Synthesis and biological evaluation of N-alkyl naphthoimidazoles derived from β-lapachone against Trypanosoma cruzi bloodstream trypomastigotes

Abstract

The QSAR study of 34 2-aryl-naphthoimidazoles screened so far revealed that σ_i is the most important factor for their lytic activity on the bloodstream trypomastigote forms of T. cruzi, the etiologic agent of Chagas disease. Based on this result, 16 new N-alkyl-naphthoimidazoles derived from 6,6-dimethyl-3,4,5,6-tetrahydrobenzo[7,8]chromene[5,6-d]imidazole (the product of the reaction of β-lapachone with paraformaldehyde) by its reaction with halo-alkanes were prepared and evaluated against the parasite and peritoneal macrophages. The N1-n-hexyl and N3-n-hexyl naphthoimidazoles were 2.2 and 3.2 times more active than the standard drug benznidazole with selectivity indices of 2.7 and 13.4, respectively.

Fig. 1. 2-Aryl-naphthoimidazoles obtained from the reaction of β-lapachone (1), which are active against the bloodstream forms of T. cruzi.

Scheme 1. Synthesis of the 2-aryl-naphthoimidazoles 5–9 derived from β-lapachone.

Scheme 2. Synthesis of BLI-H, N1-n-alkyl and N3-n-alkyl naphthoimidazoles 10–26 derived from β-lapachone.

Fig. 2. Correlation between trypanocidal activity (IC₅₀/24 h) and the number of carbon atoms for 1-N- and 3-N-alkyl-naphthoimidazoles.