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Naphthoquinones isolated from the wood of trees of the families Bignoniaceae and Verbenaceae have been subjected to an interdisciplinary study since the seventies, when Dr. Benjamin Gilbert, at the Federal University of Rio de Janeiro, launched a program on the chemistry of natural products active against endemic diseases. In this paper we describe the synthesis of five naphthoimidazoles, derived from this program and their activity towards T. cruzi, the etiologic agent of Chagas disease. We also review the influence of chemical structure on trypanocidal action of naphthoquinones and of derived heterocycles with imidazole, oxazole, phenoxazine, indole, dipyrane and cyclopentene rings. The overall analysis corroborates the tendency of trypanocidal activity in compounds with an imidazole or oxazole ring linked to a naphthopyrane structure. Two naphthoimidazoles presented higher activities (14.5x and 34.8x) than the standard crystal violet. Emphasis is given to the biodiversity of the Brazilian flora as a starting point for the development of an autonomous and creative medicinal chemistry.

Twenty-three naphthoimidazoles and six naphthoxazoles were synthesised and evaluated against susceptible and rifampicin- and isoniazid-resistant strains of Mycobacterium tuberculosis. Among all the compounds evaluated, fourteen presented MIC values in the range of 0.78 to 6.25 μg/mL against susceptible and resistant strains of M. tuberculosis. Five structures were solved by X-ray crystallographic analysis. These substances are promising antimycobacterial prototypes., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Several quinonoid and phenazine compounds were synthesized in moderate to high yields and showed activity against H(37)Rv, rifampicin and isoniazid-resistance strains of Mycobacterium tuberculosis. The cytotoxity of the compounds were evaluated against human peripheral blood mononuclear cells (PBMC) and these substances emerge as promising antitubercular prototypes., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

The increase of incidence of tuberculosis (TB) with resistant strains and HIV co-infection has reinforced the necessity of developing new drugs for its treatment. The reaction of naphthoquinones with aromatic or aliphatic aldehydes in the presence of ammonium acetate led to the synthesis of the three β-lapachone derivatives (naphthoimidazoles) that were tested in this study. Phenazines were prepared by the reaction of the respective naphtoquinone with o-phenylenediamine in acetic acid under reflux. The antimicrobial activity of the derivatives was evaluated in vitro against Mycobacterium tuberculosis H37Rv (ATCC 27294) and the rifampicin-resistant strain (ATCC 35338) containing a His-526-Tir mutation in the rpoB gene. Using the Resazurin Microtiter Assay (REMA) method, bioactive molecules were observed in the susceptible and resistant strains with MICs ranging from 2.2 μM to 17 μM. The naphthoimidazoles with p-toluyl and indolyl group attached to the imidazole ring were more active against the H37Rv strain (MIC 9.12 μM and 4.2 μM, respectively) than the rifampicin-resistant strain (MIC 8.3 μM and 17 μM, respectively). The phenazine with the allyl-pyran group was most active among the two strains and had an MIC of 2.2 mM. These results show the potential of these molecules as prototypes for future drugs used in treating TB.

The reaction of naphthoquinone-oximes (3) and (4) with diazomethane yields directly, in one step, the oxazoles (5) and (6), respectively.

We synthesized new naphthoimidazoles from beta-lapachone with an aromatic moiety linked to the imidazole ring, using phenylic and heterocyclic aldehydes. The most active compound against Trypanosoma cruzi had a p-methyl group linked to the phenyl ring, presenting an EC(50) value of 15.5 +/- 2.9 microM. No reliable correlation could be established with the biological activity and the structure of in the phenylic series. For the heterocyclic series, activity was associated with a three bond-distance from nitrogen to the imidazole ring, in accordance with our previous work.