Synthesis, Antiproliferative Activity, ADME Profiling, and Docking Studies of Novel 1, 2, 3-Triazole Derivatives of 2-Amino and 2-Mercaptobenzoxazole.

Introduction: Benzoxazole is a privileged scaffold with diverse biological activities, and its hybridization with a 1,2,3-triazole ring can improve affinity and efficacy. This study aimed to synthesize novel 1,2,3-triazole derivatives of 2-aminobenzoxazole and 2-mercaptobenzoxazole, and to evaluate their antiproliferative activity, predicted pharmacokinetic properties, and molecular interactions with kinase targets.

Methods: 1,2,3-triazole derivatives of 2-aminobenzoxazole 3-15 and 2-mercaptobenzoxazole 18-32 were synthesized via cyclization, propargylation, and copper-catalyzed click reaction. Antiproliferative activity was evaluated against human cancer cell lines: LN-229, Capan-1, HCT-116, NCI-H460, DND-41, HL-60, K-562, and Z-138. The ADME properties of 1,2,3-triazole-benzoxazole hybrids were evaluated using the SwissADME tool. The most active compounds were assessed for Human Gastrointestinal Absorption (HGA) and Blood-Brain Barrier (BBB) permeability using the Egan model. Molecular docking was performed on serine/threonine kinase TAO2 and tyrosine kinase c-Src.

Results: A series of novel 1,2,3-triazole derivatives of 2-amino 3-15 and 2-mercaptobenzoxazole 18-32 were synthesized via click chemistry. Coumarin-containing compounds 3 and 29 showed the most pronounced antiproliferative activity across all tested cell lines. Both demonstrated high predicted HGA and low likelihood of crossing the BBB. Compound 3 exhibited the highest binding affinity for TAO2, while compound 29 showed strong interaction with c-Src.

Discussion: The results highlight the favorable influence of coumarin substitution on antiproliferative activity, with computational ADME and docking data supporting the observed in vitro efficacy.

Conclusion: This study outlines a viable method for the synthesis of novel 1,2,3-triazole derivatives of 2-aminobenzoxazole and 2-mercaptobenzoxazole. Compounds 3 and 29 demonstrate promising antiproliferative activity and pharmacokinetic potential, supporting their further development as anticancer candidates.