Bioorganic & Medicinal Chemistry 2008-01-01

The use of natural product scaffolds as leads in the search for trypanothione reductase inhibitors

Betty C. Galarreta, Roxana Sifuentes, Angela K. Carrillo, Luis Sanchez, Maria del Rosario I. Amado, Helena Maruenda, Betty C. Galarreta, Roxana Sifuentes, Angela K. Carrillo, Luis Sanchez, Maria del Rosario I. Amado, Helena Maruenda

Index: Bioorg. Med. Chem. 16 , 6689, (2008)

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Abstract

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.