Novel thienopyrimidones targeting hepatic and erythrocytic stages of Plasmodium parasites with increased microsomal stability.

Based on the structure of a previously identified hit, Gamhepathiopine 1, which showed promising antiplasmodial activity, but poor microsomal stability, several strategies were investigated to improve the metabolic stability of the compounds. This included the introduction of fluorine or deuterium atoms, as well as carbocyclic groups. Among the new compounds, the 2-aminocyclobutyl derivative 5g demonstrated enhanced microsomal stability compared to compound 1, while retaining antiplasmodial activity against erythrocytic and hepatic stages of Plasmodium, without significant cytotoxicity against primary hepatocytes.

New antiplasmodial 4-amino-thieno[3,2-d]pyrimidines with improved intestinal permeability and microsomal stability.

The increasing number of Plasmodium falciparum strains resistant to current treatments justifies the urgent need to discover new compounds active on several stages of the parasite development. Based on the structure of Gamhepathiopine, a 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one previously identified for its dual activity against the sexual and asexual stages of P. falciparum, 25 new 4-amino-substituted analogues were synthesized and evaluated on the erythrocytic and hepatic stages of Plasmodium.

4-Substituted Thieno[3,2-]pyrimidines as Dual-Stage Antiplasmodial Derivatives.

Malaria remains one of the major health problems worldwide. The increasing resistance of to approved antimalarial drugs requires the development of novel antiplasmodial agents that can effectively prevent and/or treat this disease. Based on the structure of Gamhepathiopine, a 2--butylaminothieno[3,2-]pyrimidin-4(3)-one hit, active on the sexual and asexual stages of the parasite and thanked for the introduction of various substituents at position 4 of the thienopyrimidine core by nucleophilic aromatic substitution and pallado-catalyzed coupling reactions, a series of 4-substituted thieno[3,2-]pyrimidines were identified as displaying in vitro activities against both the erythrocytic stage of and the hepatic stage of Among the 28 compounds evaluated, the chloro analogue of Gamhepathiopine showed good activity against the erythrocytic stage of moderate toxicity on HepG2, and better activity against hepatic parasites, compared to Gamhepathiopine.

Synthesis of antiplasmodial 2-aminothieno[3,2-d]pyrimidin-4(3H)-one analogues using the scaffold hopping strategy.

Gamhepathiopine (also known as M1), is a multi-stage acting antiplasmodial 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hydrochloride that was first described in 2015. The development of this compound is limited by poor microsomal stability, insufficient aqueous solubility and low intestinal permeability. In order to obtain new optimized derivatives, we conducted a scaffold hopping strategy from compound M1, resulting in the synthesis of 20 new compounds belonging to six chemical series.

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

In 2015, we identified gamhepathiopine (M1), a 2--butylaminothieno[3,2-]pyrimidin-4(3)-one antiplasmodial hit targeting all development stages of the human malarial parasite . 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-]pyrimidin-4(3)-one series modulated at position 6 of this scaffold.

Thienopyrimidine: A Promising Scaffold to Access Anti-Infective Agents.

Thienopyrimidines are widely represented in the literature, mainly due to their structural relationship with purine base such as adenine and guanine. This current review presents three isomers-thieno[2,3-]pyrimidines, thieno[3,2-]pyrimidines and thieno[3,4-]pyrimidines-and their anti-infective properties. Broad-spectrum thienopyrimidines with biological properties such as antibacterial, antifungal, antiparasitic and antiviral inspired us to analyze and compile their structure-activity relationship (SAR) and classify their synthetic pathways.

A New Thienopyrimidinone Chemotype Shows Multistage Activity against Plasmodium falciparum, Including Artemisinin-Resistant Parasites.

Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. For decades, the research for novel antimalarials focused on the high-throughput screening of molecules that only targeted the asexual blood stages. In a search for new effective compounds presenting a triple action against erythrocytic and liver stages in addition to the ability to block the transmission of the disease the mosquito vector, 2-amino-thienopyrimidinone derivatives were synthesized and tested for their antimalarial activity.