Computer assisted design of potentially active anti-trypanosomal compounds

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.