Evaluation of analogues of DRDE-07 as prophylactic agents against the lethality and toxicity of sulfur mustard administered through percutaneous route.
Sulfur mustard (SM), chemically bis (2-chloroethyl) sulfide is a bifunctional alkylating agent that causes serious blisters on contact with human skin. Although several antidotes have been reported for the systemic toxicity of SM in experimental animals none of them are approved so far and decontamination of SM immediately by physical or chemical means is recommended as the best protection. Two compounds amifostine [S-2(3-aminopropylamino) ethyl phosphorothioate] and DRDE-07 [S-2(2-aminoethylamino) ethyl phenyl sulfide] gave very good protection as an oral prophylactic agent against SM the in mouse model, but in the rat model the protection was only moderate. In the search for more effective and less toxic compounds, a number of analogues of DRDE-07 were synthesised and their protective efficacy was evaluated in mouse and rat models. The LD50 of S-aryl substitution was between 1 and 2 g kg(-1) and S-alkyl substitution was more than 2 g kg(-1). In the mouse model, DRDE-07, DRDE-10, DRDE-21, DRDE-30 and DRDE-35 gave about 20 fold protection, and DRDE-23 and DRDE-38 gave less protection of 4.8 and 9.0 fold respectively, against percutaneously administered SM. In the rat model, DRDE-07, DRDE-09, DRDE-10 and DRDE-21 gave about two fold protection. Percutaneously administered SM (19.33 mg kg(-1)) significantly depleted the hepatic GSH content in mice. Pretreatment with DRDE-21 significantly elevated the levels. A 4.4 fold increase in % DNA fragmentation was observed 7 days after SM administration (19.33 mg kg(-1)) in mice. Pretreatment with DRDE-07, DRDE-09, DRDE-10, DRDE-21, DRDE-30 and DRDE-35 significantly protected the mice from SM induced DNA damage. The histopathological lesions in liver and spleen induced by percutaneously administered SM was reduced by pretreatment with DRDE-07, DRDE-09, DRDE-10 and DRDE-21. These analogues may prove as prototypes for the designing of more effective prophylactic drug for SM.
Kulkarni
A S
AS
Defence Research and Development Establishment, Gwalior - 474 002, India.
Vijayaraghavan
R
R
Anshoo
Gautam
G
Satish
H T
HT
Pathak
U
U
Raza
S K
SK
Pant
S C
SC
Malhotra
R C
RC
Prakash
A O
AO
D000284:Administration, Oral; D000287:Administration, Topical; D004999:Amifostine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002855:Chromatography, Thin Layer; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009151:Mustard Gas / Q000008:administration & dosage / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D012867:Skin / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000187:drug effects
D002619:Chemical Warfare Agents; C438646:S-2 (2-aminoethylamino)ethylphenylsulfide; D005978:Glutathione; D004999:Amifostine; D009151:Mustard Gas