Journal
RSC ADVANCES
Volume 12, Issue 31, Pages 20004-20021Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d2ra01687g
Keywords
-
Categories
Funding
- Fondation pour la Recherche Medicale (FRM) [DMC20181039565]
- Agence Nationale de la Recherche (ANR) [18-CE180009-01]
Ask authors/readers for more resources
This study describes the synthesis of 33 new compounds in the 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series via three palladium-catalyzed cross coupling reactions. The synthesized compounds were evaluated for their antiplasmodial activity and cytotoxicity. Although a better compound than the existing drug was not obtained, compound 1g with improved cytotoxicity and metabolic stability was identified as a potential starting point for further research.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available