Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents.
Yokokawa F, Wang G, Chan WL, Ang SH, Wong J, Ma I, Rao SP, Manjunatha U, Lakshminarayana SB, Herve M, Kounde C, Tan BH, Thayalan P, Ng SH, Nanjundappa M, Ravindran S, Gee P, Tan M, Wei L, Goh A, Chen PY, Lee KS, Zhong C, Wagner T, Dix I, Chatterjee AK, Pethe K, Kuhen K, Glynne R, Smith P, Bifani P, Jiricek J.
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.