BACKGROUND: Inhibitors of Trypanosoma cruzi with novel mechanisms of action are urgently required to diversify the current clinical and preclinical pipelines. Increasing the number and diversity of hits available for assessment at the beginning of the discovery process will help to achieve this aim. RESULTS: We report the evaluation of multiple hits generated from a high-throughput screen to identify inhibitors of T. cruzi and from these studies the discovery of two novel series currently in lead optimization. Lead compounds from these series potently and selectively inhibit growth of T. cruzi in vitro and the most advanced compound is orally active in a subchronic mouse model of T. cruzi infection. CONCLUSION: High-throughput screening of novel compound collections has an important role to play in diversifying the trypanosomatid drug discovery portfolio. A new T. cruzi inhibitor series with good drug-like properties and promising in vivo efficacy has been identified through this process.
BACKGROUND: Inhibitors of Trypanosoma cruzi with novel mechanisms of action are urgently required to diversify the current clinical and preclinical pipelines. Increasing the number and diversity of hits available for assessment at the beginning of the discovery process will help to achieve this aim. RESULTS: We report the evaluation of multiple hits generated from a high-throughput screen to identify inhibitors of T. cruzi and from these studies the discovery of two novel series currently in lead optimization. Lead compounds from these series potently and selectively inhibit growth of T. cruzi in vitro and the most advanced compound is orally active in a subchronic mouse model of T. cruzi infection. CONCLUSION: High-throughput screening of novel compound collections has an important role to play in diversifying the trypanosomatid drug discovery portfolio. A new T. cruzi inhibitor series with good drug-like properties and promising in vivo efficacy has been identified through this process.
Authors: Xiaofang Wang; Monica Cal; Marcel Kaiser; Frederick S Buckner; Galina I Lepesheva; Austin G Sanford; Alexander I Wallick; Paul H Davis; Jonathan L Vennerstrom Journal: Bioorg Med Chem Lett Date: 2019-10-31 Impact factor: 2.823
Authors: Kei Katsuno; Jeremy N Burrows; Ken Duncan; Rob Hooft van Huijsduijnen; Takushi Kaneko; Kiyoshi Kita; Charles E Mowbray; Dennis Schmatz; Peter Warner; B T Slingsby Journal: Nat Rev Drug Discov Date: 2015-10-05 Impact factor: 84.694
Authors: Adriana Botero; Sarah Keatley; Christopher Peacock; R C Andrew Thompson Journal: Int J Parasitol Drugs Drug Resist Date: 2016-12-23 Impact factor: 4.077
Authors: Stephen Brand; Eun Jung Ko; Elisabet Viayna; Stephen Thompson; Daniel Spinks; Michael Thomas; Lars Sandberg; Amanda F Francisco; Shiromani Jayawardhana; Victoria C Smith; Chimed Jansen; Manu De Rycker; John Thomas; Lorna MacLean; Maria Osuna-Cabello; Jennifer Riley; Paul Scullion; Laste Stojanovski; Frederick R C Simeons; Ola Epemolu; Yoko Shishikura; Sabrinia D Crouch; Tania S Bakshi; Christopher J Nixon; Iain H Reid; Alan P Hill; Tim Z Underwood; Sean J Hindley; Sharon A Robinson; John M Kelly; Jose M Fiandor; Paul G Wyatt; Maria Marco; Timothy J Miles; Kevin D Read; Ian H Gilbert Journal: J Med Chem Date: 2017-08-27 Impact factor: 7.446
Authors: Christopher Merritt; Lisseth E Silva; Angela L Tanner; Kenneth Stuart; Michael P Pollastri Journal: Chem Rev Date: 2014-10-07 Impact factor: 60.622