Green Synthesis, Molecular Docking, and QSAR Study of Coumarin Derivatives as Acaricidal Agents Against Rhipicephalus (Boophilus) microplus

Coumarins are heterocyclic compounds with diverse biological activities and potential applications as alternative acaricidal agents. In this study, nine coumarin derivatives were synthesized through a solvent-free Pechmann reaction using Preyssler heteropolyacid as a reusable catalyst under green chemistry conditions. The synthesized compounds were evaluated against adult females of Rhipicephalus (Boophilus) microplus using the adult immersion test. Survival analysis was performed using the Cox proportional hazard model, while molecular docking studies were carried out on triosephosphate isomerase (TIM). In addition, post hoc analysis of the structures predicted to be most active by the QSAR model suggested an association between higher predicted activity, the presence of hydroxyl groups, and the polarity of C7 side chains, although the topological descriptor identified by the model does not admit a direct physicochemical interpretation. The results showed that hydroxylated coumarins, particularly those substituted at C5 and C7, exhibited the highest acaricidal activity, with IC50 values between 7.24 and 8.78 mg/mL. Docking analysis suggested plausible interactions with residues located at the TIM interface cavity, mainly Lys-112, Asn-65, and Glu-77. The QSAR model indicated that hydroxyl substitution and side-chain polarity contributed positively to activity. This study integrates Preyssler heteropolyacid-catalyzed green synthesis of coumarins with Cox proportional hazard survival modeling, TIM molecular docking, and QSAR analysis within a single acaricidal evaluation against R. (B.) microplus, providing a multi-pronged framework for prioritizing structural modifications in future coumarin-based acaricide development.