title: Trypanocidal agents with low cytotoxicity to mammalian cell line: a comparison of the theoretical and biological features of lapachone derivatives.
abstract: 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.
authors.affiliation: Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, Niterói, Rio de Janeiro, Brazil. cegvito@vm.uff.br
authors.forename: Vitor F
authors.initials: VF
authors.lastname: Ferreira
authors.forename: Alessandra
authors.initials: A
authors.lastname: Jorqueira
authors.forename: Alessandra M T
authors.initials: AM
authors.lastname: Souza
authors.forename: Milton N
authors.initials: MN
authors.lastname: da Silva
authors.forename: Maria C B V
authors.initials: MC
authors.lastname: de Souza
authors.forename: Robson M
authors.initials: RM
authors.lastname: Gouvêa
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Rodrigues
authors.forename: Antonio V
authors.initials: AV
authors.lastname: Pinto
authors.forename: Helena C
authors.initials: HC
authors.lastname: Castro
authors.forename: Dilvani O
authors.initials: DO
authors.lastname: Santos
authors.forename: Humberto P
authors.initials: HP
authors.lastname: Araújo
authors.forename: Saulo C
authors.initials: SC
authors.lastname: Bourguignon
mesh_terms: D000818:Animals; D002460:Cell Line; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D055672:Static Electricity; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D009285:Naphthoquinones; D014344:Trypanocidal Agents; C014638:beta-lapachone; C415043:alpha-lapachone