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

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

Sección de Química

Pontificia Universidad Catolica del Peru

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

29 Citas (Scopus)

Resumen

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-β-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 Ki values of 35.1 ± 3.5 μM and 26.9 ± 1.9 μM, respectively. Aspidospermine (25) inhibited T. cruzi TryR with a Ki of 64.6 ± 6.2 μM. None of the compounds inhibited glutathione reductase. Their toxicity toward promastigotes of Leishmania amazonensis was assessed. © 2008 Elsevier Ltd. All rights reserved.

Idioma original	Español
Páginas (desde-hasta)	6689-6695
Número de páginas	7
Publicación	Bioorganic and Medicinal Chemistry
Volumen	16
Estado	Publicada - 15 jul. 2008

Citar esto

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title = "The use of natural product scaffolds as leads in the search for trypanothione reductase inhibitors",

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-β-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 Ki values of 35.1 ± 3.5 μM and 26.9 ± 1.9 μM, respectively. Aspidospermine (25) inhibited T. cruzi TryR with a Ki of 64.6 ± 6.2 μM. None of the compounds inhibited glutathione reductase. Their toxicity toward promastigotes of Leishmania amazonensis was assessed. {\textcopyright} 2008 Elsevier Ltd. All rights reserved.",

author = "Galarreta, {Betty C.} and Roxana Sifuentes and Carrillo, {Angela K.} and Luis Sanchez and Amado, {Maria del Rosario I.} and Helena Maruenda",

year = "2008",

month = jul,

day = "15",

language = "Espa{\~n}ol",

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journal = "Bioorganic and Medicinal Chemistry",

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T1 - The use of natural product scaffolds as leads in the search for trypanothione reductase inhibitors

AU - Galarreta, Betty C.

AU - Sifuentes, Roxana

AU - Carrillo, Angela K.

AU - Sanchez, Luis

AU - Amado, Maria del Rosario I.

AU - Maruenda, Helena

PY - 2008/7/15

Y1 - 2008/7/15

N2 - 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-β-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 Ki values of 35.1 ± 3.5 μM and 26.9 ± 1.9 μM, respectively. Aspidospermine (25) inhibited T. cruzi TryR with a Ki of 64.6 ± 6.2 μM. None of the compounds inhibited glutathione reductase. Their toxicity toward promastigotes of Leishmania amazonensis was assessed. © 2008 Elsevier Ltd. All rights reserved.

AB - 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-β-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 Ki values of 35.1 ± 3.5 μM and 26.9 ± 1.9 μM, respectively. Aspidospermine (25) inhibited T. cruzi TryR with a Ki of 64.6 ± 6.2 μM. None of the compounds inhibited glutathione reductase. Their toxicity toward promastigotes of Leishmania amazonensis was assessed. © 2008 Elsevier Ltd. All rights reserved.

M3 - Artículo

SN - 0968-0896

VL - 16

SP - 6689

EP - 6695

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

ER -