Computer assisted design of potentially active anti-trypanosomal compounds

Margot Paulino, Federico Iribarne, María Hansz, Mauricio Vega, Gustavo Seoane, Hugo Cerecetto, Rossanna Di Maio, Ignez Caracelli, Julio Zukerman-Schpector, Claudio Olea, Andrés O.M. Stoppani, Mathew Berriman, Alan H. Fairlamb, Orlando Tapia (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    22 Citations (Scopus)


    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.

    Original languageEnglish
    Pages (from-to)95-105
    Number of pages11
    JournalJournal of Molecular Structure: THEOCHEM
    Issue number1-3
    Publication statusPublished - 26 Apr 2002


    • Anti-trypanosomal compounds
    • Drug design
    • Inhibition assays
    • Molecular modeling
    • Trypanosomiasis

    ASJC Scopus subject areas

    • Biochemistry
    • Condensed Matter Physics
    • Physical and Theoretical Chemistry


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