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Shikimic acid amides as promising antitubercular agents – synthesis and in vitro studies

V Valcheva(1) I Slavcheev(2) S Dimitrov(1) T Pencheva(3) G Dobrikov(2)

1:The Stephan Angeloff Institute of microbiology, Bulgarian Academy of Sciences; 2:Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences; 3:Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences

Despite the significant progress in the development of new drugs against tuberculosis, many therapies and preventive measures do not lead to the expected favorable health outcomes for various reasons. Therefore, the discovery and/or synthesis of new potent and less toxic anti-TB compounds is very important. Here we present the synthesis, in vitro and in silico studies of 12 shikimate kinase derivatives that are vital for the metabolism of plants, bacteria and fungi but are completely absent in mammals and humans. Many of the compounds showed very good antimycobacterial and antifungal activities with MIC values ranging from 0.07–0.32 µM, which were comparable to those of isoniazid and amphotericin B. Promising docking scores were obtained for all compounds in different protein targets (PDB ID 1NYT (E. coli), 1XAJ (S. aureus), 4BQS (M.tuberculosis)) confirming the results from in vitro experiments. The newly synthesized shikimic analogues showed significant antibacterial activity comparable to reference antibiotics and could be suggested for further pharmacological studies. Acknowledgements: We gratefully acknowledge support from Bulgarian Science Foundation (Grant KP-06-H39/7).

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