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Pd-catalyzed C–C and C–N cross-coupling reactions in 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series for antiplasmodial pharmacomodulation

In 2015, we identified gamhepathiopine (M1), a 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one antiplasmodial hit targeting all development stages of the human malarial parasite P. falciparum. However, this hit compound suffers from sensitivity to hepatic oxidative metabolism. Herein, we describe...

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Autores principales: Mustière, Romain, Lagardère, Prisca, Hutter, Sébastien, Deraeve, Céline, Schwalen, Florian, Amrane, Dyhia, Masurier, Nicolas, Azas, Nadine, Lisowski, Vincent, Verhaeghe, Pierre, Mazier, Dominique, Vanelle, Patrice, Primas, Nicolas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264115/
https://www.ncbi.nlm.nih.gov/pubmed/35865200
http://dx.doi.org/10.1039/d2ra01687g
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author Mustière, Romain
Lagardère, Prisca
Hutter, Sébastien
Deraeve, Céline
Schwalen, Florian
Amrane, Dyhia
Masurier, Nicolas
Azas, Nadine
Lisowski, Vincent
Verhaeghe, Pierre
Mazier, Dominique
Vanelle, Patrice
Primas, Nicolas
author_facet Mustière, Romain
Lagardère, Prisca
Hutter, Sébastien
Deraeve, Céline
Schwalen, Florian
Amrane, Dyhia
Masurier, Nicolas
Azas, Nadine
Lisowski, Vincent
Verhaeghe, Pierre
Mazier, Dominique
Vanelle, Patrice
Primas, Nicolas
author_sort Mustière, Romain
collection PubMed
description In 2015, we identified gamhepathiopine (M1), a 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one antiplasmodial hit targeting all development stages of the human malarial parasite P. falciparum. However, this hit compound suffers from sensitivity to hepatic oxidative metabolism. Herein, we describe the synthesis of 33 new compounds in the 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series modulated at position 6 of this scaffold. The modulations were performed using three palladium-catalyzed cross coupling reactions, namely Suzuki–Miyaura, Sonogashira, and Buchwald–Hartwig. For the latter, we developed the reaction conditions. Then, we evaluated the synthesized compounds for their antiplasmodial activity on the K(1)P. falciparum strain and their cytotoxicity on the human HepG2 cell line. Although we did not obtain a compound better than M1 in terms of the antiplasmodial activity, we identified compound 1g bearing a piperidine at position 6 of the thieno[3,2-d]pyrimidin-4(3H)-one ring with an improved cytotoxicity and metabolic stability. 1g is an interesting new starting point for further pharmacomodulation studies. This study also provides valuable antiplasmodial SAR data regarding the nature of the ring at position 6, the possible substituent on this ring, and the introduction of a spacer between this ring and the thienopyrimidinone moiety.
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spelling pubmed-92641152022-07-20 Pd-catalyzed C–C and C–N cross-coupling reactions in 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series for antiplasmodial pharmacomodulation Mustière, Romain Lagardère, Prisca Hutter, Sébastien Deraeve, Céline Schwalen, Florian Amrane, Dyhia Masurier, Nicolas Azas, Nadine Lisowski, Vincent Verhaeghe, Pierre Mazier, Dominique Vanelle, Patrice Primas, Nicolas RSC Adv Chemistry In 2015, we identified gamhepathiopine (M1), a 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one antiplasmodial hit targeting all development stages of the human malarial parasite P. falciparum. However, this hit compound suffers from sensitivity to hepatic oxidative metabolism. Herein, we describe the synthesis of 33 new compounds in the 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series modulated at position 6 of this scaffold. The modulations were performed using three palladium-catalyzed cross coupling reactions, namely Suzuki–Miyaura, Sonogashira, and Buchwald–Hartwig. For the latter, we developed the reaction conditions. Then, we evaluated the synthesized compounds for their antiplasmodial activity on the K(1)P. falciparum strain and their cytotoxicity on the human HepG2 cell line. Although we did not obtain a compound better than M1 in terms of the antiplasmodial activity, we identified compound 1g bearing a piperidine at position 6 of the thieno[3,2-d]pyrimidin-4(3H)-one ring with an improved cytotoxicity and metabolic stability. 1g is an interesting new starting point for further pharmacomodulation studies. This study also provides valuable antiplasmodial SAR data regarding the nature of the ring at position 6, the possible substituent on this ring, and the introduction of a spacer between this ring and the thienopyrimidinone moiety. The Royal Society of Chemistry 2022-07-08 /pmc/articles/PMC9264115/ /pubmed/35865200 http://dx.doi.org/10.1039/d2ra01687g Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/
spellingShingle Chemistry
Mustière, Romain
Lagardère, Prisca
Hutter, Sébastien
Deraeve, Céline
Schwalen, Florian
Amrane, Dyhia
Masurier, Nicolas
Azas, Nadine
Lisowski, Vincent
Verhaeghe, Pierre
Mazier, Dominique
Vanelle, Patrice
Primas, Nicolas
Pd-catalyzed C–C and C–N cross-coupling reactions in 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series for antiplasmodial pharmacomodulation
title Pd-catalyzed C–C and C–N cross-coupling reactions in 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series for antiplasmodial pharmacomodulation
title_full Pd-catalyzed C–C and C–N cross-coupling reactions in 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series for antiplasmodial pharmacomodulation
title_fullStr Pd-catalyzed C–C and C–N cross-coupling reactions in 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series for antiplasmodial pharmacomodulation
title_full_unstemmed Pd-catalyzed C–C and C–N cross-coupling reactions in 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series for antiplasmodial pharmacomodulation
title_short Pd-catalyzed C–C and C–N cross-coupling reactions in 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series for antiplasmodial pharmacomodulation
title_sort pd-catalyzed c–c and c–n cross-coupling reactions in 2-aminothieno[3,2-d]pyrimidin-4(3h)-one series for antiplasmodial pharmacomodulation
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264115/
https://www.ncbi.nlm.nih.gov/pubmed/35865200
http://dx.doi.org/10.1039/d2ra01687g
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