Epoxyethane-/ethynesulfonamides with antifilarial activities. Degradation kinetics and inhibitory effect on filarial malate dehydrogenase and lactate dehydrogenase.
Some epoxyethane-/ethynesulfonamides had shown strong filaricidal activity with inconstant reproducibility as a result of a lack of stability in aqueous solution. The degradation in hydroxylic and aprotic solutions of two epoxyethanesulfonamides and one ethynesulfonamide was investigated using TLC, HPLC, GC and mass spectrometry. For both epoxydes, the degradation rate followed first-order kinetics and was more rapid in hydroxylic than in aprotic solutions. The degradation increased with the temperature whereas it was not modified with and without light exposure. Four kinds of degradation products were found: the first one involved the oxidation of the epoxyde bond, the second the breaking of the N-S bond, the third a desulfonation product and the fourth was not identified. In contrast, the stability of ethynesulfonamide was better than those of epoxyethanesulfonamide. These results suggest that epoxyethanesulfonamides should be kept at +4 degrees C before being injected to animals during the study of biological activity. Since epoxyde compounds are known to have inhibitory effects on parasite energy metabolism enzymes, the compunds were evaluated on two major filarial enzymes: lactate dehydrogenase (LDH) and cytoplasmic malate dehydrogenase (MDH). Both epoxyethanesulfonamides showed only a slight inhibitory effect on filarial LDH and MDH confirming the evidence that the main mode of action of these compounds remains to discover. Moreover, ethynesulfonamide and the degradation products of both epoxyethane-sulfonamides had no effect on LDH and MDH.
Radembino
N
N
Laboratoire de Méthodologies Bioanalytiques, Faculté de Pharmacie, Châtenay-Malabry, France.
Loiseau
P M
PM
Dessalles
M C
MC
Marchat
L
L
Bories
C
C
Gayral
P
P
Mahuzier
G
G
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005368:Filariasis / Q000188:drug therapy / Q000523:psychology; D005369:Filaricides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors*; D008291:Malate Dehydrogenase / Q000037:antagonists & inhibitors*; D012377:Rodentia; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005369:Filaricides; D013449:Sulfonamides; D007770:L-Lactate Dehydrogenase; D008291:Malate Dehydrogenase