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. method: 1,2,3-triazole derivatives of 2-aminobenzoxazole 3−15 and 2-mercaptobenzoxazole 18−32 were prepared through a three-step synthesis. The first step involved the cyclization of the benzoxazole ring, followed by a propargylation reaction, and finally, the introduction of a 4-substituted 1,2,3-triazole ring using a copper-catalyzed click reaction. All prepared benzoxazole derivatives were evaluated for their antiproliferative activity against the following human cancer cell lines: LN-229 (glioblastoma), Capan-1 (pancreatic adenocarcinoma), HCT-116 (colorectal carcinoma), NCI-H460 (lung carcinoma), DND-41 (acute lymphoblastic leukemia), HL-60 (acute myeloid leukemia), K-562 (chronic myeloid leukemia), and Z-138 (non-Hodgkin lymphoma). The ADME properties of the 1,2,3-triazole derivatives of benzoxazole with moderate to strong antiproliferative activity were assessed using the SwissADME web tool. The potential for passive gastrointestinal absorption (HGA) and blood-brain barrier (BBB) permeability were calculated using the Egan computational model to predict drug absorption. Molecular docking studies were performed for the 1,2,3-triazole derivatives with the most significant antiproliferative activities on two kinases: proto-oncogene tyrosine-protein kinase Src (c-Src) and serine/threonine-protein kinase TAO2. 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.