优化并表征来源于磺胺苯吡唑的功能化磺胺类化合物，以降低对 CYP2C9 的抑制作用，从而达到针对结核分枝杆菌的效果。

The optimization and characterization of functionalized sulfonamides derived from sulfaphenazole against Mycobacterium tuberculosis with reduced CYP 2C9 inhibition.

机构信息

Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-engineering, Beijing University of Technology, Beijing 100124, PR China.

Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149, PR China.

出版信息

Bioorg Med Chem Lett. 2021 May 15;40:127924. doi: 10.1016/j.bmcl.2021.127924. Epub 2021 Mar 9.

DOI:10.1016/j.bmcl.2021.127924

PMID:33705901

Abstract

In this study, a series of sulfonamide compounds was designed and synthesized through the systematic optimization of the antibacterial agent sulfaphenazole for the treatment of Mycobacterium tuberculosis (M. tuberculosis). Preliminary results indicate that the 4-aminobenzenesulfonamide moiety plays a key role in maintaining antimycobacterial activity. Compounds 10c, 10d, 10f and 10i through the optimization on phenyl ring at the R site on the pyrazole displayed promising antimycobacterial activity paired with low cytotoxicity. In particular, compound 10d displayed good activity (MIC = 5.69 μg/mL) with low inhibition of CYP 2C9 (IC > 10 μM), consequently low potential risk of drug-drug interaction. These promising results provide new insight into the combination regimen using sulfonamide as one component for the treatment of M. tuberculosis.

摘要

在这项研究中，通过对治疗结核分枝杆菌（M. tuberculosis）的抗菌药物磺胺苯哒唑进行系统优化，设计并合成了一系列磺胺类化合物。初步结果表明，4-氨基苯磺酰胺部分在保持抗分枝杆菌活性方面起着关键作用。通过对吡唑环上 R 位苯环的优化，化合物 10c、10d、10f 和 10i 表现出有希望的抗分枝杆菌活性和低细胞毒性。特别是化合物 10d 表现出良好的活性（MIC=5.69μg/mL），对 CYP2C9 的抑制作用低（IC>10μM），因此药物相互作用的潜在风险低。这些有希望的结果为使用磺胺作为治疗结核分枝杆菌的联合方案提供了新的思路。