Lead Optimization of Spiropyrazolopyridones: A New and Potent Class of Dengue Virus Inhibitors

Spiropyrazolopyridone <b>1</b> was identified, as a novel dengue virus (DENV) inhibitor, from a DENV serotype 2 (DENV-2) high-throughput phenotypic screen. As a general trend within this chemical class, chiral resolution of the racemate revealed that <i>R</i> enantiomer was significantly more potent than the <i>S</i>. Cell-based lead optimization of the spiropyrazolopyridones focusing on improving the physicochemical properties is described. As a result, an optimal compound <b>14a</b>, with balanced <i>in vitro</i> potency and pharmacokinetic profile, achieved about 1.9 log viremia reduction at 3 × 50 mg/kg (bid) or 3 × 100 mg/kg (QD) oral doses in the dengue <i>in vivo</i> mouse efficacy model

Discovery of Tetrahydropyrazolopyrimidine Carboxamide Derivatives As Potent and Orally Active Antitubercular Agents

Tetrahydropyrazolo­[1,5-<i>a</i>]­pyrimidine scaffold was identified as a hit series from a <i>Mycobacterium tuberculosis</i> (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 <b>9</b> 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 <b>9</b> is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB