Exploration of novel series of chalcone-phosphonates derivatives as Anticancer Agents: Synthesis, spectral characterization, in vitro anti-proliferative evaluation, molecular docking and in silico ADMET prediction

Abstract

Abstract Based on the wide range of pharmacological aspects related to organophosphates, a novel type of compound, containing chalcones-phosphonates derivative was synthesized by the reaction of dialkyl phosphite and substituted chalcones using anhydrous Mg(ClO4)2 at 80 °C under solvent-free conditions. All the obtained structures were confirmed by IR, 1H NMR 13C NMR, and HRMS techniques. The synthesized compounds were tested in vitro against a panel of three human cancer cell lines against MCF7, HeLa, and A549 cell lines. As compared to the reference drug Doxorubicin (IC50 = 4.17, 3.31, 6.61 µM against MCF7, HeLa, and A549 cell lines, respectively), most of the synthesized derivatives exhibited moderate to good antiproliferative activity. The structure-activity relationship of synthesized compounds is discussed. To speculate on the mechanism of anticancer activity, a molecular docking study was carried out. The molecular docking investigation indicates that all of the synthesized derivatives have good binding ability in the active site of the Vaccinia H1-related (VHR) phosphatase (PDB: 3F81), PI3- kinase (PDB: 3R7Q), androgen receptor (PDB: 3V49) and VEGFR2 kinase (PDB: 3VHE). Furthermore, all compounds were screened for in silico drug-likeness, and all were found to have drug-like properties, following the Lipinski rule of 5, with no PAINS alarms. Thus, the in vitro inhibitory activity and in silico molecular studies confirmed the potency of the chalcone-phosphonate derivatives for anti-proliferative activity.