Discovery of Tetrahydropyrazolopyrimidine Carboxamide De-rivatives as Potent and Orally Active Novel Anti-Tubercular Agents

ABSTRACT: Tetrahydropyrazolopyrimidine 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 showed potent bactericidal effect and activity against multi-drug resistant tuberculosis (MDR TB) strains. Furthermore 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 the compound 9 is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB.