Green synthesis of N-aryl-1-(2-bromo-4-methyl phenyl)-1H-tetrazol-5-amines as novel anti-cancer agents targeting tubulin-Combretastatin A4 complex and human non-small cell lung cancer cell lines.

Abstract

A series of N-aryl-1-(2-bromo-4-methyl phenyl)-1H-tetrazol-5-amines was synthesized through a two-step microwave-assisted protocol from 2-bromo-1-isothiocyanato-4-methylbenzene and substituted aryl amines. Initially, thiourea derivatives were prepared under solvent-free microwave conditions, followed by cyclization with sodium azide in the presence of potassium hydroxide and molecular iodine to afford the desired tetrazole derivatives in good to excellent yields within short reaction times. All synthesized compounds were characterized by FT-IR, ¹H NMR, ¹³C NMR, and mass spectral analysis. The anti-lung cancer activity of compounds was evaluated against A549, EKVX, and NCI-H460 cell lines. Compounds substituted with isopropyl and benzo[d][1,3]dioxole exhibited the most potent anti-proliferative activity compared to the reference drug Combretastatin A4. Molecular docking studies against tubulin protein (PDB ID: 5LYJ) revealed favorable binding interactions within the colchicine binding pocket, mainly involving GLU22 amino acid residue. Furthermore, ADMET, QSAR, bioactivity, toxicity risk, drug property and molecular fingerprint property evaluation studies indicated favorable drug-like properties, good absorption characteristics, and non-toxic nature of the synthesized compounds. Overall, the present study identifies tetrazole derivatives as promising scaffolds for the development of potential anti-lung cancer agents.