The use of natural product scaffolds as leads in the search for trypanothione reductase inhibitors.
Twenty-three heterocyclic compounds were evaluated for their potential as trypanothione reductase inhibitors. As a result, the harmaline, 10-thiaisoalloxazine, and aspidospermine frameworks were identified as the basis of inhibitors of Trypanosoma cruzi trypanothione reductase. Two new compounds showed moderately strong, linear competitive inhibition, namely N,N-dimethyl-N-[3-(7-methoxy-1-methyl-3,4-dihydro-9H-beta-carbolin-9-yl)propyl]amine (15) and 1,3-bis[3-(dimethylamino)propyl]-1,5-dihydro-2H-pyrimido[4,5-b][1,4]benzothiazine-2,4(3H)-dione (21), with K(i) values of 35.1+/-3.5microM and 26.9+/-1.9microM, respectively. Aspidospermine (25) inhibited T. cruzi TryR with a K(i) of 64.6+/-6.2microM. None of the compounds inhibited glutathione reductase. Their toxicity toward promastigotes of Leishmania amazonensis was assessed.
Pontificia Universidad Catolica del Peru, Departamento de Ciencias-Quimica, Avenida Universitaria 1801, Lima 32, Peru.
Betty C
BC
Galarreta
Roxana
R
Sifuentes
Angela K
AK
Carrillo
Luis
L
Sanchez
Maria Del Rosario I
Mdel R
Amado
Helena
H
Maruenda
D000818:Animals; D001688:Biological Products; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005415:Flavins / Q000737:chemistry / Q000494:pharmacology; D006246:Harmaline / Q000737:chemistry / Q000494:pharmacology; D026121:Indole Alkaloids / Q000737:chemistry / Q000494:pharmacology; D007891:Leishmania / Q000187:drug effects; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000737:chemistry*; D014349:Trypanosoma cruzi / Q000201:enzymology
D001688:Biological Products; D004791:Enzyme Inhibitors; D005415:Flavins; D026121:Indole Alkaloids; D011804:Quinolines; D014344:Trypanocidal Agents; C008173:isoalloxazine; D006246:Harmaline; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; C091896:aspidospermine