Thieno(2,3-c)quinolines - synthesis and biological investigation

摘要

pH-Dependant reduction of the methyl 3-(2-nitrophenyl)thiophene-2-carboxylate (3), obtained by Suzuki cross-coupling of the methyl 3-iodothiophene-2-carboxylate with 2-nitrophenyl boronic acid yields the cyclic hydroxamic acid 4 and the lactam 5, respectively. The lactam 5 is also formed by reacting the compound 2 with pinacolato 2-aminophenylboronate. The 4-chlorothieno[2,3-c]quinoline 6 is formed from the lactam 5 by heating with POCl3/PCl5. Melting of 6 with the novaldiamine base in phenol gives the chloroquine analogue 7, whereas the amodiaquine and the cycloquine analogues 8 and 9 are obtained using phenol Mannich bases. The hydroxamic acid 4 has a moderate effect on eicosanoid biosynthesis in human whole blood. The growth of the chloroquine resistent Plasmodium falciparum strain Dd2 is inhibited by the pyronaridine derivative 9 with an IC50 value of 650 nM.