Anti-leishmanial activity of disubstituted purines and related pyrazolo[4,3-d]pyrimidines

Radek Jorda*, Nina Sacerdoti-Sierra, Jiří Voller, Libor Havlíček, Kateřina Kráčalíková, Matthew W. Nowicki, Abedelmajeed Nasereddin, Vladimír Kryštof, Miroslav Strnad, Malcolm D. Walkinshaw, Charles L. Jaffe

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)4233-4237
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number14
DOIs
StatePublished - 15 Jul 2011

Bibliographical note

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.

Keywords

  • Cyclin-dependent kinase
  • Inhibitor
  • Leishmania
  • Therapy

Fingerprint

Dive into the research topics of 'Anti-leishmanial activity of disubstituted purines and related pyrazolo[4,3-d]pyrimidines'. Together they form a unique fingerprint.

Cite this