Synthesis and Antifungal\nActivity Evaluation of Novel <i>L</i>-Carvone-Based 1,3,4-Thiadiazole-amide\nDerivatives as a\nPotential Succinate Dehydrogenase Inhibitor

In an effort to explore new-type high-efficiency antifungal\nagents,\n25 novel <i>L</i>-carvone-based 1,3,4-thiadiazole-amide\nderivatives were designed, synthesized, and structurally characterized\nby IR, <sup>1</sup>H NMR, <sup>13</sup>C NMR, and high-resolution\nmass spectrometry (HRMS) analyses. The antifungal activity of the\ntarget compounds was preliminarily assayed at a concentration of 50\nμg/mL, and boscalid, a commercialized fungicide identified as\na succinate dehydrogenase inhibitor (SDHI), was employed as the positive\ncontrol. It was found that all of the target compounds showed moderate\nto potent antifungal activity against the tested fungi compared to\nboscalid. Surprisingly, compound <b>4b</b> exhibited broad-spectrum\nand significant inhibition activity against the growth of eight phytopathogenic\nstrains with inhibitory rates of 67–89%. Further, the results\nof the EC<sub>50</sub> value test suggested that the EC<sub>50</sub> values of compound <b>4b</b> against Physalospora\npiricola and Colletotrichum orbiculare were 16.33 and 18.06 μg/mL, respectively, and both of them\nwere better than those of boscalid (16.64 and >50). Therefore,\ncompound <b>4b</b> deserves further study as a lead compound\nfor novel fungicides.\nIn addition, the inhibitory activity of compound <b>4b</b> against\nsuccinate dehydrogenase (SDH) was evaluated as well to prove that\ncompound <b>4b</b> (IC<sub>50</sub> = 3.38 μM) displayed\nhigher SDH-inhibition activity than boscalid (IC<sub>50</sub> = 7.02\nμM). The binding mode of compound <b>4b</b> and SDH was\nsimulated by molecular docking and found to be similar to that of\nboscalid. The structure–activity relationships (SARs) of the\ntarget compounds were analyzed by establishing a 3D-QSAR model. Besides,\na <b>4b</b>-loaded complex <b>4b/CSTA</b> on a reported <i>L</i>-carvone-based nanochitosan carrier <b>CSTA</b> containing\nthe 1,3,4-thiadiazole-amide group was constructed, and its sustained\nrelease performance was investigated in the EtOH–H<sub>2</sub>O system (1:9, v/v). The complex <b>4b/CSTA</b> exhibited preferred\nsustained release performance, indicating its potential for developing\nenvironmentally friendly nanofungicides.