Synthetic antimalarials. Part XLIX. The structure and synthesis of the dihydrotriazine metabolite of proguanil

Abstract

The reaction between fi-chlorophenyldiguanide and acetone under acid conditions yields a compound identical with the highly active metabolite (Crowther and Levi, Brit. J . Pharnzacol., 1953, 8, 93) of the antimalarial drug " Paludrine " (proguanil, W-p-chlorophenyl-N%sopropyldiguanide). The compound is readily converted under alkaline conditions into an inactive isomer, 4-amino-6-~-chloroanilino-l : 2-dihydro -2 : 2dimethyl -1 : 3 : 5-triazine (I1 ; R = R' = Me) (cf. Birtwell, Curd, Hendry, and Rose, J., 1948, 1645), the structure of which has been confirmed by the optical resolution of its 2-ethyl-2-methyl homologue (11; R = Me, R' = Et).From a study of the reactions of the active metabolite of proguanil, and of the condensation under both acid and basic conditions of a number of N1-aryldiguanides bearing other substituents on one or more of the nitrogen atoms, it is concluded that the active metabolite is 4 : 6-diamino-l-~-chlorophenyl-THE isolation of a metabolite of " Paludrine " (proguanil, N1-f-chlorophenyl-N5-isopropyldiguanide) (I) with high antimalarial activity, from the urine of rabbits and of human volunteers receiving the drug, was described by Carrington, Crowther, Davey, Levi, and Rose (Nature, 1951, 168, lOSO), and a detailed account of this work has since been given by Crowther and Levi (Brit. J . Pharmacol., 1953,8,93). The present communication describes studies on the structure of this and related substances.The active metabolite, strongly basic in nature, was characterised first as the picrate, and then as the free base, and was found to have the empirical formula Cl1H1,N,Cl, the molecule having two atoms of hydrogen less than that of proguanil itself. On treatment with warm dilute aqueous sodium hydroxide, it was readily converted into an isomeric compound which had no antimalarial activity and was identical with 4-amino-6-f-chloroanilino-1 : Z-dihydro-2 : 2-dimethyl-1 : 3 : 5-triazine (IT; R = R' = Me) which Birtwell, Curd, Hendry, and Rose (J., 1948Rose (J., , 1645 had already prepared both by heating fi-chlorophenyldiguanide with * Patent protection pending.

The surface properties of some neoplastic cells

“…Antrycide dimethyl sulphate (Curd & Davey, 1949;Ainley, Curd, Hepworth, Murray & Vasey, 1953), Paludrine hydro-33 Bioch. 1962, 84 chloride (Curd & Rose, 1946a, b), 4-methylPaludrine (Curd, Hendry, Kenny, Murray & Rose, 1948) and Paludrine metabolite (Carrington, Crowther & Stacey, 1954) were obtained from the Pharmaceuticals Division, Imperial Chemical Industries Ltd., as were the Antrycide analogues, referred to in this paper as (A) and (B) respectively, i.e. 1-allyl-4-allylamino -6 -(2 -amino-1,6-dimethylpyrimid -4ylamino)quinaldine 1,1'-di-iodide and 4-amino-6-(6-methyl-2-methylthiopyrimid-4-ylamino)quinaldine 1,1'-dimethiodide (W. G. M. Jones, personal communication).…”

Mechanisms of Resistance of Malaria Parasites to Antifolates

“…WR99210 (the active metabolite of PS-15) is the most potent plasmodial DHFR inhibitor identified thus far, whereas cycloguanil (DHFR-inhibiting active metabolite of proguanil) and chlorcycloguanil (DHFRinhibiting active metabolite of chlorproguanil) (Hawking, 1947;Carrington et al, 1954) are more potent than pyrimethamine (Ferone et al, 1969;Milhous et al, 1985;Winstanley et al, 1995;Sirawaraporn et al, 1997a;Nzila-Mounda et al, 1998). Trimethoprim is the least potent of the antimalarial DHFR inhibitors (Ferone et al, 1969;Iyer et al, 2001).…”

Activities of respository preparations of cycloguanil pamoate and 4,4'-diacetyldiaminodiphenylsulfone, alone and in combination, against infections with Plasmodium cynomolgi in rhesus monkeys

“…Pyrimethamine-resistant strains of P. falciparum are distributed worldwide, wherever infections with this plasmodium are transmitted (66). In some settings, but reportedly not all, infections with these resistant strains are crossresistant to chlorguanide (66) and presumably to its active mnetabolite, CGT (6,7,18,30). Such cross-resistance could seriously impair the effectiveness of CGT-P as a repository antimalarial agent.…”