Ng Pearly Shuyi, Manjunatha Ujjini H, Rao Srinivasa P S, Camacho Luis R, Ma Ngai Ling, Herve Maxime, Noble Christian G, Goh Anne, Peukert Stefan, Diagana Thierry T, Smith Paul W, Kondreddi Ravinder Reddy
Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
Eur J Med Chem. 2015 Dec 1;106:144-56. doi: 10.1016/j.ejmech.2015.10.008. Epub 2015 Oct 14.
Pyridone 1 was identified from a high-throughput cell-based phenotypic screen against Mycobacterium tuberculosis (Mtb) including multi-drug resistant tuberculosis (MDR-TB) as a novel anti-TB agent and subsequently optimized series using cell-based Mtb assay. Preliminary structure activity relationship on the isobutyl group with higher cycloalkyl groups at 6-position of pyridone ring has enabled us to significant improvement of potency against Mtb. The lead compound 30j, a dimethylcyclohexyl group on the 6-position of the pyridone, displayed desirable in vitro potency against both drug sensitive and multi-drug resistant TB clinical isolates. In addition, 30j displayed favorable oral pharmacokinetic properties and demonstrated in vivo efficacy in mouse model. These results emphasize the importance of 4-hydroxy-2-pyridones as a new chemotype and further optimization of properties to treat MDR-TB.
吡啶酮1是通过针对结核分枝杆菌（Mtb）（包括耐多药结核病（MDR-TB））的基于细胞的高通量表型筛选鉴定出的一种新型抗结核药物，随后使用基于细胞的Mtb试验对其进行了系列优化。吡啶酮环6位上具有较高环烷基的异丁基的初步构效关系使我们能够显著提高对Mtb的效力。先导化合物30j，吡啶酮6位上的二甲基环己基，对药物敏感和耐多药结核临床分离株均表现出理想的体外效力。此外，30j具有良好的口服药代动力学特性，并在小鼠模型中显示出体内疗效。这些结果强调了4-羟基-2-吡啶酮作为一种新化学类型的重要性以及进一步优化治疗MDR-TB的特性。
