Three new nonquaternary oximes have been evaluated with respect to their antidotal activities against organophosphate poisoning. The oximes 1,2,3-thiadiazole-5-carboxaldoxime (1, pKa = 7.6), 2-methyl-1,3,4-thiadiazole-5-carboxaldoxime (2, pKa = 8.4), and 3-methyl-1,2,4-thiadiazole-5-carboxaldoxime (3, pKa = 7.0) were prepared in yields of 56, 24, and 58%, respectively, by nitrosation of the corresponding methyl derivatives with isoamyl nitrite in the presence of potassium ethoxide. The new compounds are substantially more lipophilic and much less toxic than the well-known antidote P2S. They reactivate phosphylated AChE slowly. In the five animal species investigated, they disappear from the blood stream after iv administration at approximately the same rates as Obidoxime. It was shown that the disappearance of 1 from rabbit blood is not due to rapid renal excretion of the unchanged oxime, as is the case for Obidoxime and P2S. Since an unidentified derivative of 1 has been found in the urine, rapid metabolic conversion of 1 is most likely responsible. Therapeutic administration (ip) of 2-3 at 250 mg/kg, in combination with atropine, saves mice from four to five times the LD50 of sarin. Much lower doses (33-75 mg/kg) of 1 save rats and mice from five times the LD50 of sarin, whereas P2S cannot save mice from the same challenge dose. In contrast herewith, 1 does not save rats from five times the LD50 of paraoxon, whereas P2S is effective in this case. For oral prophylaxis against sarin, 1 is inferior to P2S. This inferiority may be partly ascribed to the combined effects of rapid absorption of 1 from the gastrointestinal tract and rapid elimination. Chemicals/CAS: acetylcholinesterase, 9000-81-1; atropine, 51-55-8, 55-48-1; diacetyl oxime, 57-71-6; obidoxime, 114-90-9, 7683-36-5; paraoxon, 311-45-5; sarin, 107-44-8; tri ortho cresyl phosphate, 78-30-8; Acetylcholinesterase, EC 3.1.1.7; Antidotes; Enzyme Reactivators; Organophosphorus Compounds; Oximes; Sarin, 107-44-8