title: Leishmanicidal activities of novel synthetic furoxan and benzofuroxan derivatives.
abstract: A novel series of furoxan (1,2,5-oxadiazole 2-oxide) (compounds 3, 4a and -b, 13a and -b, and 14a to -f) and benzofuroxan (benzo[c][1,2,5]oxadiazole 1-oxide) (compounds 7 and 8a to -c) derivatives were synthesized, characterized, and evaluated for in vitro activity against promastigote and intracellular amastigote forms of Leishmania amazonensis. The furoxan derivatives exhibited the ability to generate nitric oxide at different levels (7.8% to 27.4%). The benzofuroxan derivative 8a was able to increase nitrite production in medium supernatant from murine macrophages infected with L. amazonensis at 0.75 mM after 48 h. Furoxan and benzofuroxan derivatives showed remarkable leishmanicidal activity against both promastigote and intracellular amastigote forms. Compounds 8a, 14a and -b, and 14d exerted selective leishmanicidal activities superior to those of amphotericin B and pentamidine. In vitro studies at pH 5.4 reveal that compound 8a is stable until 8 h and that compound 14a behaves as a prodrug, releasing the active aldehyde 13a. These compounds have emerged as promising novel drug candidates for the treatment of leishmaniasis.
authors.affiliation: Faculdade de Ciências Farmacêuticas-Universidade Estadual Paulista-UNESP, Araraquara, SP, Brazil.
authors.forename: Luiz Antônio
authors.initials: LA
authors.lastname: Dutra
authors.affiliation: Faculdade de Ciências Farmacêuticas-Universidade Estadual Paulista-UNESP, Araraquara, SP, Brazil.
authors.forename: Letícia
authors.initials: L
authors.lastname: de Almeida
authors.affiliation: Faculdade de Ciências Farmacêuticas-Universidade Estadual Paulista-UNESP, Araraquara, SP, Brazil.
authors.forename: Thais G
authors.initials: TG
authors.lastname: Passalacqua
authors.affiliation: Faculdade de Ciências Farmacêuticas-Universidade Estadual Paulista-UNESP, Araraquara, SP, Brazil.
authors.forename: Juliana Santana
authors.initials: JS
authors.lastname: Reis
authors.affiliation: Faculdade de Ciências Farmacêuticas-Universidade Estadual Paulista-UNESP, Araraquara, SP, Brazil.
authors.forename: Fabio A E
authors.initials: FA
authors.lastname: Torres
authors.affiliation: Faculdade de Ciências Farmacêuticas-Universidade Estadual Paulista-UNESP, Araraquara, SP, Brazil.
authors.forename: Isabel
authors.initials: I
authors.lastname: Martinez
authors.affiliation: Faculdade de Ciências Farmacêuticas-Universidade Estadual Paulista-UNESP, Araraquara, SP, Brazil.
authors.forename: Rosangela Gonçalves
authors.initials: RG
authors.lastname: Peccinini
authors.affiliation: Faculdade de Ciências Farmacêuticas-Universidade Estadual Paulista-UNESP, Araraquara, SP, Brazil.
authors.forename: Chung Man
authors.initials: CM
authors.lastname: Chin
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, Italy.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Chegaev
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Guglielmo
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.affiliation: Faculdade de Ciências Farmacêuticas-Universidade Estadual Paulista-UNESP, Araraquara, SP, Brazil graminha@fcfar.unesp.br santosjl@fcfar.unesp.br.
authors.forename: Marcia A S
authors.initials: MA
authors.lastname: Graminha
authors.affiliation: Faculdade de Ciências Farmacêuticas-Universidade Estadual Paulista-UNESP, Araraquara, SP, Brazil graminha@fcfar.unesp.br santosjl@fcfar.unesp.br.
authors.forename: Jean Leandro
authors.initials: JL
authors.lastname: dos Santos
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007894:Leishmania mexicana / Q000187:drug effects* / Q000254:growth & development; D008018:Life Cycle Stages / Q000187:drug effects* / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D009573:Nitrites / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D010419:Pentamidine / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D001583:Benzoxazoles; D009573:Nitrites; D010069:Oxadiazoles; C010166:furoxans; D009569:Nitric Oxide; D010419:Pentamidine; D000666:Amphotericin B