Starting from the structure of previously reported 3-Br-isoxazoline-based covalent inhibitors of P. falciparum glyceraldehyde 3-phosphate dehydrogenase, and with the intent to improve their metabolic stability and antimalarial activity, we designed and synthesized a series of simplified analogues that are characterized by the insertion of the oxadiazole ring as a bioisosteric replacement for the metabolically labile ester/amide function. We then further replaced the oxadiazole ring with a series of five-membered heterocycles and finally combined the most promising structural features. All the new derivatives were tested in vitro for antimalarial as well as antileishmanial activity. We identified two very promising new lead compounds, endowed with submicromolar antileishmanial activity and nanomolar antiplasmodial activity, respectively, and a very high selectivity index with respect to mammalian cells.

Development of Potent 3-Br-isoxazoline-Based Antimalarial and Antileishmanial Compounds / A. Galbiati, A. Zana, C. Coser, L. Tamborini, N. Basilico, S. Parapini, D. Taramelli, P. Conti. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 12:11(2021 Nov 11), pp. 1726-1732. [10.1021/acsmedchemlett.1c00354]

Development of Potent 3-Br-isoxazoline-Based Antimalarial and Antileishmanial Compounds

A. Galbiati
Primo
;
C. Coser;L. Tamborini;N. Basilico;S. Parapini;D. Taramelli
Penultimo
;
P. Conti
Ultimo
2021

Abstract

Starting from the structure of previously reported 3-Br-isoxazoline-based covalent inhibitors of P. falciparum glyceraldehyde 3-phosphate dehydrogenase, and with the intent to improve their metabolic stability and antimalarial activity, we designed and synthesized a series of simplified analogues that are characterized by the insertion of the oxadiazole ring as a bioisosteric replacement for the metabolically labile ester/amide function. We then further replaced the oxadiazole ring with a series of five-membered heterocycles and finally combined the most promising structural features. All the new derivatives were tested in vitro for antimalarial as well as antileishmanial activity. We identified two very promising new lead compounds, endowed with submicromolar antileishmanial activity and nanomolar antiplasmodial activity, respectively, and a very high selectivity index with respect to mammalian cells.
3-bromoisoxazoline; bioisosterism; covalent inhibitor; leishmania; malaria; oxadiazole;
Settore MED/04 - Patologia Generale
Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio
Settore CHIM/08 - Chimica Farmaceutica
   Towards multi-stage drugs to fight poverty related and neglected parasitic diseases: synthetic and natural compounds directed against Leishmania, Plasmodium and Schistosoma life stages and assessment of their mechanisms of action.
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
   20154JRJPP_004
11-nov-2021
13-ott-2021
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/878566
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