| Literature DB >> 24900693 |
Fumiaki Yokokawa1, Gang Wang1, Wai Ling Chan1, Shi Hua Ang1, Josephine Wong1, Ida Ma1, Srinivasa P S Rao1, Ujjini Manjunatha1, Suresh B Lakshminarayana1, Maxime Herve1, Cyrille Kounde1, Bee Huat Tan1, Pamela Thayalan1, Seow Hwee Ng1, Mahesh Nanjundappa1, Sindhu Ravindran1, Peck Gee1, Maria Tan1, Liu Wei1, Anne Goh1, Pei-Yu Chen1, Kok Sin Lee1, Chen Zhong2, Trixie Wagner3, Ina Dix3, Arnab K Chatterjee2, Kevin Pethe2, Kelli Kuhen2, Richard Glynne2, Paul Smith1, Pablo Bifani1, Jan Jiricek1.
Abstract
Tetrahydropyrazolo[1,5-a]pyrimidine scaffold was identified as a hit series from a Mycobacterium tuberculosis (Mtb) whole cell high through-put screening (HTS) campaign. A series of derivatives of this class were synthesized to evaluate their structure-activity relationship (SAR) and structure-property relationship (SPR). Compound 9 had a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse efficacy model, achieving a reduction of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. Thus, compound 9 is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB.Entities:
Keywords: Antituberculosis; structure−activity relationship; structure−property relationship; tetrahydropyrazolo[1,5-a]pyrimidine
Year: 2013 PMID： 24900693 PMCID： PMC4027361 DOI： 10.1021/ml400071a
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345