title: 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, ¹H-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'-chloro-phenyl)carbamoyl norcantharidate II-8 showed the most significant fungicidal activity against Sclerotinia fructigena and S. sclerotiorum, with IC50 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', C-3' and C-4' positions of the phenyl ring, the presence of a halogen atom at the C-3'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' 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.
authors.affiliation: State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A &amp; F University, Yangling 712100, China. wangyang2006@nwsuaf.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Plant Protection Resources and Pest Management, Ministry of Education, Northwest A &amp; F University, Yangling 712100, China. wbsun06@163.com.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A &amp; F University, Yangling 712100, China. zsq2623@163.com.
authors.forename: Shunqing
authors.initials: S
authors.lastname: Zha
authors.affiliation: Key Laboratory of Plant Protection Resources and Pest Management, Ministry of Education, Northwest A &amp; F University, Yangling 712100, China. huanwang1107@gmail.com.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Key Laboratory of Plant Protection Resources and Pest Management, Ministry of Education, Northwest A &amp; F University, Yangling 712100, China. yalinzh@nwsuaf.edu.cn.
authors.forename: Yalin
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000588:Amines / Q000737:chemistry*; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001203:Ascomycota / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000935:Antifungal Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C069741:norcantharidin
keywords: arylamine; cantharidin; fungicidal activity; natural product; structural modification