title: Benzophenone derivatives as cysteine protease inhibitors and biological activity against Leishmania(L.) amazonensis amastigotes.
abstract: The leishmanicidal potential of benzophenones has been described, some of them highlighting their potential as cysteine protease inhibitors. Therefore, this work described leishmanicidal activity of nine benzophenone derivatives (1a-c;2a-c;3a-c) against intramacrophage amastigote forms of Leishmania(L.)amazonensis (IC50) and the cytotoxic effect on murine peritoneal macrophages (CC50). The derivative 1c exhibited a selectivity index SI (CC50/IC50) of 6.7, besides cytotoxicity lower than Amphotericin B (p< 0.05). Moreover it showed inhibitory activity against papain (42.8±0.3, p<0.05), and when tested on trypanosomatids cysteine proteases 1c also proved to be a potent inhibitor of rCPB2.8, rCPB3.0 and cruzain, showing non-competitive inhibition mechanism by enzymatic assays in vitro.So, benzophenone 1c is interesting drug candidate prototype, with a multi-target directed mode of action, inhibiting rCPB2.8, rCPB3.0 and cruzain.
authors.affiliation: Laboratório de Biologia Molecular de Micro-organismos - Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, 37130-000, Alfenas-MG, Brazil. Electronic address: leticia.almeida.le@gmail.com.
authors.forename: Letícia
authors.initials: L
authors.lastname: de Almeida
authors.affiliation: Laboratório de Biologia Molecular de Micro-organismos - Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, 37130-000, Alfenas-MG, Brazil.
authors.forename: Karina Ferreira
authors.initials: KF
authors.lastname: Alves
authors.affiliation: Laboratório de Fitoquímica e Química Medicinal - Instituto de Química, Universidade Federal de Alfenas, 37130-000, Alfenas-MG, Brazil.
authors.forename: Claudia Mara
authors.initials: CM
authors.lastname: Maciel-Rezende
authors.affiliation: Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi das Cruzes, 08780-911, Mogi das Cruzes, SP, Brazil.
authors.forename: Larissa de Oliveira Passos
authors.initials: Lde O
authors.lastname: Jesus
authors.affiliation: Laboratório de Fitoquímica e Química Medicinal - Instituto de Química, Universidade Federal de Alfenas, 37130-000, Alfenas-MG, Brazil.
authors.forename: Francieli Ribeiro
authors.initials: FR
authors.lastname: Pires
authors.affiliation: Laboratório de Fitoquímica e Química Medicinal - Instituto de Química, Universidade Federal de Alfenas, 37130-000, Alfenas-MG, Brazil.
authors.forename: Claudio Viegas
authors.initials: CV
authors.lastname: Junior
authors.affiliation: Laboratório de Biologia Celular de Parasitas - Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, 04039-032, São Paulo-SP, Brazil.
authors.forename: Mario Augusto
authors.initials: MA
authors.lastname: Izidoro
authors.affiliation: Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi das Cruzes, 08780-911, Mogi das Cruzes, SP, Brazil.
authors.forename: Wagner Alves de Souza
authors.initials: WA
authors.lastname: Júdice
authors.affiliation: Laboratório de Fitoquímica e Química Medicinal - Instituto de Química, Universidade Federal de Alfenas, 37130-000, Alfenas-MG, Brazil.
authors.forename: Marcelo Henrique
authors.initials: MH
authors.lastname: dos Santos
authors.affiliation: Laboratório de Biologia Molecular de Micro-organismos - Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, 37130-000, Alfenas-MG, Brazil.
authors.forename: Marcos José
authors.initials: MJ
authors.lastname: Marques
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D007891:Leishmania / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D010206:Papain / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014344:Trypanocidal Agents / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001577:Benzophenones; D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; C047723:benzophenone; D003546:Cysteine Endopeptidases; D010206:Papain
keywords: Benzophenone derivatives; Cysteine proteases; Leishmania amazonensis