6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors

Abstract

From a whole-organism high throughput screen of approximately 87000 compounds against Trypanosoma brucei brucei, we recently identified eight new unique compounds for the treatment of human African trypanosomiasis. In an effort to understand the structure−activity relationships around these compounds, we report for the first time our results on a new class of trypanocides, the pyrazine carboxamides. Attracted by the low molecular weight (270 g•mol −1 ) of our starting hit (9) and its potency (0.49 μM), the SAR around the core was explored, leading to compounds having an EC 50 as low as 25 nM against T. b. brucei and being more than 1500 times less toxic against mammalian L6 and HEK293 cell lines. The most potent compounds in the series were exquisitely selective for T. brucei over a panel of other protozoan parasites, showing an excellent correlation with the human infective parasite Trypanosoma brucei rhodesiense, the most potent compound (65) having an EC 50 of 24 nM. The compounds are highly drug-like and are able to penetrate the CNS, their only limitation currently being their rate of microsomal metabolism. To that effect, efforts to identify potential metabolites of selected compounds are also reported.

New thiazolidine‐2,4‐dione derivatives combined with organometallic ferrocene: Synthesis, structure and antiparasitic activity

“…Since the only major differences between compounds 5a , 5b , 5c , 8a and 8b are the size of secondary cyclic amino side groups and the presence of electronegative atoms other than nitrogen (oxygen and sulfur), the observed enhanced activity appeared to suggest that hydrophobicity is an important parameter. However, the introduction of bulkier amide group as exemplified by 5d leads to marked loss of activity, and these results mirror a similar trend observed by Rahmani et al …”

Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides

“…1 H NMR (CDCl 3 , 400 MHz) δ 7. 2H,Ar),2H,Ar) 2- ethyl)isoindoline-1,3-dione (58). A mixture of 33% HBr in acetic acid (30 mL), 57 (3.4 g, 12 mmol) and DCM (50 mL) was stirred for 24 h. Water (50 mL) was added, and the mixture was extracted with EtOAc (3 × 40 mL).…”

“…Eleven hits with novel, drug-like structures and physicochemical properties were identified. We have already published the hit-to-lead optimization of five of these hits. − Herein we report our work based on hit 1 (Figure ). This compound offers a very attractive starting point for hit-to-lead optimization because it exhibits good physicochemical properties, including a low molecular weight (306 g·mol –1 ), a low polar surface area (41 Å 2 ), which is necessary for CNS penetration in order to treat the second stage of HAT, and a relatively simple structure amenable to analogue synthesis.…”

Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections

“…In the context of a high throughput screening campaign of 87000 compounds against T. b. brucei, Rahmani et al (2015) identified a new class of potential trypanocides, pyrazine carboxamides. This screening delivered a starting hit, compound 69 (EC 50 = 0.49 μM) and subsequent SAR studies were conducted concerning structural changes around the core.…”