Synergistic Warriors: Design and Synthesis of Dual-Acting Schiff-Based Threaded 1,2,3-Triazole Hybrids for Potent Antineoplastic and Anti-Mycobacterial Activities.

Objective: In the pursuit of identifying divergent scaffolds for potential anticancer and anti-mycobacterial agents, a novel series of Schiff-based threaded 1,2,3-triazoles was designed and synthesized.

Methods: In this study, novel Schiff-based threaded 1,2,3-triazoles have been meticulously crafted and synthesized. Chemical structures of the synthesized molecules were confirmed by 1H NMR, 13C NMR and Mass spectra. Synthetic analogs were further evaluated for their antiproliferative, antitubercular and antimicrobial potentials by in vitro assays.

Results: The in vitro anti-tumor (anti-proliferative) evaluation on HT29 cancer cells revealed that compounds 8b and 8h exhibited remarkable inhibitory activity with IC50 values of 25±0.8 and 24±0.9 μM. In the context of anti-mycobacterial analysis, compound 8c demonstrated promising activity (6.25 μM) against Mycobacterium tuberculosis H37Rv. Moreover, compounds 8d and 8e displayed equipotent antimicrobial potential (3.12 μM) comparable to Ciprofloxacin against both Staphylococcus aureus and Escherichia coli. Molecular docking studies unveiled that 8c exhibited robust binding within the active pocket of carbonic anhydrase XII (docking energy -8.4 kcal/mol) and demonstrated a promising docking profile with β-ketoacyl ACP synthase I (docking energy - 9.5 kcal/mol) in the enzyme's binding pocket.

Conclusion: Structure-activity relationship (SAR) analysis identified three pivotal pharmacophores; 1,2,3-triazole, aromatic ring system (substituted with halogens and -NO2), and imine functionalities as crucial for the development of dual inhibitors targeting cancer and tuberculosis, showcasing an outstanding in silico ADMET profile. Therefore, these compounds merit consideration as noteworthy pharmacological lead molecules in the realm of cancer and tuberculosis drug discovery and development.