Synthesis, bioactivity and computational simulation study of novel ( Z )-3-caren-5-one oxime ethers as potential antifungal agents

In search of potent antifungal agents derived from natural product 3-carene, 19 novel ( Z )-3-caren-5-one oxime ethers 3a–3s were synthesized by multi-step reaction and characterized by UV–Vis, IR, NMR, ESI–MS and elemental analysis. The in vitro antifungal activity of all the target compounds was preliminarily evaluated, and the test results indicated that some of the target compounds displayed excellent inhibitory activity against R. Solani. For example, the inhibition percentages against R. Solani of compounds 3b (R = 2 ' –CH 3 ), 3c (R = 3 ' –CH 3 ) and 3i (R = 3 ' –Cl) were 98.4, 93.7 and 94.9%, respectively, which were superior or comparable to that of positive control chlorothalonil. The computational simulation study was also carried out to elucidate the structure–activity relationship (SAR) of the title compounds. Firstly, an effective and reasonable 3D-QSAR model, valuable for the optimization of the title compounds, was built by CoMFA method. In addition, DFT calculation uncovered that both 3-carene moiety and oxime ether group were the potential pharmacophores of compound 3b with the best antifungal activity. Meanwhile, molecular docking and dynamic simulation were employed for investigating the binding mode and dynamic stability of compound 3b in the Q 0 -site of cytochrome bc 1 complex, using original ligand JZV (trifloxystrobin) as comparison. Compounds 3b (R = 2 ' –CH 3 ) deserved further study as a leading compound.