Salophen shows promise as a catalyst and bioactive compound, but poor reactivity under physiological conditions limits practical use. We designed six heterocyclic derivatives incorporating benzofuran (BF), benzoxazole (BFz), benzothiophene (BT), benzothiazole (BTz), indole (ID), and benzimidazole (IDz) to improve its biological and catalytic profile. DFT calculations at the B3LYP/6-31G(d) level mapped thermochemical and electronic properties. Molecular docking tested binding interactions against Aurora-A kinase (1MQ4) and Mycobacterium tuberculosis beta-lactamase (3ZHH). We ran 100-nanosecond molecular dynamics (MD) simulations and MM-GBSA binding free-energy calculations to assess stability. ADMET and PASS analyses evaluated pharmacokinetic and toxicological profiles comprehensively. SBTz proved most electronically stable (HOMO-LUMO gap: 3.72 eV), while SID showed the highest reactivity (3.28 eV). Docking results favored the derivatives over the parent compound: SBF gave the strongest binding to 1MQ4 (- 12 kcal/mol) and SIDz to 3ZHH (- 9.2 kcal/mol). MM-GBSA calculations confirmed SIDz as the top predicted binder with 3ZHH (- 36.65 kcal/mol versus – 33.70 kcal/mol for parent S). All compounds displayed favorable oral absorption and low predicted toxicity across the series. These results identify promising computational leads warranting experimental validation in anticancer and antitubercular applications.