Pyrazole derivatives as photosynthetic electron transport inhibitors: new leads and structure-activity relationship

Four series of new pyrazoles, namely, 5 4-carboxypyrazolo-3-tert-butylcarboxamide and 6 4-carboxypyrazolo-3-cyclopropylcarboxamide derivatives and 10 pyrazolo[3,4-d][1,3]thiazine-4-one and 9 pyrazolo[3,4-d][1,3]thiazine-4-thione derivatives, were synthesized and screened as potential inhibitors of photosynthetic electron transport. The structures were confirmed by 1H NMR, elemental, and IR analyses. Their biological activity was evaluated in vitro as the ability to interfere with the light-driven reduction of ferricyanide by isolated spinach chloroplasts. Only a few compounds exhibited excellent inhibitory properties in the micromolar range, comparable to those of commercial herbicides sharing the same target, such as diuron, lenacil, and hexazinone. Nevertheless, most of the remaining molecules exerted a remarkable inhibition in the millimolar range. Combined with previous results on 6 pyrazolo[1,5-a][1,3,5]triazine-2,4-dione and 4 pyrazolo[1,5-c][1,3,5]thiadiazine-2-one derivatives, these data allowed a comprehensive analysis of structure-activity relationship. Molecular modeling studies were undertaken to rationalize the structural determinants of activity in terms of shape, size, and molecular fields. Results suggested that the inhibitory potential of these compounds is associated mainly with their electrostatic properties.