Synthesis and Biological Activity of Potential Antimalarial Agents Containing a 2,4-Pyrimidinediamine Moiety. Synthesis of Dihydrothioxanthenedione Analogs as Potential Antimalarial Agents.

Abstract

A series of 6-alkyl-5-(1-azaheterocyclic)-2,4-pyrimidinediamine analogs, 6-methylamino-5-(1-azaheterocyclic)-2,4-pyrimidinediamine analogs, and 6-ethyl-5-substituted anilinophenyl-2,4-pyrimidinediamine analogs were synthesized as potential antimalarial agents. They were designed as pyrimethamine analogs with the intent to increase binding affinity to the target enzyme, the dihydrofolate reductase, therefore overcoming the resistance problem which occurs in the plasmodial parasite against pyrimethamine. The available test results showed that some of the 6-alkyl-5-(1-azaheterocyclic)-2,4-pyrimidinediamine analogs have limited antimalarial activity. The most active compound was 6-methyl-5-(4-phenyl-1-piperazinyl)-2,4-pyrimidinediamine which showed curative activity in suppressive antimalarial screening against P. berghei in mice at the dose level of 640 mg/kg. Since dihydrofolate reductase inhibitors often showed antitumor activity, these compounds were also tested in vitro against L1210 murine leukemia cell line. Most of 6-alkyl-5-(1-azaheterocyclic)-2,4-pyrimidinediamine analogs showed antileukemic activity with ID(,50)'s of 10('-7) M or below. The most active among them, 5-(azabicyclo{3,2,2}-non-3-yl)-6-ethyl-2,4-pyrimidinediamine (I) had an ID(,50) of 2.9 x 10('-9) M. N-{4-{4-(2,4-Diamino-6-methyl-5-pyrimidinyl)-1-piperazinyl}benzoyl}-L-glutamic acid (II) and its synthetic intermediate, 4-{4-(2,4-diamino-6-methyl-5-pyrimidinyl)-1-piperazinyl}-benzoic acid, hydrochloride (III) had ID(,50)'s of 1.1 x 10('-8) M and 1.1 x 10('-8) M, respectively. Compounds I, II and III were also tested against lymphocytic leukemia P388 in mouse model. Compound I was inactive. The increases of life span for compound II and III were 122 (50 mg/kg) and 127 (12.5 mg/kg), respectively. The free carboxyl groups in both molecules might improve the activity, as predicted from the enzyme-inhibitor interaction. A novel tetracyclic compound, 11H-pyrimido{5',4':4,5}pyrrolo{3,2-c}quinoline-7,9-diamine (IV), was synthesized as an analog of pyrimethamine and 4-aminoquinoline antimalarials with fixed geometry. However, it showed no activity in antimalarial screen against P. berghei in mice. 7-Chloro-3-(2,4-dichlorophenyl)-3,4-dihydro-1H-thioxanthene-1,9(2H)dione and its derivatives were prepared as structural modifications of floxacrine and lucanthone. However, none of these compounds showed activity against P. berghei in the mouse model. The rational design of dihydrofolate reductase inhibitors led to the synthesis of some novel pyrimidine compounds which, although not active against malarial parasites, are potential antitumor agents.