Design, synthesis, DFT, molecular modelling studies and biological evaluation of novel 3-substituted ( E )-5-(arylidene)-1-methyl-2-thioxoimidazolidin-4-ones with potent cytotoxic activities against breast MCF-7, liver HepG2, and lung A549

We report the synthesis of novel 3-substituted ( E )-5-(arylidene)-1-methyl-2-thioxoimidazolidin-4-ones 6 - 11, and their biological evaluation. Based on structural and pharmacophore analyses of known inhibitors such as fluorouracil (5-FU), we envisioned interesting 2-thioxoimidazolidin-4-one compounds, 3-substituted ( E )-5-(arylidene)-1-methyl-2-thioxoimidazolidin-4-ones 6-11 that would be expected to well match the structural features in 5-FU. Efficient synthesis of twenty-four target compounds 6-11 were achieved through the synthetic pathway of 5  →  6  →  7  →  10  →  11, established after consideration of several plausible synthetic pathways. A series of ( E )-5-(arylidene)-1-methyl-2-thioxoimidazolidinoneones 5a-d were synthesized via the reaction of 1-methyl-2-thioxoimidazolidin-4-one ( 3 ), which in turn was prepared via the reaction of N -methyl glycine ( 2 ) with NH 4 SCN, followed by Knoevenagel condensation. N -alkylation and N -glycosylation were carried via the reaction of 5a-d with alkyl bromides and α-glycopyranosyl bromides 9a,b under alkaline and glycoside conditions, respectively. The N -alkylated and N -glycosylated structures have been selected for the products. Conformational analysis has been studied by homonuclear and heteronuclear two-dimensional NMR methods (DQF-COSY, HMQC, and HMBC). The N site of alkylation and glycosylation were determined from the 1 H, 13 C heteronuclear multiple-quantum coherence (HMQC) experiments. Molecular modelling and DFT calculations using B3LYP/6-31+G (d, p) level were performed to study the electronic and geometric properties obtained from the stable structure of the investigated compounds. A good correlation between the quantum chemical descriptors and experimental observations was found. The synthesized derivatives exhibited good binding interactions towards the cyclin-dependent kinase 2, especially compound 11b, which have better key interactions than the co-crystallized ligand. Additionally, it had potent cytotoxic activities with IC 50  = 4.30, 5.53, 9.43 against MCF-7, HepG2, and A549, respectively.