Protoporphyrinogen-IX oxidase inhibitors: Bioactivation of thiadiazolidines

The bioactivation of thiadiazolidine-type peroxidizing compounds was examin ed with thiosemicarbazides as model intermediates, Peroxidizing activities of three sets of thiadiazolidines (5-arylimino-3,4-tetramethylene-1,3,4-thi adiazolidines), thiosemicarbazides (4-aryl-1-ethylthiocarbonyl-1,2-tetramet hylenethiosemicarbazides), and triazolidines (4-aryl-1,2-tetramethylene-1,2 ,4-triazolidines) were assayed for protoporphyrinogen-IX oxidase (Protox) i nhibition with Protox isolated from com etioplasts and for phytotoxic param eters of growth, chlorophyll content, and ethane evolution obtained with Sc enedesmus acutus cells. Protox inhibitory activity of thiosemicarbazides wa s intermediate between that of thiadiazolidines and triazolidines, Phytotox ic parameters of thiosemicarbazides obtained from S. acutus cells were quit e identical to those of triazolidines, although phytotoxic parameters of th iadiazolidines exhibited a slightly different pattern. Phytotoxic activitie s of 5-(4-bromophenyl)-3,4-tetramethylene-1,3,4-thiadiazolidin-2-one (thiad iazolidine 1) and 5-(4-chloro-2-fluoro-5-propargyloxyphenyl)-3,4-tetramethy lene-1,3,4-thiadiazolidin-2-one (thiadiazolidine 4) were similar to those o f the corresponding triazolidines, but phytotoxicities exhibited by 5-(4-(4 -chlorobenzyloxy)phenyl)-3,4-tetramethylene-1,3,4-thiadiazolidin-2-one (thi adiazolidine 7) were 10 times less active with S. acutus than those of the corresponding triazolidine. Three thiosemicarbazides exhibited rapid conver sion into triazolidines both in buffer at pH 7 (ca. 25-50%, 5 min incubatio n) and in Scenedesmus cultures (ca. 75%, 5 h incubation). Thiadiazolidines 1 and 4 were converted into corresponding triazolidines (ca. 70%) in S. acu tus but were converted in buffer only in the presence of glutathione S-tran sferase plus ethylmercaptan. although thiadiazolidine 7 was not converted i n the Scnedesmus culture. Apparently, the conversion step from thiadiazolid ine to the thiosemicarbazide intermediate is enzymatic and the thiosemicarb azide inter-mediate to triazolidine is a spontaneous, nonenzymatic step. (C ) 2001 Academic Press.