Design, synthesis, and pharmacological evaluation of novel hybrid compounds to treat sickle cell disease symptoms. part II: furoxan derivatives.
Phthalimide derivatives containing furoxanyl subunits as nitric oxide (NO)-donors (3a-g) were designed, synthesized, and evaluated in vitro and in vivo for their potential uses in the oral treatment of sickle cell disease symptoms. All compounds (3a-g) demonstrated NO-donor properties at different levels. Moreover, compounds 3b and 3c demonstrated analgesic activity. Compound 3b was determined to be a promising drug candidate for the aforementioned uses, and it was further evaluated in K562 culture cells to determine its ability to increase levels of γ-globin expression. After 96 h at 5 μM, compound 3b was able to induce γ-globin expression by nearly three times. Mutagenic studies using micronucleus tests in peripheral blood cells of mice demonstrated that compound 3b reduces the mutagenic profile as compared with hydroxyurea. Compound 3b has emerged as a new leading drug candidate with multiple beneficial effects for the treatment of sickle cell disease symptoms and provides an alternative to hydroxyurea treatment.
Lapdesf-Laboratório de Pesquisa e Desenvolvimento de Fármacos, Departamento de Fármacos e Medicamentos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista-UNESP, Rodovia Araraquara Jaú Km. 01, 14801-902 Araraquara, SP, Brazil. santosjl@fcfar.unesp.br
Jean Leandro
JL
Dos Santos
Carolina
C
Lanaro
Rafael Consolin
RC
Chelucci
Sheley
S
Gambero
Priscila Longhin
PL
Bosquesi
Juliana Santana
JS
Reis
Lídia Moreira
LM
Lima
Hugo
H
Cerecetto
Mercedes
M
González
Fernando Ferreira
FF
Costa
Man Chin
MC
Chung
D000755:Anemia, Sickle Cell / Q000188:drug therapy*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D016133:Polymerase Chain Reaction
C528141:1,2,5-oxadiazole 2-oxide; D020030:Nitric Oxide Donors; D010069:Oxadiazoles