Title:Design, Synthesis, and Anti-tuberculosis Activity of Streptomycin Derivatives
Volume: 21
Issue: 4
Author(s): Yinyong Zhang, Wenhao Zhao, Yushe Yang, Xianli Zhou*Bin Guo*
Affiliation:
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering,
Southwest Jiaotong University, Chengdu 610031, P.R. China
- Southwest Jiaotong University, Affiliated Hospital, The Third
People’s Hospital of Chengdu, Chengdu, 610000, P.R. China
- State Key Laboratory of Drug Research, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China
- School of Pharmacy, University
of Chinese Academy of Sciences, Beijing 100049, P.R. China
Keywords:
Multidrug-resistant, hydrazine, hydrazide, sulfonyl hydrazide, siderophore, synthesis, anti-tuberculosis activity.
Abstract:
Background: The treatment of tuberculosis has been a serious medical and health problem that
needs to be solved urgently. Streptomycin has been one of the important anti-tuberculosis drugs for decades;
however, no systematic structural modification of streptomycin has been done, which means that the
anti-tuberculosis ability of streptomycin derivatives deserves further exploration.
Objective: In this study, we investigated the effect of systematic structural modification of the aldehyde
groups in streptomycin on its anti-tuberculosis activity.
Methods: Streptomycin was selected as the lead compound, and its aldehyde group was modified to obtain
hydrazone, amino hydrazide, and sulfonyl hydrazide derivatives, respectively. In addition, siderophore
fragments were introduced into streptomycin. The anti-tuberculosis activities of the new compounds
against H37Rv were evaluated.
Results: A total of 21 novel streptomycin derivatives have been designed and synthesized. All compounds
were characterized with 1H NMR, 13C NMR, and HRMS. The preliminary bioactivity test showed
that most analogues bearing hydrazine, acylhydrazine, or sulfonyl hydrazine, such as 12a, 13a-d, and
15a-f, possessed potent anti-tuberculosis activity with MIC value of 2 μg/mL, which was comparable to
streptomycin, while secondary amine or siderophore derivatives caused a dramatic reduction in activity.
Conclusion: The structural modification and structure-activity relationship of the aldehyde group of
streptomycin were systematically studied for the first time. The results showed that the aldehyde group
was not necessary for exhibiting its activity. It was well tolerated when the aldehyde group was converted
into hydrazine, acylhydrazine, or sulfonyl hydrazine. These novel analogues provide potential lead structures
for further modification in the future.
