title: Antimalarial activities of new pyrrolo[3,2-f]quinazoline-1,3-diamine derivatives.
abstract: WR227825 is an antimalarial pyrroloquinazolinediamine derivative with a high potency but a low therapeutic index. A series of carbamate, carboxamide, succinimide, and alkylamine derivatives of WR227825 were prepared to search for compounds with an improved therapeutic index. The new acetamides and imide showed potent cell growth inhibition against four clones of Plasmodium falciparum (D-6, RCS, W-2, and TM91C235), with a 50% inhibitory concentration of approximately 0.01 ng/ml, and were highly active against Plasmodium berghei, with 100% cure at doses from <0.1 mg/kg of body weight to 220 mg/kg. The carbamates and alkyl derivatives, however, showed weak activity against Plasmodium falciparum cell growth but were highly efficacious in tests against P. berghei by the Thompson test. The best compounds, bis-ethylcarbamate (compound 2a) and tetra-acetamide (3a) derivatives, further demonstrated high potency against the sporozoite Plasmodium yoelii in mice and P. falciparum and Plasmodium vivax in aotus monkeys. Against the AMRU-1 strain of P. vivax, which has four dihydrofolate reductase mutations and is highly resistant to antifolates, tetra-acetamide 3a cured the monkeys at doses of 1 and 3 mg/kg. Compound 2a cured only one out of two monkeys at 3 mg/kg. The results indicated that the new derivatives 2a and 3a not only have retained/improved the antimalarial efficacy of the parent compound WR227825 but also were less toxic to the animals used in the tests.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Guan
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: O'Neil
authors.forename: Nicanor
authors.initials: N
authors.lastname: Obaldia
authors.forename: Arba
authors.initials: A
authors.lastname: Ager
authors.forename: Lucia
authors.initials: L
authors.lastname: Gerena
authors.forename: Ai J
authors.initials: AJ
authors.lastname: Lin
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D008288:Malaria / Q000097:blood / Q000188:drug therapy; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D011758:Pyrroles; D011799:Quinazolines