Synthesis and quantitative structure-antifungal activity relationships of clovane derivatives against Botrytis cinerea.
Twenty-three clovane derivatives, nine described here for the first time, bearing substituents on carbon C-2, have been synthesized and evaluated for their in vitro antifungal activity against the phytopathogenic fungus Botrytis cinerea. The results showed that compounds 9, 14, 16, and 18 bearing nitrogen atoms in the chain attached at C-2 displayed potent antifungal activity, whereas mercapto derivatives 13, 19, and 22 displayed low activity. The antifungal activity showed a clear structure-activity relationship (SAR) trend, which confirmed the importance of the nature of the C-2 chain on the antifungal activity. On the basis of these observations, the metabolism of compounds 8 and 14 by the fungus B. cinerea, and the metabolism of other clovanes by this fungus, described previously, a pro-drug action mechanism for 2-alkoxyclovane compounds is proposed. Quantitative structure-activity relationship (QSAR) studies were performed to rationalize the results and to suggest further optimization, using a topological sub-structural molecular design (TOPS-MODE) approach. The model displayed good fit and predictive capability, describing 85.5% of the experimental variance, with a standard deviation of 9.502 and yielding high values of cross-validation determination coefficients (q2CV-LOO = 0.784 and q2boot = 0.673). The most significant variables were the spectral moments weighted by bond dipole moment (Dip), hydrophobicity (Hyd), and the combined dipolarity/polarizability Abraham molecular descriptor (Ab-pi2H).
Saiz-Urra
Liane
L
Departamento de Qumica Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Cádiz, Spain.
Racero
Juan C
JC
Macías-Sáchez
Antonio J
AJ
Hernández-Galán
Rosario
R
Hanson
James R
JR
Perez-Gonzalez
Maykel
M
Collado
Isidro G
IG
D020171:Botrytis / Q000187:drug effects*; D005659:Fungicides, Industrial / Q000138:chemical synthesis* / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000737:chemistry*; D013329:Structure-Activity Relationship
D005659:Fungicides, Industrial; D012717:Sesquiterpenes