Estimates of as many as one in six in the world population (over 1 billion people) are infected by one or more of them, Neglected tropical diseases (NTDs) represent a significant global health burden, particularly in developing regions of the world. Because the limited investment in treating or preventing them, cost-effective approaches for identification of drug leads, as the “repurpose” of classes of proven molecular targets, are needed in order to spawn the discovery of new drugs. Specifically, Kinase inhibitors have received high attention as one of the principal enzyme target classes in drug discovery for a wide variety of indications. Funded by EU inside 7FP framework, inside the TAKTIC project three kinases involved in the NFkB cascade (IKKalfa, IKKbeta and NIK) have been deeply targeted. In this occasion, a repurpose approach, based on the result of that experience allowed us to quickly identify a small library of 4-phenyl-3-amino-1H-pyrazols analogues presenting a potent, similar to Miltefosine itself, anti-leishmanial activity profile. The compounds selection was ruled by an in silico evaluation of the interaction with Cdc2-related protein kinase 3 (CRK3). As in human, where cyclin dependent kinases (CDKs) are know to play important roles in cell division, transcription, etc., also in Leishmania, the Cdc2-related kinase family have attracted attention as potential drug targets. In particular, the CRK3 isoform is postulated to be an essential enzyme for transition through the G2/M phase checkpoint of the Leishmania cell cycle, responsible for parasite growth and survival1. Based from a homology model of Leishmania Mexicana CRK3 recently reported,2 our in-house library of about 30 aminopyrazoles was therefore docked against the template protein (PDB: 1VYZ) selecting five compounds, based on best scores and valuable poses, for the next biological evaluation. In this occasion, in silico general strategy, specific binding modes, synthesis and biological evaluation of active compounds against Leishmania Braziliensis and Leishmania Amazonensisare presented and fully discussed.

Antileishmanial activity of some 4-phenyl-3-amino-1H-pyrazols designed as CRK3 kinase inhibitors

Agnese Chiara Pippione;Piermichele Kobauri;Stefano Sainas;Antonella Federico;Donatella Boschi;Marco Lucio Lolli
2016

Abstract

Estimates of as many as one in six in the world population (over 1 billion people) are infected by one or more of them, Neglected tropical diseases (NTDs) represent a significant global health burden, particularly in developing regions of the world. Because the limited investment in treating or preventing them, cost-effective approaches for identification of drug leads, as the “repurpose” of classes of proven molecular targets, are needed in order to spawn the discovery of new drugs. Specifically, Kinase inhibitors have received high attention as one of the principal enzyme target classes in drug discovery for a wide variety of indications. Funded by EU inside 7FP framework, inside the TAKTIC project three kinases involved in the NFkB cascade (IKKalfa, IKKbeta and NIK) have been deeply targeted. In this occasion, a repurpose approach, based on the result of that experience allowed us to quickly identify a small library of 4-phenyl-3-amino-1H-pyrazols analogues presenting a potent, similar to Miltefosine itself, anti-leishmanial activity profile. The compounds selection was ruled by an in silico evaluation of the interaction with Cdc2-related protein kinase 3 (CRK3). As in human, where cyclin dependent kinases (CDKs) are know to play important roles in cell division, transcription, etc., also in Leishmania, the Cdc2-related kinase family have attracted attention as potential drug targets. In particular, the CRK3 isoform is postulated to be an essential enzyme for transition through the G2/M phase checkpoint of the Leishmania cell cycle, responsible for parasite growth and survival1. Based from a homology model of Leishmania Mexicana CRK3 recently reported,2 our in-house library of about 30 aminopyrazoles was therefore docked against the template protein (PDB: 1VYZ) selecting five compounds, based on best scores and valuable poses, for the next biological evaluation. In this occasion, in silico general strategy, specific binding modes, synthesis and biological evaluation of active compounds against Leishmania Braziliensis and Leishmania Amazonensisare presented and fully discussed.
XXIV EFMC International Symposium on Medicinal Chemistry (EFMC-ISMC 2016)
Manchester (United Kingdom).
28 Agosto - 1 Settembre, 2016
XXIV EFMC International Symposium on Medicinal Chemistry (EFMC-ISMC 2016)
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Agnese Chiara Pippione, Piermichele Kobauri, Stefano Sainas, Alberto Gimenez, Antonella Federico, Rodolpho Campos Braga, Carolina Horta Andrade, Donatella Boschi, Efrain Salamanca, Juan Carlos Ticona, Marco Lucio Lolli
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1852019
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