Computational design and evaluation employed DFT, molecular docking, molecular dynamics, and ADMET analysis of salen-based drug candidates for potential cancer and tuberculosis treatment.

Salen (SL) ligands are known for their tetradentate N2O2 coordination, planar, and rigid structure. It attracts significant interest due to its diverse biological activities. However, challenges like cytotoxicity, low solubility, and physiological instability hinder the therapeutic applications. To overcome these challenges, an in-silico approach has been utilized to design SL-based compounds with functional group modifications and evaluate them to enhance their anticancer and antituberculosis activities. The B3LYP functional and 6-31 + G (d, p) basis set were used to optimize the modified structures. Most of the derivatives, especially SL5 ( - 1295.03 Hartree), SL6 ( - 1327.15 Hartree), and SL7 ( - 1703.61 Hartree), showed better thermodynamic stability than the parent ( - 879.06 Hartree), and higher dipole moments ranging from 3.65 to 6.68 than the parent (1.25) in Debye. The energy gap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) was lower, indicating these compounds have higher chemical reactivity. Docking results revealed stronger binding affinities for SL5 ( - 8.9 kcal/mol), SL6 ( - 8.9 kcal/mol), and SL7 ( - 9.3 kcal/mol) derivatives. Hydrogen bonds, carbon-hydrogen bonds, alkyl, and π-alabsorptionkyl are the crucial non-bonding interactions. Further, molecular dynamics (MD) simulations were done to investigate the stability and interaction of drugs and proteins. The RMSD value of Mean ± SD for SL6 is 1.21 ± 0.13 and for SL5 is 1.48 ± 0.26, as the most promising drug within 3ZHH and 1MQ4 protein, respectively. ADMET predicts better pharmacokinetic properties, such as high human intestinal absorption (HIA) values for SL5 (0.97), SL6 (0.96), and SL7 (0.99), and minimum blood-brain barrier (BBB) penetration, such as SL5 (0.21), SL6 (0.07). Additionally, gastrointestinal bleeding, atrial fibrillation, and allergic dermatitis adverse effects have been reduced in the most promising drugs than the parent. This computational study proves that these drug candidates can be utilized as medicines, as they exhibit higher stability and safety with enhanced drug-like properties. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00500-8.