In silico Investigations of Triazole-Tromethoxyphenyl Derivatives as Anti-Proliferative Agents against Adenocarcinomic Human Alveolar Basal Epithelial Cells (A549): DFT, QSAR and Molecular Docking Approaches

Twenty-eight sets of synthesized triazole-trimethoxyphenyl derivatives (TPDs) were considered as anti-proliferative drugs against human alveolar basal epithelial (A549) cancer cell lines using DFT, QSAR, ADMET profile and molecular docking methods. The considered compounds were used to develop a robust QSAR model, which was used to design new TPD compounds that could serve as anti-proliferative drug candidate against human alveolar basal epithelial (A549) cancer. The parameters obtained from DFT calculations such as the HOMO, LUMO, Dipole moment, chemical hardness and softness favoured TPD-11 and TPD-25 over etopoxide as strong inhibitors against human alveolar basal epithelialcancer cell (A549), which agreed with the experimental data. The QSAR modeling and validation indicated the major influence of Moran autocorrelation – lag 4/weighted by polarizabilities (MATS4p), Centered Broto-Moreau autocorrelation - lag 7/weighted by charges (ATSC7c), Minimum E-State descriptors of strength for potential Hydrogen Bonds of path length 3 (minHBint3) and Count of atom-type E-State: C (naasC) descriptors on the reported anticancer activity of the drugs in the A549- MLR-GFA QSAR (R2 = 0.8146, adjusted R2 = 0.7874, Q2Loo = 0.6015 and R2 - Q2Loo = 0.2582). Using the model data, four new TPDs (NTPD-3, NTPD-4, NTPD-6 and NTPD-9) were proposed. The DFT and molecular docking analysis showed that these four compounds could be good inhibitors against A549 than etopoxide. However, the ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties revealed NTPD-6 showed excellent pharmacokinetic and toxicological profiles and might serve as a road map for new and more effective anticancer agents.