Trypanocidal agents with low cytotoxicity to mammalian cell line: a comparison of the theoretical and biological features of lapachone derivatives.

Starting from alpha- and beta-lapachones, in this work we compared the biological and theoretical profile of several oxyran derivatives of lapachone as potential trypanocidal agents. Our biological results showed that the oxyrans tested act as trypanocidal agents against Trypanosoma cruzi with minimal cytotoxicity in the VERO cell line compared to naphthoquinones. The oxyran derivative of alpha-lapachone (7a) showed to be one of the most potent compounds. In our molecular modeling study, we analyzed the C-ring moiety and the redox center of beta-lapachone molecule as the moieties responsible for the trypanocidal and cytotoxic effects on mammalian cell line. The computational methods used to delineate the structural requirements for the trypanocidal profile pointed out that the transposition of the C-ring moiety of beta-lapachone, combined with its oxyran ring, introduced important molecular requirements for trypanocidal activity in the HOMO energy, HOMO orbital coefficient, LUMO density, electrostatic potential map, dipole moment vector, and calculated logP (clogP) parameter. This study could lead to the development of new antichagasic medicines based on alpha-lapachone analogs.

Oxyrane derivative of alpha-lapachone is potent growth inhibitor of Trypanosoma cruzi epimastigote forms.

The investigation of trypanocidal effects against Trypanosoma cruzi and cytotoxicity in VERO cell line of several oxyranes structurally related to beta-lapachone, nor-beta-lapachone, alpha-lapachone, and 4-methoxy-1,2-naphthoquinone is described. It was found that the oxyranes 10 derived from alpha-lapachone showed an approximately the same trypanocidal activity of beta-lapachone. In addition, all the oxyranes showed less cytotoxicity than the corresponding naphthoquinones.

Preparation of alpha-diazocarbonyl compounds from beta-lapachone derivatives and other 1,2-naphthoquinones: use of the 2D NMR 1H,15N and 1H,13C HMBC techniques in assigning regiochemistry.

The assignment of the diazo site in products of the reaction of p-toluenesulfonylhydrazine with beta-lapachone, 3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione, and other 1,2-naphthoquinones in methanol solution at room temperature has been accomplished using 1H,13C HMBC and 1H,15N HMBC NMR experiments. Only one diazo-naphthalenone product was isolated in yields ranging from 50-100% from each reaction. The site of diazo substitution of beta-lapachone and derivatives is the 1-position, in contrast to substitution at the 2-position in 4-MeO-1,2-naphthoquinone. Steric factors, rather than electronic factors, control the reaction site. Along with 2-diazo-1(2H)-naphthalenone, an additional product isolated from the reaction of p-toluenesulfonylhydrazide with 1,2-naphthoquinone was 2-diazo-4-hydroxy-1(2H)-naphthalenone. Confirmation of the formation of 6-diazo-2,2-dimethyl-2,3,4,6-tetrahydro-2H-benzo[h]cromen-5-one, obtained from beta-lapachone, was achieved using single crystal X-ray diffraction.