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Background
Breast cancer is a major form of health problem on the globe and the second cause of death related to cancer amidst women. A prediction of about 1 to 1.3 million cases on cancer of the breast are detected yearly globally. Triple-negative type of breast cancers (TNBCs) are described by the lack of human epidermal growth factor receptor 2...
Citations
... Compound 67 (− 7.4 kcal/moL) would be the most effective TR1 inhibitor (Fig. 26). The ligands had docking scores better than the standard anti-breast cancer drug gefitinib (− 5.3 kcal/mol) [42]. ...
... .(15). Structure of compound(41)(42)(43). ...
Anilinopyrimidines have a wide range of biological activities, including antibacterial, antifungal, and anticancer effects. They have a wide range of uses and opportunities due to their varied experimental preparation and study activities. This creates a lot of interest, experiments and analytical analyses are still being conducted to understand their medicinal chemistry better. According to their effects, which can include antifungal and antibacterial, anticancer or antitumor, and other properties, anilinopyrimidines are categorized in this review. In conclusion, it is critical to base the design of new anilinopyrimidine derivatives and the creation of novel synthesis methodologies on the most recent information discovered through recent research. This review intends to shed light on advancements in the synthetic and biological activity of analogs of anilinopyrimidines.
Our cascading attempt to develop new potent molecules now involves designing a series of imidazole derivatives and synthesizing two sets of 2,4,5- tri-substituted (4a-4d) and 1,2,4,5-tetra-substituted (6a-6d) imidazole by the principle of Debus-Radziszewski multicomponent synthesis reaction. The structures of the obtained compounds were confirmed by 1H/13C NMR, FT-IR, elemental analysis, purity and the retention time was analyzed by HPLC. Based upon the binding affinity in the molecular docking studies, we have synthesized different imidazole derivatives from which compound 6c have been found to show more anti-proliferative activity by inducing apoptosis at a higher rate than the other compounds corroborating the in-silico prediction. The structure and crystallinity of compound 4d have been confirmed by single XRD analysis. The synthesized molecules were screened for their in vitro anti-cancer properties in triple negative breast cancer cell line (MDA-MB-231), pancreatic cancer cell lines (MIA PaCa-2) and oral squamous cell carcinoma cell line (H357) and results indicated that all the compounds inhibited the cell proliferation in a concentration-dependent manner at different time points. The compounds 4b and 6d were found to be effective against the S. aureus bacterial strain whereas only compound 4d fairly inhibited the fungal strain of T. rubrum with a MIC 12.5 μg/mL. Molecular docking study reveals good interaction of the synthesized compounds with known target MELK involved in oncogenesis having high binding profiles. The lead compound 6c was further analyzed by the detailed molecular dynamics study to establish the stability of the ligand-enzyme complex.
Background
Cancer of the breast is known to be among the top spreading diseases on the globe. Triple-negative breast cancer is painstaking the most destructive type of mammary tumor because it spreads faster to other parts of the body, with high chances of early relapse and mortality. This research would aim at utilizing computational methods like quantitative structure–activity relationship (QSAR), performing molecular docking studies and again to further design new effective molecules using the QSAR model parameters and to analyze the pharmacokinetics “drug-likeliness” properties of the new compounds before they could proceed to pre-clinical trials.
Results
The QSAR model of the derivatives was highly robust as it also conforms to the least minimum requirement for QSAR model from the statistical assessments of ( R ² ) = 0.6715, ( R ² adj ) = 0.61920, ( Q ² ) = 0.5460 and ( R ² pred) of 0.5304, and the model parameters (AATS6i and VR1_Dze) were used in designing new derivative compounds with higher potency. The molecular docking studies between the derivative compounds and Maternal Embryonic Leucine Zipper Kinase (MELK) protein target revealed that ligand 2, 9 and 17 had the highest binding affinities of − 9.3, − 9.3 and − 8.9 kcal/mol which was found to be higher than the standard drug adriamycin with − 7.8 kcal/mol. The pharmacokinetics analysis carried out on the newly designed compounds revealed that all the compounds passed the drug-likeness test and also the Lipinski rule of five.
Conclusions
The results obtained from the QSAR mathematical model of parthenolide derivatives were used in designing new derivatives compounds that were more effective and potent. The molecular docking result of parthenolide derivatives showed that compounds 2, 9 and 17 had higher docking scores than the standard drug adriamycin. The compounds would serve as the most promising inhibitors (MELK). Furthermore, the pharmacokinetics analysis carried out on the newly designed compounds revealed that all the compounds passed the drug-likeness test (ADME and other physicochemical properties) and they also adhered to the Lipinski rule of five. This gives a great breakthrough in medicine in finding the cure to triple-negative breast cancer (MBA-MD-231 cell line).
The anti-proliferative activities of Novel series of 2-(4-fluorophenyl) imidazol-5-ones against MCF-7 breast cancer cell line were
explored via in-slico studies which includes Quantitative structure–activity relationship QSAR, molecular docking studies,
designing new compounds, and analyzing the pharmacokinetics properties of the designed compounds. From the QSAR anal�ysis, model number one emerged the best as seen from the arithmetic assessments of (R2
) = 0.6981, (R2
adj) = 0.6433, (Q2
) =
0.5460 and (R2
pred) of 0.5357. Model number one was used in designing new derivative compounds, with higher effectiveness
against estrogen positive breast cancer (MCF-7 cell line). The Molecular docking studies between the derivatives and Polo-like
kinases (Plk1) receptor proved that the derivatives of 2-(4-fluorophenyl) imidazol-5-ones bind tightly to the receptor, thou ligand
24 and 27 had the highest binding affinities of −8.8 and − 9.1 kcal/mol, which was found to be higher than Doxorubicin with a
docking score of −8.0 kcal/mol. These new derivatives of 2-(4-fluorophenyl) imidazol-5-ones shall be excellent inhibitors against
(plk1). The pharmacokinetics analysis performed on the new structures revealed that all the structures passed the test and also the
Lipinski rule of five, and they could further proceed to pre-clinical tests. They both revealed a revolution in medicine for
developing novel anti-breast cancer drugs against MCF-7 cell line.
