Design and Synthesis of Thymol Derivatives Bearing a 1,2,3-Triazole Moiety for Papaya Protection against .

Azole-based fungicides are among the market's most widely used and effective agents. However, their indiscriminate use can lead to reduced efficacy and increased pathogen resistance. This highlights the need for novel fungicides that offer improved efficiency and lower environmental impact for controlling phytopathogenic fungi. In this study, a series of 20 novel thymol derivatives, incorporating a 1,2,3-triazole moiety, were synthesized via a three-step process, with the key step being the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The antifungal activity of these compounds was evaluated against , the etiological agent of papaya fruit and stem rot. Additionally, molecular docking was performed to assess the binding energy and interaction modes of these derivatives with the lanosterol 14α-demethylase (CYP51) enzyme. Docking results demonstrated that all derivatives bound to the catalytic pocket of CYP51 with lower binding energy (<-10 kcal/mol) compared to the azole fungicide tebuconazole (-8.2 kcal/mol) and the substrate lanosterol (-9.0 kcal/mol). The observed fungicidal activity is likely due to the occupancy of the entrance tunnel and active site of the CYP51 by these derivatives, thereby blocking lanosterol and its conversion into ergosterol.