Novel bis pyrimidine-pyrazolone and pyridinyl-4,5-dihydropyrimido[2,1[1]-c,1,2,4]triazepine utilized ultrasonic energy, anti-proliferative activity, docking simulation, and theoretical investigation

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Eco-friendly synthesis of novel bis heterocyclic compounds containing pyridine derivatives utilized green tools such as ultrasonication energy. Moreover, the nucleophilic substitution of bis pyrimidine-2-thiol derivatives with hydrazine hydrate in glacial acetic acid in order to form the corresponding bis(hydrazinyl-6-(pyridin-yl)pyrimidin-4-yl) derivatives 3a-c in excellent yield. Furthermore, the latter obtained hydrazinyl pyrimidine derivatives 3a-c can easily be attacked with ethylacetoactate to give bis dihydro-3H-pyrazol-3-one derivatives 5a-c, while the reactivity of acetyl acetone in glacial acetic acid using ultrasonic energy affords the dihydropyrimido[2,1-c][1,2,4]triazepin-9-yl)-5-methyl-1H-1,2,3-triazol-1-yl)benzene derivatives 7a-c, and these compounds were elucidated utilized spectrum analysis. These obtained compounds were exhibited as having antitumor activity against MCF-7 breast and A-549 carcinoma cell lines via neutral red uptake assays, and bis compounds 5c and 7cshowed excellent activity comparable to the doxorubicin drug. Moreover, these biological evaluations were confirmed through molecular docking simulation with PDBID: 4hdq and PDBID:2ito, which showed the least binding affinity with -11.641 and -13.646 kcal/mol, respectively. Also, the theoretical calculation of these bis heterocycles was optimized through the DFT/B3LYP/6-31(G) basis set, which identified their physical descriptors and showed the stability of these bis compounds, confirmed the experimental work with FMO, ESP, and MEP.