Computer assisted design of potentially active anti-trypanosomal compounds

TY - JOUR

T1 - Computer assisted design of potentially active anti-trypanosomal compounds

AU - Paulino, Margot

AU - Iribarne, Federico

AU - Hansz, María

AU - Vega, Mauricio

AU - Seoane, Gustavo

AU - Cerecetto, Hugo

AU - Di Maio, Rossanna

AU - Caracelli, Ignez

AU - Zukerman-Schpector, Julio

AU - Olea, Claudio

AU - Stoppani, Andrés O.M.

AU - Berriman, Mathew

AU - Fairlamb, Alan H.

AU - Tapia, Orlando

N1 - Funding Information: AHF is supported by the Wellcome Trust. OT thanks NFR (Swedish Research Council) for financial support. Most of the work carried out in South America was funded by SAREC/SIDA.

PY - 2002/4/26

Y1 - 2002/4/26

N2 - A computer assisted molecular modeling was used to design molecules having a shape complementary to the active site of glutathione reductase (GR) and trypanothione reductase (TR). The designed 5-nitro compound derivatives, were obtained from structural knowledge gleaned on glutathione (GSSG), trypanothione (T[S]2) and GSP disulfide (glutathionylspermidine disulfide). These molecules form complexes with the enzymes GR and TR. The theoretical lead compound was: N1-[1-(5-nitro-2- furyl)methylidene]-N4-{4-[3-(2,2,2-trifluoroacetyl)hexahydro-1-1 -pyrimidynillbutyl} semicarbazide (NPIPCO). A multi-disciplinary team developed around the efforts to synthesize this lead. In this work we report on eight compounds that were synthesized in the pathway to NPIPCO: 4-(2-methoxyethyl)-1-, 4-butyl-1-, 4-hexyl-1- and 2-methoxphenyl-1-(5-nitrofurfurilidene) semicarbazides and the corresponding 5-nitrothiophenes. These substances are expected to act as pro-transition state analogues. Enzymologic studies proved that many of these compounds are inhibitors of TR. Furthermore, they showed inhibitory activity on Tripanosoma cruzi growth in vitro.

AB - A computer assisted molecular modeling was used to design molecules having a shape complementary to the active site of glutathione reductase (GR) and trypanothione reductase (TR). The designed 5-nitro compound derivatives, were obtained from structural knowledge gleaned on glutathione (GSSG), trypanothione (T[S]2) and GSP disulfide (glutathionylspermidine disulfide). These molecules form complexes with the enzymes GR and TR. The theoretical lead compound was: N1-[1-(5-nitro-2- furyl)methylidene]-N4-{4-[3-(2,2,2-trifluoroacetyl)hexahydro-1-1 -pyrimidynillbutyl} semicarbazide (NPIPCO). A multi-disciplinary team developed around the efforts to synthesize this lead. In this work we report on eight compounds that were synthesized in the pathway to NPIPCO: 4-(2-methoxyethyl)-1-, 4-butyl-1-, 4-hexyl-1- and 2-methoxphenyl-1-(5-nitrofurfurilidene) semicarbazides and the corresponding 5-nitrothiophenes. These substances are expected to act as pro-transition state analogues. Enzymologic studies proved that many of these compounds are inhibitors of TR. Furthermore, they showed inhibitory activity on Tripanosoma cruzi growth in vitro.

KW - Anti-trypanosomal compounds

KW - Drug design

KW - Inhibition assays

KW - Molecular modeling

KW - Trypanosomiasis

UR - https://www.scopus.com/pages/publications/0037177688

U2 - 10.1016/S0166-1280(02)00009-X

DO - 10.1016/S0166-1280(02)00009-X

M3 - Article

AN - SCOPUS:0037177688

SN - 0166-1280

VL - 584

SP - 95

EP - 105

JO - Journal of Molecular Structure: THEOCHEM

JF - Journal of Molecular Structure: THEOCHEM

IS - 1-3

ER -