Quantum Chemical Calculations and Statistical Analysis: Structural Cytotoxicity Relationships of some Synthesized 2-thiophen-naphtho(benzo)oxazinone Derivatives

Twenty-two 2-thiophen-naphtho(benzo)oxazinone derivatives are prepared using 3-amino-2-naphthoic and 5-nitroanthranilic acids as building blocks. The target compounds (1–22) were evaluated quantitatively for their cytotoxic effects in vitro against three cancer cell lines, including the lung A549, the hepatocyte HepG2, and the breast MCF-7 carcinoma cells. Compounds 1, 12, 14, and 21 were found to exhibit remarkable cytotoxicity against the tested cancer cell lines. Compound 21 has shown the highest activity against A549 and MCF-7 (IC₅₀: 9.8 & 3.6 µg mL⁻¹) whereas 1 (IC₅₀: 5.9 µg mL⁻¹) and 5 (3.6 µg mL⁻¹) were the most active against HepG2. To elucidate the structure–cytotoxicity relationships of the synthesized compounds, a number of their chemical descriptors are determined including electronic, steric and hydrophobicity descriptors. The electronic properties were calculated through density functional theory (DFT) calculations at the B3LYP/6-31 + G(d,p). The impact of the chosen descriptors is evaluated statistically through simple and multiple linear regression analyses (SLR and MLR). SLR analyses reveal that the impact of each descriptor on the cell lines are relatively weak except for MCF-7, where hardness and softness show moderate correlations with correlation coefficients higher than 60%. The correlations were improved by considering MLR analyses (R² ≥ 90%), which showed that the cytotoxicity of synthesized compounds is correlated with their combined descriptors hardness, softness, electrophiliciy and hydrophobicity (LogP).