Six-membered cyclic phosphonate GABA antagonists, 2,5-disubstituted 1,3,2-dioxaphosphorinanes.

The trans isomer of 2-(4-bromophenyl)-5-tert-butyl-2-thiono-1,3,2-dioxaphosphorinane competitively inhibited the specific binding of 35S-tert-butylbicyclophosphorothionate to rat brain membranes with an IC50 value of 0.52 microM, and showed insecticidal activity against houseflies with an LD50 value of 2.4 micrograms/fly. This compound and its analogues acted as noncompetitive GABAA receptor antagonists (NGRAs), and phosphorus-containing cyclohexane skeletons may prove useful for the design of novel NGRAs.

Effect of phosphonium salts and phosphoranes on the acetylcholinesterase activity and on the viability of Schistosoma mansoni parasites.

In this study we investigated the effects of a series of phosphonium salts and phosphoranes on the catalytic activity of acetylcholinesterase and on the viability of the various life stages of Schistosoma mansoni worms. All the tested compounds showed an inhibitory effect towards the S. mansoni acetylcholinesterase (AChE) activity. The most effective compound, p-xylylene bis(triphenylphosphonium) dibromide (No. 16) displayed approximately 100% inhibition at concentration of 10(-5)-10(-6)M. No significant difference was found in the sensitivity of the enzyme obtained from the various stages of the parasite life cycle to the effect of the drugs. Each compound was also tested for its toxicity towards 3 h old schistosomula and 7-9 week adult worms under in vitro culture conditions. In the case of the larvae, after 2 days in culture, only three compounds (Nos. 4, 11 and 12) out of sixteen tested exhibited efficient killing of the schistosomula while the others had a very slight toxic activity or no toxicity at all. On the other hand, all the compounds showed a significant toxicity towards the adult worms and the most effective one, allytriphenylphosphonium bromide (No. 11), retained its toxic effect even at an extremely high dilution (10(-8)M). However, the cumulative results in this paper do not demonstrate a significant correlation between the inhibitory effect of the phosphonium salts and phosphoranes on the AChE activity of the schistosomes and their toxicity towards the worms. The LD50 value (i.v.) of the compound which showed the highest toxic effect in vitro (No. 11) was found to be 30 +/- 1.7 mg/kg in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and properties of 2-S-(N,N-dialkylamino)ethyl)thio-1,3,2-dioxaphosphorinane 2-oxide and of the corresponding quaternary derivatives as potential nontoxic antiglaucoma agents.

A new series of cyclic organophosphorus esters, 2-S-[2'-N,N-dialkylamino)ethyl]thio-1,3,2-dioxaphosphorinane 2-oxide and their quaternary derivatives, was synthesized and studied as potential antiglaucoma agents. Thes compounds inhibit acetylcholinesterase (E.C.3.1.1.7)at a bimoecular rate constant (ki) in the range of 10(3)-10(4) M-1 min-1. Values of the affinity (K) and phosphorylation (k') rate constants for this enzyme indicate that k' is responsible for the relatively low values of ki as compared with similar data for the open-chain analogues, O,O-diethyl phosphorothiolates (10(6) M-1 min-1). The mammalian toxicity of the new compounds in terms of acute LD50 values in mice is 1-3 x 10(3) less than that of phospholine, an open-chain analogue. In an initial clinical trial, one member of the new series (alkyl = C2H5) caused a significant decrease of intraocular pressure in aphakic glaucoma, while phospholine proved to be ineffective.