Abstract
The title compounds can be considered as simple analogues of quaternary benzo[c]phenanthridine alkaloids (QBAs). In order to develop potent QBA-like antifungal agents, as our continuing study, a series of new title compounds were synthesized and evaluated for bioactivity against five plant pathogenic fungi by the mycelium growth rate method in this study. The SAR were also derived. The majority of the compounds showed good to excellent inhibition activity with average EC50 values of 7.87–20.0 μM for the fungi, superior to sanguinarine and cherythrine (two QBAs) and the commercial fungicide azoxystrobin. Part of the compounds were more active than commercial fungicides thiabendazole or carbendazim against F. solani, F. graminearum and C. gloeosporioides. Six compounds with average EC50 of 3.5–5.1 μg/mL possessed very great potential for development of new antifungal agents. SAR found that substitution patterns of the two aryl-rings significantly affect the activity. There exists a complex interaction effect between substituents of the two aryl-rings on the activity. Generally, the presence of electron-withdrawing groups on the C-ring can significantly increase the activity. These findings will be of great importance for the design of more potent antifungal isoquinoline agents.
Highlights
The title compounds can be considered as simple analogues of quaternary benzo[c]phenanthridine alkaloids (QBAs)
Our previous study proved that like SA and CH5–8, ADHIQs generally possessed excellently antifungal[9,10,11,12,13], acaricidal[14, 15] and anticancer activities[5, 16], and showed high safety to plant growth[17, 18]. These results show that ADHIQs are of great potential as new or secondary lead compounds to develop QBA-like antifungal agents
Our study found that the C=N+ moiety in ADHIQs is a determinant for their bioactivities including antifungal properties[5, 9], and the antifungal activity of ADHIQs is closely related to the electron density distribution in its conjugated system, especially in the C=N+ bond[9,10,11,12,13]
Summary
Compound 3 was treated with n-butyllithium, and followed by the treatment of water to give 4 in 79% yield. For key intermediates 7 and 8, we initially attempted to obtain them by our reported method[9], i.e., 1-bromination of 3 or 4 with Br2 followed by the treatment of aqueous hydrobromic acid. 7 or 8 reacted with various primary aromatic amines to yield two series of the target compounds A and B. It was worth mentioning that for some primary aromatic amines with a strong electron-withdrawing group such as nitro, trifluoromethyl or cyano, we did not obtain the desired target compounds with enough purity by the reaction above. Due to the same synthetic method and structural similarity, only part of the compounds were performed for HR-MS and analysized for bromine ion.
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