title: Anti-leishmanial activity of disubstituted purines and related pyrazolo[4,3-d]pyrimidines.
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 EC(50) in a range 1.5-12.4μM. Structure-activity relationships for the tested compounds are discussed and related to the lipophilicity of the compounds.
authors.affiliation: Laboratory of Growth Regulators, Faculty of Science, Palacký University, Šlechtitelů 11, 783 71 Olomouc, Czech Republic. radek.jorda@upol.cz
authors.forename: Radek
authors.initials: R
authors.lastname: Jorda
authors.forename: Nina
authors.initials: N
authors.lastname: Sacerdoti-Sierra
authors.forename: Jiří
authors.initials: J
authors.lastname: Voller
authors.forename: Libor
authors.initials: L
authors.lastname: Havlíček
authors.forename: Kateřina
authors.initials: K
authors.lastname: Kráčalíková
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Nowicki
authors.forename: Abedelmajeed
authors.initials: A
authors.lastname: Nasereddin
authors.forename: Vladimír
authors.initials: V
authors.lastname: Kryštof
authors.forename: Miroslav
authors.initials: M
authors.lastname: Strnad
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Walkinshaw
authors.forename: Charles L
authors.initials: CL
authors.lastname: Jaffe
mesh_terms: D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007893:Leishmania donovani / Q000187:drug effects*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D015800:Protozoan Proteins; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; C031280:pyrazole; D016203:CDC2 Protein Kinase