharmacokinetic and pharmacodynamic properties of the compounds were promising suggesting that they can be developed as putative lead compounds for developing new anti-cancer drugs.

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