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Design and development of an efficient convergent synthetic strategy for novel β-lactam enhancer zidebactam (WCK 5107)

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Abstract

Zidebactam (WCK 5107) is a novel β-lactam enhancer (BLE), developed by Wockhardt, exhibiting standalone antimicrobial activities against panel of gram-negative pathogens. Zidebactam is referred as β-lactam ‘enhancer’, because in combination with a partner β-lactam drug, zidebactam not only inhibits the β-lactamases, but also targets PBP2 and enhances the potency of partner drug. The manuscript details the stereoselective synthesis of Zidebactam, as well as the technique/process for preparing the stable sodium salt of (2S,5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]-octane-2-carboxylic acid and the chirally pure side chain, N-Boc-(R)-(-)-ethyl nipecotate hydrazide via chiral resolution. The convergent synthesis of zidebactam has achieved by coupling between sodium salt of DBO carboxylic acid and Boc-(R)-(-)-ethyl nipecotate hydrazide followed by requisite chemical transformations. Single crystal X-ray analysis established the stereochemistry of zidebactam with empirical formula, C13H21N5O7S.2H2O. Currently, two drug combination products zidebactam with cefepime (WCK 5222) and zidebactam with ertapenem (WCK 6777) awarded qualified infectious disease product (QIDP) status by U.S. Food and Drug Administration (USFDA). WCK 5222 has completed phase I clinical trial studies in the USA and is currently undergoing global phase III clinical studies, WCK 6777 is progressing through phase I clinical studies.

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Acknowledgements

Authors are thankful to Dr. Vipul Rane and Mr. Badrinarayan Chandak for providing analytical data.

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Authors and Affiliations

  1. Wockhardt Research Centre, D-4, MIDC, Chikalthana, Aurangabad, MS, 431006, India

    Satish Bhavsar, Sanjeev Joshi, Vikas Deshmukh, Shivaji Pawar, Bharat Dond, Amit Mishra, Abhijeet K. Kayastha, Ravindra Yeole, Prasad Deshpande, Sachin Bhagwat & Mahesh Patel

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  1. Satish Bhavsar
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  2. Sanjeev Joshi
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  3. Vikas Deshmukh
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  4. Shivaji Pawar
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  6. Amit Mishra
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  7. Abhijeet K. Kayastha
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Correspondence to Satish Bhavsar.

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Bhavsar, S., Joshi, S., Deshmukh, V. et al. Design and development of an efficient convergent synthetic strategy for novel β-lactam enhancer zidebactam (WCK 5107). Chem. Pap. 78, 1493–1504 (2024). https://doi.org/10.1007/s11696-023-03176-6

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