Trypanocidal 1,3-arylene diketone bis(guanylhydrazone)s. Structure-activity relationships among substituted and heterocyclic analogues.
Based on the antitrypanosomal activity of 1,3-diacetylbenzene bis(guanylhydrazone) (4) and 2,6-diacetylpyridine bis(guanylhydrazone) (17), a number of substituted and heterocyclic 1,3-arylene diketone bis(guanylhydrazone)s were prepared and tested against Trypanosoma brucei infections in mice. A wide range of ED50 values was observed among 5-substituted derivatives of 4. The 5-amino analogue 5 and 5-acetamido analogue 6 were about twice as active as 4. 1,3,5-Triacetylbenzene tris(guanylhydrazone) (12) was about 9 times as active as 4 and was approximately one-half as active as the currently used trypanocide diminazene aceturate in this test system. Other 5-derivatives had activity equivalent to or less than that of the parent compound 4. Three new heterocyclic analogues were all less active than 2,6-diacetylpyridine derivative 17 and benzene derivative 4. Ring substitution ortho to the guanylhydrazone side chains was invariably detrimental to activity. Side-chain homologues 1,3-dipentanoylbenzene bis(guanylhydrazone) and 1,3-diacetylbenzene bis(2-imidazolin-2-ylhydrazone) were essentially inactive.
D000818:Animals; D004353:Drug Evaluation, Preclinical; D005260:Female; D006146:Guanidines / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008935:Mitoguazone / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000188:drug therapy
D006146:Guanidines; D007202:Indicators and Reagents; D014344:Trypanocidal Agents; C040056:1,3,5-triacetylbenzene tris(guanylhydrazone); D008935:Mitoguazone