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

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• 作者：Radek Jorda^a ; ^{radek.jorda@upol.cz"" rel=""nofollow} ; Nina Sacerdoti-Sierra^b ; Jiř ; &#xed ; Voller^a ; Libor Havl&#xed ; č ; ek^c ; Kateř ; ina Krá ; č ; al&#xed ; ková ; ^c ; Matthew W. Nowicki^d ; Abedelmajeed Nasereddin^e ; Vladim&#xed ; r Kryš ; tof^a ; Miroslav Strnad^a ; Malcolm D. Walkinshaw^d ; Charles L. Jaffe^b
• 关键词：Leishmania ; Cyclin-dependent kinase ; Inhibitor ; Therapy
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：15 July 2011
• 年：2011
• 卷：21
• 期：14
• 页码：4233-4237
• 全文大小：319 K

文摘

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.