HI-6, an oxime which is an effective antidote of soman poisoning: A structure-activity study

Abstract

In contrast to other organophosphates, soman poisoning is resistant to atropine (AT) + oxime therapy. However, new bispyridinium-type oximes + AT are effective antidotes of soman poisoning. In structure-activity studies, T 4925 (1,1′-[oxybis(methylene)]bispyridinium dichloride) had an LD 50 of 178 mg/kg and HS-14 (1-[[[pyridinio]methoxy]methyl]-2[(hydroxyiminio)methyl]pyridinium dichloride) had an LD 50 of 130 mg/kg. DL-10 (1-[[[3-(aminocarbonyl)pyridinio]methoxy]methyl]pyridinium dichloride) and DL-11 (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]pyridinium dichloride) had LD 50's of 326 and 715 mg/kg, respectively, whereas HS-6 (Reg. No. 22625-23-6) and HI-6 (Reg. No. 34433-31-3) had LD 50s of 316 and 514 mg/kg (ip), respectively. T 4925, HS-14, DL-10, and DL-11 at an LD 1 dose + AT (17.4 mg/kg) were relatively ineffective against soman (540 μg/kg; sc) compared to HI-6 and HS-6. Prophylactic ED 50s for HI-6 and HS-6 vs soman were 17 and 110 mg/kg, producing safety ratios of 30 and 2.9, respectively. The therapeutic ED 50 for HI-6 was 20 mg/kg. Brain cholinesterase (ChE) in mice surviving soman (540 μg/kg; sc) + HI-6 (94 mg/kg) + AT was 0% of control activity at 1 and 2 hr, 5% at 24 hr, and 15% 48 hr later. Mice which died postsoman (540 μg/kg; sc) had 20% brain ChE activity. These results show that HI-6 was one of the least toxic and most efficacious compounds studied and suggest brain ChE inhibition was not the primary lesion in soman poisoning.