Synthesis and Biological Evaluation of Norcantharidin Derivatives Possessing an Aromatic Amine Moiety as Antifungal Agents

Abstract

Based on the structure of naturally produced cantharidin, different arylamine groups were linked to the norcantharidin scaffold to provide thirty six compounds. Their structures were confirmed by melting point, 1 H-NMR, 13 C-NMR and HRMS-ESI studies. These synthetic compounds were tested as fungistatic agents against eight phytopathogenic fungi using the mycelium growth rate method. Of these thirty six derivatives, seven displayed stronger antifungal activity than did norcantharidin, seven showed higher activity than did cantharidin and three exhibited more significant activity than that of thiabendazole. In particular, 3-(3 1 -chloro-phenyl)carbamoyl norcantharidate II-8 showed the most significant fungicidal activity against Sclerotinia fructigena and S. sclerotiorum, with IC 50 values of 0.88 and 0.97 µg/mL, respectively. The preliminary structure-activity relationship data of these compounds revealed that: (1) the benzene ring is critical for the improvement of the spectrum of antifungal activity (3-phenylcarbamoyl norcantharidate II-1 vs norcantharidin and cantharidin); (2) among the three sites, including the C-2 1 , C-3 1 and C-4 1 positions of the phenyl ring, the presence of a halogen atom at the C-3 1 position of the benzene ring caused the most significant increase in antifungal activity; (3) compounds with strongly electron-drawing or electron-donating groups substitutions were found to have a poor antifungal activity; and (4) compared with fluorine, bromine and iodine, chlorine substituted at the C-3 1 position of the benzene ring most greatly promoted fungistatic activity. Thus, compound II-8 has emerged as new lead structure for the development of new fungicides.

Microemulsion formulation of a new biopesticide to control the diamondback moth (Lepidoptera: Plutellidae)

“…Norcantharidin, as an animal-derived variant compound of cantharidin, has shown insecticidal and anti-fungal activities 19 , 20 . But its agricultural use is restricted to some extent due to poor water solubility.…”

“…xylostella in vitro 18 . Norcantharidin has also been utilized as a pesticide in pest control and against pathogenic fungi 19 , 20 . Norcantharidin therefore has potential to be an eco-friendly pesticide in the case of the control the diamondback moth for ecologically sustainable development because of its fast degradation rate and new mode of action 21 .…”

Non-target effects on soil microbial parameters of the synthetic pesticide carbendazim with the biopesticides cantharidin and norcantharidin

“…Protein phosphorylation and dephosphorylation act on living cells to participate in a suite of cellular metabolic activities in response to changing circumstances, internal developmental cues or external environmental stimuli in eukaryotes 24 . Even though cantharidin and norcantharidin have been utilized as pesticides, limited work has been done to study the effect of cantharidin and norcantharidin on pest control and anti-pathogenic fungi 25 , 26 .…”

Formulation and evaluation of norcanthridin nanoemulsions against the Plutella xylostella (Lepidotera: Plutellidae)

“…Both cantharidin and NCTD have been shown to be inhibitor of the highly conserved serine/threonine protein phosphatases (PPs) of eukaryote [ 11 ]. In addition, NCTD can act as a natural pesticide because of its effective oral toxicity [ 12 , 13 ] and strong antifungal activity [ 14 ]. Nevertheless, applications of NCTD in agriculture are limited by its poor aqueous solubility and high dosage requirement.…”