title: 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 EC50 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 EC50 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.
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Rahmani
authors.affiliation: The Walter and Eliza Hall Institute , 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Kung
authors.initials: K
authors.lastname: Ban
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane Innovation Park, Don Young Road, Nathan, Queensland 4111, Australia.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Jones
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Lori
authors.initials: L
authors.lastname: Ferrins
authors.affiliation: The Walter and Eliza Hall Institute , 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Danny
authors.initials: D
authors.lastname: Ganame
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane Innovation Park, Don Young Road, Nathan, Queensland 4111, Australia.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Sykes
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane Innovation Park, Don Young Road, Nathan, Queensland 4111, Australia.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.affiliation: University of Basel , Petersplatz 1, Basel, 4003, Switzerland.|Swiss Tropical and Public Health Institute , Socinstrasse 57, Basel, 4051, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: C000603345:3-amino-N-cyclopentyl-6-(m-tolyl)pyrazine-2-carboxamide; D000577:Amides; D011719:Pyrazines; D014344:Trypanocidal Agents