Synthesis and Antifungal Activity of Novel 3-Caren-5-One Oxime Esters

Abstract

A series of novel 3-caren-5-one oxime esters were designed and synthesized by multi-step reactions in an attempt to develop potent antifungal agents. Two E-Z stereoisomers of the intermediate 3-caren-5-one oxime were separated by column chromatography for the first time. The structures of all the intermediates and target compounds were confirmed by UV-Vis, FTIR, NMR, ESI-MS, and elemental analysis. The antifungal activity of the target compounds was preliminarily evaluated by the in vitro method against Fusarium oxysporum f. sp. cucumerinum, Physalospora piricola, Alternaria solani, Cercospora arachidicola, Gibberella zeae,Rhizoeotnia solani, Bipolaris maydis, and Colleterichum orbicalare at 50 µg/mL. The target compounds exhibited best antifungal activity against P. piricola, in which compounds (Z)-4r (R = β-pyridyl), (Z)-4q (R = α-thienyl), (E)-4f' (R = p-F Ph), (Z)-4i (R = m-Me Ph), (Z)-4j (R = p-Me Ph), and (Z)-4p (R = α-furyl) had inhibition rates of 97.1%, 87.4%, 87.4%, 85.0%, 81.9%, and 77.7%, respectively, showing better antifungal activity than that of the commercial fungicide chlorothanil. Also, compound (Z)-4r (R = β-pyridyl) displayed remarkable antifungal activity against all the tested fungi, with inhibition rates of 76.7%, 82.7%, 97.1%, 66.3%, 74.7%, 93.9%, 76.7% and 93.3%, respectively, showing better or comparable antifungal activity than that of the commercial fungicide chlorothanil. Besides, the E-Z isomers of the target oxime esters were found to show obvious differences in antifungal activity. These results provide an encouraging framework that could lead to the development of potent novel antifungal agents.

Keywords: 3-caren-5-one; 3-caren-5-one oxime ester; 3-carene; E-Z stereoisomer; antifungal activity.

Scheme 1

Synthesis of 3-caren-5-one oxime esters (Z)-4a–4w, and (E)-4f′, 4l′, 4r′. 4a: R = Ph; 4b: R = o-Cl Ph; 4c: R = m-Cl Ph; 4d: R = p-Cl Ph; 4e: R = o-F Ph 4f: R = p-F Ph; 4g: R = o-OMe Ph; 4h: R = o-Me Ph; 4i: R = m-Me Ph; 4j: R = p-Me Ph; 4k: R = 2,4-Cl Ph; 4l: R = 2,3-Cl Ph; 4m: R = p-CH₂Cl Ph; 4n: R = cyclopentyl; 4o: R = cyclohexyl; 4p: R = α-furyl; 4q: R = α-thienyl; 4r: R = β-pyridyl; 4s: R = α-Cl-β-pyridyl; 4t: R = n-pentyl; 4u: R = ethyl; 4v: R = n-propyl; 4w: R = n-butyl; 4f′: R = p-F Ph; 4l′: R = 2,3-Cl; 4r′: R = β-pyridyl.

Figure 1

¹H-NMR spectra of (Z)-3a and (E)-3b.

Figure 2

The coupling of C₄-H and hydroxyl hydrogen in ¹H-¹H NOESY spectra.