Takahiro Kataoka

Quantitative structure-activity study of fungicidal 1-substituted cis-2-(1H-1,2,4-triazol-1-yl)cycloalkanols

Abstract Antifungal activities of 20 cis-2-(1H-1,2,4-triazol-1-yl)cycloalkanols substituted at the 1-position with halo-aryl or halo-benzyl groups were measured in vitro against Botrytis cinerea. The relationship between structure and activity was examined quantitatively using physicochemical and structural parameters and regression analysis. The activity increased as the hydrophobicity of the molecule increased and as the size of the cycloalkane ring was enlarged from five to seven members. Unfavorable to the activity were structural features for the 1-substituent such as the phenyl residue carrying substituents at one of the meta-positions, thiophen-2-yl with 3,4,5-trichloro substitution, and substituted benzyl. The 5-chlorothiophen-2-yl residue, which has a 5-substituent at a position nearly equivalent to the meta-position on the phenyl group, did not show such an unfavorable effect on the activity. Conformational analyses and computer-aided structure modelings showed that (i) a conformer at the global energy minimum can interact favorably with the target site (the cytochrome P450); (ii) the substituent at the meta-position on the phenyl residue may sterically interfere with the binding of the molecule to the target site since the phenyl residue cannot rotate freely, whereas the 5-chlorothiophen-2-yl residue can rotate to avoid such a sterically unfavorable effect; and (iii) derivatives having the benzyl residue cannot fit well with the target site.