Synthesis and Evaluation of New 3,4-Dihydropyrimidin-2-(1H)-Ones and -Thiones as Anti-Cancer Agents: In Vitro, Molecular Docking and SAR Studies

Abstract

Using Silica Sulfuric Acid (SSA) as an eco-friendly, readily available, and reusable catalyst, herein we were prepared a new series of 3,4-dihydropyrimidin-2-(1H)ones and -thiones 4–16 (DHMPs). The condensation reaction of 2,5-dimethoxybenzaldehyde, 1,3-diphenylpropane-1,3-dione, and thiourea as one-pot reaction (known as Biginelli reaction) by using different catalysts. Silica sulfuric acid (SSA) showed the best catalytic activity (with yield 99%) using 0.11 mol at 15 min in the presence of ethylene glycol as green solvent. The targeted compounds of 3,4-dihydropyrimidin-2-(1H)ones and -thiones 4–16 have been fully characterized and tested as novel anti-cancer agents. The biological activity of the synthesized compounds 4–16, were evaluated in vitro as anti-cancer agents against both liver (Huh7 cell line) and lung cancer (A549) cells. Most of the tested compounds showed potential cytotoxic activity against liver cancer (Huh7) cell line, while they had moderate to week cytotoxic activity against lung cancer (A549) cell line. Most notably, compound 13 was the most effective cytotoxic agent against both liver and lung cancer cell lines, with less toxicity against non-cancer cell line MDCK, when compared to Doxorubicin as reference drug. Therefore, the mode of action of this compound using flow cytometry and molecular docking was investigated. The SAR study showed that the pyrimidines that contains chloride, florid or methoxy groups in their structures gave potent anti-cancer activity than that contains phenyl or naphthalene moieties, while the presence of sulfur as a substitution on the pyrimidine ring increased the anti-cancer activity than that observed in the presence of oxygen.