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

doi:10.1016/j.bmcl.2011.05.076

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

School of Biological Sciences

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

Original language	English
Pages (from-to)	4233-4237
Number of pages	5
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	21
Issue number	14
DOIs	https://doi.org/10.1016/j.bmcl.2011.05.076
Publication status	Published - 15 Jul 2011

Keywords / Materials (for Non-textual outputs)

Leishmania
Cyclin-dependent kinase
Inhibitor
Therapy

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Jorda, R., Sacerdoti-Sierra, N., Voller, J., Havlíček, L., Kráčalíková, K., Nowicki, M. W., Nasereddin, A., Kryštof, V., Strnad, M., Walkinshaw, M. D., & Jaffe, C. L. (2011). Anti-leishmanial activity of disubstituted purines and related pyrazolo[4,3-d]pyrimidines. Bioorganic & Medicinal Chemistry Letters, 21(14), 4233-4237. https://doi.org/10.1016/j.bmcl.2011.05.076

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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.",

keywords = "Leishmania, Cyclin-dependent kinase, Inhibitor, Therapy",

author = "Radek Jorda and Nina Sacerdoti-Sierra and Ji{\v r}{\'i} Voller and Libor Havl{\'i}{\v c}ek and Kate{\v r}ina Kr{\'a}{\v c}al{\'i}kov{\'a} and Nowicki, {Matthew W} and Abedelmajeed Nasereddin and Vladim{\'i}r Kry{\v s}tof and Miroslav Strnad and Walkinshaw, {Malcolm D} and Jaffe, {Charles L}",

year = "2011",

month = jul,

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doi = "10.1016/j.bmcl.2011.05.076",

language = "English",

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journal = "Bioorganic & Medicinal Chemistry Letters",

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Jorda, R, Sacerdoti-Sierra, N, Voller, J, Havlíček, L, Kráčalíková, K, Nowicki, MW, Nasereddin, A, Kryštof, V, Strnad, M, Walkinshaw, MD & Jaffe, CL 2011, 'Anti-leishmanial activity of disubstituted purines and related pyrazolo[4,3-d]pyrimidines', Bioorganic & Medicinal Chemistry Letters, vol. 21, no. 14, pp. 4233-4237. https://doi.org/10.1016/j.bmcl.2011.05.076

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

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 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.

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 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.

KW - Leishmania

KW - Cyclin-dependent kinase

KW - Inhibitor

KW - Therapy

U2 - 10.1016/j.bmcl.2011.05.076

DO - 10.1016/j.bmcl.2011.05.076

M3 - Article

C2 - 21683592

SN - 0960-894X

VL - 21

SP - 4233

EP - 4237

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 14

ER -

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

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Keywords / Materials (for Non-textual outputs)

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