Abstract:Several substituted indolin-2-one derivatives were synthesized and evaluated for their activities against Src kinase. Several compounds showed activity against Src, with IC50 values in the low micromolar range. Among them, compound 2f showed the most significant activity with an IC50 value of 1.02 μM. Molecular docking studies have been performed for evaluation of the binding modes of compound 2f into the Src active site. The docking structure of compound 2f disclosed that the indole NH forms a hydrogen bond w… Show more
“…1, a highly conserved kinase domain is present in those three proteins. This region contains a ligand binding site targeted to design anticancer drugs in human, and many protein structures of this domain are available in the Protein Data Bank (PDB) [28–30]. Thus, these proteins (SRC, ABL1 and FAK1) were selected for further modelling of the target of our compounds.Fig.…”
BackgroundThis study aims to synthesise and characterise novel compounds containing 2-amino-1,3,4-thiadiazole and their acyl derivatives and to investigate antifungal activities. Similarity search, molecular dynamics and molecular docking were also studied to find out a potential target and enlighten the inhibition mechanism.ResultsAs a first step, 2-amino-1,3,4-thiadiazole derivatives (compounds 3 and 4) were synthesised with high yields (81 and 84%). The target compounds (6a–n and 7a–n) were then synthesised with moderate to high yields (56–87%) by reacting 3 and 4 with various acyl chloride derivatives (5a–n). The synthesized compounds were characterized using the IR, 1H-NMR, 13C-NMR, Mass, X-ray (compound 7n) and elemental analysis techniques. Later, the in vitro antifungal activities of the synthesised compounds were determined. The inhibition zones exhibited by the compounds against the tested fungi, their minimum fungicidal activities, minimum inhibitory concentration and the lethal dose values (LD50) were determined. The compounds exhibited moderate to high levels of activity against all tested pathogens. Finally, in silico modelling was used to enlighten inhibition mechanism using ligand and structure-based methods. As an initial step, similarity search was carried out and the resulting proteins that belong to Homo sapiens were used as reference in sequence similarity search to find the corresponding amino acid sequences in target organisms. Homology modelling was used to construct the protein structure. The stabilised protein structure obtained from molecular dynamics simulation was used in molecular docking.ConclusionThe overall results presented here might be a good starting point for the identification of novel and more active compounds as antifungal agents.Electronic supplementary materialThe online version of this article (10.1186/s13065-018-0485-3) contains supplementary material, which is available to authorized users.
“…1, a highly conserved kinase domain is present in those three proteins. This region contains a ligand binding site targeted to design anticancer drugs in human, and many protein structures of this domain are available in the Protein Data Bank (PDB) [28–30]. Thus, these proteins (SRC, ABL1 and FAK1) were selected for further modelling of the target of our compounds.Fig.…”
BackgroundThis study aims to synthesise and characterise novel compounds containing 2-amino-1,3,4-thiadiazole and their acyl derivatives and to investigate antifungal activities. Similarity search, molecular dynamics and molecular docking were also studied to find out a potential target and enlighten the inhibition mechanism.ResultsAs a first step, 2-amino-1,3,4-thiadiazole derivatives (compounds 3 and 4) were synthesised with high yields (81 and 84%). The target compounds (6a–n and 7a–n) were then synthesised with moderate to high yields (56–87%) by reacting 3 and 4 with various acyl chloride derivatives (5a–n). The synthesized compounds were characterized using the IR, 1H-NMR, 13C-NMR, Mass, X-ray (compound 7n) and elemental analysis techniques. Later, the in vitro antifungal activities of the synthesised compounds were determined. The inhibition zones exhibited by the compounds against the tested fungi, their minimum fungicidal activities, minimum inhibitory concentration and the lethal dose values (LD50) were determined. The compounds exhibited moderate to high levels of activity against all tested pathogens. Finally, in silico modelling was used to enlighten inhibition mechanism using ligand and structure-based methods. As an initial step, similarity search was carried out and the resulting proteins that belong to Homo sapiens were used as reference in sequence similarity search to find the corresponding amino acid sequences in target organisms. Homology modelling was used to construct the protein structure. The stabilised protein structure obtained from molecular dynamics simulation was used in molecular docking.ConclusionThe overall results presented here might be a good starting point for the identification of novel and more active compounds as antifungal agents.Electronic supplementary materialThe online version of this article (10.1186/s13065-018-0485-3) contains supplementary material, which is available to authorized users.
“…The nitrogen and oxygen atoms of indolin-2one ring expressed three hydrogen bonds with Glu342 and Thr341 amino acids. [50] A series of new benzofuran fused pyrazole templates were designed and synthesized by Abd El-Karim and group. These synthesized derivatives were tested for a panel 60 cancer cell lines for different cancers such as breast, colon, prostate, renal, ovarian, melanoma, CNS, Leukemia, non-small lung cancer.…”
Section: Recent Development Of Src Kinase Inhibitorsmentioning
confidence: 99%
“…The 4‐flurophenyl substituted benzylidene containing indolin‐2‐one derivative 53 (Figure 29) was the most potent molecules against Src kinase with IC 50 of 1.02 μM but less potent than imatinib (IC 50 : 0.717 μM) and PP1 (IC 50 : 0.17 μM) reference drugs. The nitrogen and oxygen atoms of indolin‐2‐one ring expressed three hydrogen bonds with Glu342 and Thr341 amino acids [50] …”
Section: Recent Development Of Src Kinase Inhibitorsmentioning
The physiological Src proto‐oncogene is a protein tyrosine kinase receptor that served as the essential signalling pathway in different types of cancer. The etiology of cancer involved various signalling pathways and Src signalling pathways are also involved in those clusters. Although the dysregulation of Src kinase resulted in cancer being discovered in the late 19th century it is still considered a cult pathway because it is not much explored by different medicinal chemists and oncologists. In this review, we have elaborated about the structure and activation of Src kinase, as well as the development of Src kinase inhibitors. Our group also provided a comprehensive overview of Src inhibitors throughout the last two decades, including their biological activity, structure‐activity relationship, and Src kinase selectivity. The Src binding pocket has been investigated in detail to better comprehend the interaction of Src inhibitors with amino acid residues. We have strengthened the literature with our contribution in terms of molecular docking and ADMET studies of top compounds. We hope that the current analysis will be a useful resource for researchers and provide glimpse of direction toward the design and development of more specific, selective, and potent Src kinase inhibitors.
“…To achieve this goal within a reasonable timeframe, we needed a rapid and robust docking tool. Docking studies have been used previously to find novel inhibitors with different biological properties [41][42][43] in particular in the discovery of Src kinase inhibitors [44][45][46][47]. Our studies were performed with the software PLANTS as virtual screening software and 16 compounds were evaluated.…”
A series of 1,4-disubstituted 1,2,3-triazole compounds were synthesized through an easy, convenient Cu(I) catalyzed click reaction and evaluated for their Src kinase activity. Compound 3m exhibited significant inhibitory activity against Src Kinase. These results, along with molecular design docking observations, are significant evidence to demonstrate the compound 3m could be optimized as a potential Src kinase inhibitor in further studies.
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