Design, Synthesis, and Anti-tuberculosis Activity of Streptomycin Derivatives

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.