Trypanosoma brucei parasites cause Human African Trypanosomiasis and the current drugs for its treatment are often inefficient and toxic. This urges the need to development of new antitrypanosomal agents. We report the synthesis and biological profiling of 3'-deoxy-3'-fluororibonucleosides derived from 7-deazaadenine nucleosides bearing diverse substituents at position 7. They were synthesized through glycosylation of 6-chloro-7-bromo- or -7-iodo-7-deazapurine with protected 3'-fluororibose followed by cross-coupling reactions at position 7 and/or deprotection. Most of the title nucleosides displayed micromolar or submicromolar activity against Trypanosoma brucei brucei. The most active were the 7-bromo- and 7-iododerivatives which exerted double-digit nanomolar activity against T. b. brucei and T. b. gambiense and no cytotoxicity and thus represent promising candidates for further development.

• MeSH
• fibroblasty účinky léků   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• parazitické testy citlivosti MeSH
• ribonukleosidy chemická syntéza   farmakologie   toxicita   MeSH
• trypanocidální látky chemická syntéza   farmakologie   toxicita   MeSH
• Trypanosoma brucei brucei účinky léků   MeSH
• Trypanosoma brucei gambiense účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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.

• MeSH
• Leishmania donovani účinky léků   MeSH
• proteinkinasa CDC2 antagonisté a inhibitory   genetika   metabolismus   MeSH
• protozoální proteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• puriny chemická syntéza   chemie   farmakologie   MeSH
• pyrazoly chemie   MeSH
• pyrimidiny chemická syntéza   chemie   farmakologie   MeSH
• rekombinantní proteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• trypanocidální látky chemická syntéza   chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH