Design of New Fungicides by Application of the QSAR Technique

Abstract

The design of new cyclic N-phenylimide fungicides was performed by using a QSAR technique, the Hansch-Fujita method. Furthermore, a computer program called PREHAC, which aids in the impartial selection of substituents for the synthesis of highly bioactive compounds among congeners based on the Hansch-Fujita method, was developed and used effectively for the above-mentioned fungicide design. 3, 5-Dihalo substituents on the benzene ring moiety enhance greatly the antifungal activity of cyclic N-phenylimides against Sclerotinia sclerotiorum, Botrytis cinerea, etc. The relationships between the chemical structure and antifungal activity against B. cinerea of a number of N-phenylsuccinimides and related N-phenyl-1, 2-dimethylcyclopropanedicarboximides having various benzene ring substituents were analyzed for the purpose of the clarification of the physicochemical meaning of 3, 5-dihalo substituents and the search for substitutes for them. The high antifungal activity of the cyclic N-(3, 5-dihalophenyl) imides was rationalized by the hydrophobicity and electron-withdrawing properties of halogen atoms. In addition, the steric bulk of one of the two halogen atoms was revealed to be unfavorable to this activity. It was concluded that 3, 5-dihalo substitutions were most desirable for high activity of this series of compounds. The antifungal activity of N-(3, 5-dichlorophenyl) succinimides and 3-(3, 5-dichlorophenyl)-2, 4-oxazolidinediones, having various substituents on the imido rings, against B. cinerea was related only with the hydrophobicity of the imido ring moieties including the substituents. The 1-isovaleroyl derivative of 3-(3, 5-dichlorophenyl)-2, 4-imidazolidinedione (isovaledione) was designed as a new fungicide against Alternaria diseases. The activity of 1-acyl-3-(3, 5-dichlorophenyl)-2, 4-imidazolidinediones against A. kikuchiana was related parabolically with both the hydrophobicity and steric bulkiness of the aryl moiety substituents. The higher the electroN-donating power of the substituents and the smaller their minimum width in the direction perpendicular to the bond axis, the greater was the activity.