Hu Xianglong, Wan Baojie, Liu Yang, Shen Jiayi, Franzblau Scott G, Zhang Tianyu, Ding Ke, Lu Xiaoyun
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States.
ACS Med Chem Lett. 2019 Feb 21;10(3):295-299. doi: 10.1021/acsmedchemlett.8b00410. eCollection 2019 Mar 14.
A series of pyrazolo[1,5-]pyridine-3-carboxamide (PPA) derivatives bearing diaryl side chain was designed and synthesized as new antituberculosis agents, aiming to improve the efficacy toward drug resistant () strains. Most of the substituted diphenyl and heterodiaryl PPAs exhibited excellent potency against the drug susceptive H37Rv strain (MIC < 0.002-0.381 μg/mL) and drug resistant strains (INH-resistant (rINH), MIC < 0.002-0.465 μg/mL; RMP-resistant (rRMP), MIC < 0.002-0.004 μg/mL). Noticeably, some compounds also showed very low cytotoxicity against Vero cells. Further, compound displayed good pharmacokinetic profiles with oral bioavailability (F) of 41% and significantly reduced the bacterial burden in an autoluminescent H37Ra infected mouse model.
设计并合成了一系列带有二芳基侧链的吡唑并[1,5 -]吡啶 - 3 - 甲酰胺（PPA）衍生物作为新型抗结核药物，旨在提高对耐药（）菌株的疗效。大多数取代的二苯基和杂二芳基PPA对药物敏感的H37Rv菌株（MIC < 0.002 - 0.381μg/mL）和耐药菌株（耐异烟肼（rINH），MIC < 0.002 - 0.465μg/mL；耐利福平（rRMP），MIC < 0.002 - 0.004μg/mL）表现出优异的活性。值得注意的是，一些化合物对Vero细胞也显示出非常低的细胞毒性。此外，化合物表现出良好的药代动力学特征，口服生物利用度（F）为41%，并在自发光H37Ra感染的小鼠模型中显著降低了细菌载量。
