Synthesis, Biological Evaluation, Molecular Docking, and Dynamics, DFT Studies of Amide-functionalized 1,2,3-Triazole-Acridone Conjugates

The development of multifunctional small molecules with combined anti-inflammatory, antioxidant, and antitubercular potential remains an important strategy in medicinal chemistry. Acridone and 1,2,3-triazole scaffolds are well recognized for their diverse biological activities; however, amide-functionalized 1,2,3-triazole–acridone conjugates have been insufficiently explored for their therapeutic potential. In this study, a focused library of amide-functionalized 1,2,3-triazole–acridone conjugates 8a–n was designed and synthesized via a click chemistry approach to investigate their biological activities and structure–activity relationships. Evaluation revealed that conjugates 8a, 8b, 8f, 8i, and 8k exhibited significant in vitro anti-inflammatory activity, while 8a and 8k demonstrated the strongest antioxidant activity among the synthesized derivatives. None of the synthesized compounds showed appreciable antitubercular activity. Molecular docking studies supported the observed biological activities by revealing favorable interactions of the active conjugates with the target protein. Density functional theory (DFT) calculations provided insight into the electronic properties, molecular electrostatic potential, and frontier molecular orbitals, while molecular dynamics simulations confirmed the stable binding of the most active conjugate, 8k, within the target binding site. This study introduces a new class of amide-functionalized 1,2,3-triazole–acridone conjugates and demonstrates the synergistic integration of biological evaluation with computational investigations to establish the structure–activity relationships. The findings identify conjugate 8k as a promising lead for the development of novel anti-inflammatory and antioxidant agents and provide a rational framework for the future optimization of this molecular scaffold.