Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3] thiazine 8-oxides

作者：Thompson Andrew M^*; Marshall Andrew J; Maes Louis; Yarlett Nigel; Bacchi Cyrus J; Gaukel Eric; Wring Stephen A; Launay Delphine; Braillard Stephanie; Chatelain Eric; Mowbray Charles E; Denny William A

来源：Bioorganic & Medicinal Chemistry Letters, 2018, 28(2): 207-213.

DOI：10.1016/j.bmcl.2017.10.067

• African trypanosomiasis
• Pretomanid
• Library screening
• In vivo efficacy
• Pharmacokinetics
• Nitroimidazole

A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3] thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activi

• 出版日期2018-1-15