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

Trypanocidal effects against Trypanosoma cruzi and cytotoxicity to mammalian cells of several oxyrans structurally related to β-lapachone, nor-β-lapachone, α-lapachone, and 4-methoxy-1,2-naphthoquinone are described. It was found that the compound 7a derived from α-lapachone ( 7) exhibits higher try...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2006-08, Vol.14 (16), p.5459-5466
Main Authors: Ferreira, Vitor F., Jorqueira, Alessandra, Souza, Alessandra M.T., da Silva, Milton N., de Souza, Maria C.B.V., Gouvêa, Robson M., Rodrigues, Carlos R., Pinto, Antonio V., Castro, Helena C., Santos, Dilvani O., Araújo, Humberto P., Bourguignon, Saulo C.
Format: Article
Language:English
Subjects:
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiparasitic agents
Biological and medical sciences
Cell Line
Computational
Cytotoxicity
Medical sciences
Naphthoquinones - chemistry
Naphthoquinones - pharmacology
Oxidation-Reduction
Pharmacology. Drug treatments
Static Electricity
Trypanocidal agent
Trypanocidal Agents - pharmacology
Trypanosoma cruzi
Trypanosoma cruzi - drug effects
α-Lapachone
β-Lapachone
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Summary:Trypanocidal effects against Trypanosoma cruzi and cytotoxicity to mammalian cells of several oxyrans structurally related to β-lapachone, nor-β-lapachone, α-lapachone, and 4-methoxy-1,2-naphthoquinone are described. It was found that the compound 7a derived from α-lapachone ( 7) exhibits higher trypanocidal activity than β-lapachone with less cytotoxicity. A theoretical study was performed in order to determine structural and stereoelectronic effects that are related with the trypanocidal activity. Starting from α- and β-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 α-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 β-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 β-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 log P (c log P) parameter. This study could lead to the development of new antichagasic medicines based on α-lapachone analogs.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2006.04.046