title: Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei.
abstract: A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 μM, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC50 of 0.045 μM against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line.
authors: Medicinal Chemistry, ‡Centre for Drug Candidate Optimisation, and §Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors: Lori
authors: L
authors: Ferrins
authors: Michelle
authors: M
authors: Gazdik
authors: Raphaël
authors: R
authors: Rahmani
authors: Swapna
authors: S
authors: Varghese
authors: Melissa L
authors: ML
authors: Sykes
authors: Amy J
authors: AJ
authors: Jones
authors: Vicky M
authors: VM
authors: Avery
authors: Karen L
authors: KL
authors: White
authors: Eileen
authors: E
authors: Ryan
authors: Susan A
authors: SA
authors: Charman
authors: Marcel
authors: M
authors: Kaiser
authors: Christel A S
authors: CA
authors: Bergström
authors: Jonathan B
authors: JB
authors: Baell
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000254:growth & development
chemical_list: D001549:Benzamides; D011725:Pyridines; D014344:Trypanocidal Agents