In Silico Study, Synthesis, Characterisation And Cytotoxicity Activity Of New Chalcone, Pyrazoline And Pyrimidine Derivatives

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Date
2021-05
Authors
Alanazi, Menier Meteb Mohammad
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Universiti Sains Malaysia
Abstract
Three new series of novel chalcone derivatives with promising anti-cancer activity were studied which are two series of tri-chalcone derivatives S1(1-7) and S2(1-7) and a series of mono-chalcone derivatives S3(1-7). Another three series of pyrazoline Ai-Aiii and pyrimidine Bi-Biii from mono-chalcone were also studied by AutoDock 4.2.6. The intermolecular interactions and binding energies of the proposed compounds were determined to be synthesised and characterized. The best compounds were selected for further investigation by MD simulation using AMBER 14. The following compounds of chalcone derivatives S1-1, S1-2, S2-1, S2-2, S3-1, S3-(3-5), pyrazoline derivatives Ai-Aiii and pyrimidine Bi-Biii from mono-chalcone S3-(1,3-5) demonstrated the highest binding affinity for the interaction with the active EGFR binding site. These selected chalcones, pyrazoline and pyrimidine derivatives were synthesised to test their cytotoxicity activity against breast cancer cell lines and EGFR inhibitory activity. Synthesis of the chalcone derivatives was performed via a Claisen-Schmidt condensation while the ring-closing of mono-chalcones formed the pyrazoline and pyrimidine derivatives. The chemical structures of the synthesised compounds were confirmed using spectroscopic techniques such as FTIR, 1H NMR, 13C NMR and elemental analysis (CHN analysis). Antiproliferative activity of the synthesised compounds against breast cancer cell lines (MCF-7 and MDA-MB-231) were evaluated using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT). The epidermal growth factor inhibition activity of the most cytotoxic compounds was assessed using ADP-Glo™ Kinase Assay (Promega, Madison). Interestingly, compounds S1-1 and S1-2 showed potent antiproliferative activity of MCF-7 (2.23 ± 0.11 and 2.04 ± 0.71 μM) and MDA-MB-231 (6.44 ± 0.01 and 3.75 ± 0.26 μM), relative to tamoxifen IC50 of 9.3 ± 0.44 and 18.92 ± 1.43 μM, respectively. Extensive hydrogen bond analysis throughout 7 ns molecular dynamics simulation of compounds S1-1 and S1-2 demonstrated the capacity of these compounds to retain the interactions that exert the inhibitory effect, especially interactions with MET 793 and LYS 745. The MM-GBSA calculations illustrated that the ligands form a powerful bond within the target site with binding energies of -56.6 and -44.04 kcal/mol for compounds S1-1 and S1-2, respectively. These binding energies were comparable with TAK-285 (-66.17 kcal/mol), which indicated that compounds S1-1 and S1-2 showed a significant improvement in the anticancer resistant treatment. This is due to their potential effects on the EGFR as inhibitors which were predicted by molecular dynamics simulation studies and in-vitro EGFR analysis. Their possible anti-ER effect was predicted by the in-vitro studies.
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Chemistry
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