Novel 1,3-oxathiole derivatives: Efficient one-pot synthesis, antitumor efficiency, X-ray crystallographic, Hirshfeld surface, and Fukui function analysis

An efficient one-pot access of two novel 1,3-oxathiole derivatives namely, ethyl (Z)-2-(4-acetyl-5-methyl-1,3- oxathiol-2-ylidene)-2-cyanoacetate; 7a and ethyl (Z)-2-(1-cyano-2-ethoxy-2-oxoethylidene)-5-methyl-1,3-oxathiole-4-carboxylate; 7b is described. The title compounds were prepared from the reaction of ethyl 2-cyanoacetate with carbon disulfide and 3-chloropentane-2,4‑dione or ethyl 2‑chloro-3-oxobutanoate in a K2CO3/DMF mixture. Their chemical structures were fully identified and characterized using spectral (IR, NMR, MS) and Xray single-crystal structure analysis. The molecules of 7a and 7b are connected in the 3D via C–H…O and π-π stacking interactions, respectively. Using Hirshfeld analysis, the H…H, O…H, and N…H contacts dominate the molecular packing of 7a 28.3, 25.0, and 15.9 %, respectively, while 38.8, 20.3 and 15.0 % for 7b, respectively. The local reactivity was determined using Fukui functions and dual descriptor indices. According to the Fukui function, the susceptibility to nucleophilic attack was mainly detected on C2, C5, C6, and O7 in 7a, and C2, C5, and O7 in 7b The in vitro cytotoxicity of the synthesized compounds was evaluated against cancer cell lines: MCF-7 (breast cancer), HepG2 (liver cancer), and HCT116 (colorectal cancer). Compound 7a is particularly effective against HepG2 cells with an IC50 value of 7.8 ± 0.7 μg/mL and impacts MCF-7 and HCT116 with IC50 values of 26.5 ± 1.8 and 26.3 ± 1.4 μg/mL, respectively. In contrast, compound 7b has moderate activity against HepG2 but limited effect on the other two lines.