SYNTHESIS OF TRIFLUOROMETHYL AMODIAQUINE ANALOGS AND ANTIMALARIAL ACTIVITY

In searching for new effective antimalarial agent against both chloroquine-sensitive and chloroquineresistant strains of P. berghei, eleven 4-(3'-alkylaminomethyl-4'-hydroxyl-pehnylamino) and 4-(3',5'-bis-alkylaminomethyl-4'-hydroxyl-phenylamino)-7-trifluoromethyl-quinolines and eleven 4-(3'-alkylamino-methyl- 4'-hydroxyl-phenylamino)-and 4-(3', 5'-bis-alkylaminomethyl-4'-hydroxyl-phenylamino)-2-methyl-7-trifluoromethyl-quinolines have been synthesized andscreened for their antimalarial activities.The title compounds were prepared in the following way; 1. Mannich reaction of p-acetylaminophenol with formaldehyde and amines. 2. Hydrolysis of the acetyl group. 3. Ullmann reaction of the formed amino compound with 4-chloro-/-trifluoromethyl-quinoline (I₀ or 4-chloro-2-methyl-7-trifluoromethyl-quinoline (Ⅱ₀). They can also be obtained through the Ullmann reaction of p-aminophenol at first then followed by the Mannich reation.Preliminary screening tests in mice infected with chloroquine-sensitive ANKA strain of Plasmodium berghei showed that eleven (Ⅰ_1～9,Ⅱ_3,6) of these comounds produced 100% suppression of the parasites when administered orally at doses of (20 mg/kg)/d×4 and (10 mg/kg)/d×4. Among them, three (Ⅰ_{2, 6～7} suppressed parasitomia at (5 mg/kg)/d×4. Two (Ⅰ₄, Ⅱ₃) out of twelve compounds given orally at dose of (20 mg/kg)/d×4 were shown to have three and four negative mice respectively in each five mice infected with chloroquine-resistance ANKA strain of P. berghei, while amodiaquine had no negative mice.