TY - JOUR
T1 - Synthesis and antileishmanial activity of new 1-(pyridin-2- yl)imidazolidin-2-ones derived from 2-amino-4,6-dimethylpyridine
AU - Abdala, Hiam
AU - Robert, Jean Michel
AU - Le Pape, Patrice
AU - Wielgosz, Gaétane
AU - Robert-Piessard, Sylvie
AU - Le Baut, Guillaume
PY - 2000/1/1
Y1 - 2000/1/1
N2 - Derivatives of 2-amino-4,6-dimethylpyridine resulting from the integration of the amino function into a 2-imidazolidinone were synthesized via the corresponding 2-chloroethylurea. N3-benzylation, acylation or sulfonylation afforded the target compounds 6-14 which were evaluated for their in vitro and in vivo antileishmanial activity. Two compounds, the N3- benzyl derivative 7 and the N3-tolylsulfonyl derivative 14, exhibited potent inhibition against cultured extracellular promastigotes of Leishmania mexicana with IC50 comparable to that of the previously studied N-(4,6- dimethylpyridin-2-yl) furan-2-carboxamide 2: 32.4, 46 and 69 μmol/l, respectively. Experimentation of their activity against mice macrophage amastigotes pointed out that IC50 of imidazolidones 7 and 14 were 7 and 13- fold lower than that of amide 2: 13.7 and 89 μmol/l. In vivo evaluation in Balb/c mice, intradermally infested with Leishmania mexicana, confirmed that, in the lesion site, compound 14 was able to significantly reduce the parasite burden at a daily i.p. dose of 10 mg/kg. It was demonstrated that these N- pyridinylimidazolidinones could act by interference with the parasite PLA2 activity.
AB - Derivatives of 2-amino-4,6-dimethylpyridine resulting from the integration of the amino function into a 2-imidazolidinone were synthesized via the corresponding 2-chloroethylurea. N3-benzylation, acylation or sulfonylation afforded the target compounds 6-14 which were evaluated for their in vitro and in vivo antileishmanial activity. Two compounds, the N3- benzyl derivative 7 and the N3-tolylsulfonyl derivative 14, exhibited potent inhibition against cultured extracellular promastigotes of Leishmania mexicana with IC50 comparable to that of the previously studied N-(4,6- dimethylpyridin-2-yl) furan-2-carboxamide 2: 32.4, 46 and 69 μmol/l, respectively. Experimentation of their activity against mice macrophage amastigotes pointed out that IC50 of imidazolidones 7 and 14 were 7 and 13- fold lower than that of amide 2: 13.7 and 89 μmol/l. In vivo evaluation in Balb/c mice, intradermally infested with Leishmania mexicana, confirmed that, in the lesion site, compound 14 was able to significantly reduce the parasite burden at a daily i.p. dose of 10 mg/kg. It was demonstrated that these N- pyridinylimidazolidinones could act by interference with the parasite PLA2 activity.
KW - 1-(4,6-dimethylpyridin-2- yl)imidazolidin-2-ones
KW - 2-Amino-4,6-dimethylpiridine derivatives
KW - Anti-leishmania activity
KW - PLA inhibition
UR - http://www.scopus.com/inward/record.url?scp=0043260382&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0043260382&partnerID=8YFLogxK
U2 - 10.1055/s-0031-1300233
DO - 10.1055/s-0031-1300233
M3 - Article
C2 - 10858876
AN - SCOPUS:0043260382
SN - 0004-4172
VL - 50
SP - 479
EP - 484
JO - Arzneimittel-Forschung/Drug Research
JF - Arzneimittel-Forschung/Drug Research
IS - 5
ER -