Spectinomycin was modified using structure based drug design to generate a novel series of 3'-substituted spectinamides.  The synthesis of spectinamides was achieved in 4 steps from spectinomycin, their activities were tested against M. tuberculosis by microbroth dilution and inhibition of protein synthesis was studied at the ribosomal level in a cell free mycobacterial transcription assay.  From the 84 spectinamides synthesized, a clear structure activity relationship has been established with respect to antitubercular activity and protein synthesis inhibition.  Analogs with 2-heteroaryl acetic acid substitution displayed the best activities.  From this panel, the most potent compounds showed M. tuberculosis MICs that are far superior to the MIC of Spectinomycin and comparable to Streptomycin.  Importantly these Spectinamides were not cross resistant to any current tuberculosis therapeutics including other protein synthesis inhibitors.  The tight SAR developed was rationalized using molecular modeling and molecular dynamics calculations.  Lead spectinamides show low protein binding, excellent solubility, no hepatic metabolism and are excreted unchanged renally.  These compounds show good antituberculosis activity in a mouse model of tuberculosis infection and are undergoing further pre-clinical development as selective and safe tuberculosis therapeutics to treat MDR tuberculosis.

Discovery and development of spectinomycin analogs as antitubercular agents

243rd National Meeting (2012)

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