TY - JOUR
T1 - Anti-leishmanial activity of disubstituted purines and related pyrazolo[4,3-d]pyrimidines
AU - Jorda, Radek
AU - Sacerdoti-Sierra, Nina
AU - Voller, Jiří
AU - Havlíček, Libor
AU - Kráčalíková, Kateřina
AU - Nowicki, Matthew W.
AU - Nasereddin, Abedelmajeed
AU - Kryštof, Vladimír
AU - Strnad, Miroslav
AU - Walkinshaw, Malcolm D.
AU - Jaffe, Charles L.
N1 - Funding Information: The work was supported by grants from the Czech Science Foundation (204/08/0511; 301/08/1649), from the Ministry of Education, Youth and Sports of the Czech Republic (MSM 6198959216) and by a grant of the European Commission (Contract No. LSHB-CT-2004-503467; C.L.J.). The Center for Translational and Chemical Biology and Edinburgh Protein Production Facility (University of Edinburgh) were funded by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council. C.L.J. holds the Michael and Penny Feiwel Chair in Dermatology. We are very grateful to Dr. Jeremy C. Mottram for contributing constructs of recombinant CRK3 and CYC6.
PY - 2011/7/15
Y1 - 2011/7/15
N2 - We report here results of screening directed to finding new anti-leishmanial drugs among 2,6-disubstituted purines and corresponding 3,7-disubstituted pyrazolo[4,3-d]pyrimidines. These compounds have previously been shown to moderately inhibit human cyclin-dependent kinases. Since some compounds reduced viability of axenic amastigotes of Leishmania donovani, we screened them for interaction with recombinant leishmanial cdc-2 related protein kinase (CRK3/CYC6), an important cell cycle regulator of the parasitic protozoan. Eighteen pairs of corresponding isomers were tested for viability of amastigotes and for inhibition of CRK3/CYC6 kinase activity. Some compounds (9A, 12A and 13A) show activity against amastigotes with EC50 in a range 1.5-12.4 μM. Structure-activity relationships for the tested compounds are discussed and related to the lipophilicity of the compounds.
AB - We report here results of screening directed to finding new anti-leishmanial drugs among 2,6-disubstituted purines and corresponding 3,7-disubstituted pyrazolo[4,3-d]pyrimidines. These compounds have previously been shown to moderately inhibit human cyclin-dependent kinases. Since some compounds reduced viability of axenic amastigotes of Leishmania donovani, we screened them for interaction with recombinant leishmanial cdc-2 related protein kinase (CRK3/CYC6), an important cell cycle regulator of the parasitic protozoan. Eighteen pairs of corresponding isomers were tested for viability of amastigotes and for inhibition of CRK3/CYC6 kinase activity. Some compounds (9A, 12A and 13A) show activity against amastigotes with EC50 in a range 1.5-12.4 μM. Structure-activity relationships for the tested compounds are discussed and related to the lipophilicity of the compounds.
KW - Cyclin-dependent kinase
KW - Inhibitor
KW - Leishmania
KW - Therapy
UR - http://www.scopus.com/inward/record.url?scp=79959911608&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.bmcl.2011.05.076
DO - https://doi.org/10.1016/j.bmcl.2011.05.076
M3 - مقالة
C2 - 21683592
SN - 0960-894X
VL - 21
SP - 4233
EP - 4237
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 14
ER -
