Synthesis of potential inhibitors of hypoxanthine-guanine phosphoribosyltransferase for testing as antiprotozoal agents. 2. 1-Substituted hypoxanthines

Abstract

Evidence indicating that effective in vivo inhibition of hypoxanthine-guanine phosphoribosyltransferase (HGPRT, EC 2.4.2.8) should produce antiprotozoal activity without significant toxic effects on mammalian hosts prompted syntheses of 1-substituted hypoxanthines bearing functionalized side-chains whose groupings might interact with appropriate groupings of HGPRT to form covalent bonds or strong hydrophobic bonds. 3-(Fluorosulfonyl)benzoyl, 4-(fluorosulfonyl)benzoyl, 4-chlorobenzoyl and bromoacetyl derivatives of 2 parent amines, 1-(2-aminoethyl)-hypoxanthine and 1-(4-aminobenzyl)hypoxanthine, were synthesized for evaluation in this connection. None of these compounds extended the life span of Plasmodium berghei infected mice or showed significant in vitro inhibition of HGPRT from H.Ep.-2 [human oral carcinoma] cells, but 1-[2-(bromoacetamido)ethyl]hypoxanthine displayed in vivo activity against Trypanosoma rhodesiense.