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Synthetic sansanmycin analogues as potent mycobacterium tuberculosis translocase I inhibitors

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Tran, Wendy, Kusay, Ali S., Hawkins, Paige M. E., Cheung, Chen-Yi, Nagalingam, Gayathri, Pujari, Venugopal, Ford, Daniel J., Stoye, Alexander, Ochoa, Jessica L., Audette, Rebecca E. et al.
(2021) Synthetic sansanmycin analogues as potent mycobacterium tuberculosis translocase I inhibitors. Journal of Medicinal Chemistry, 64 (23). pp. 17326-17345. doi:10.1021/acs.jmedchem.1c01407

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Official URL: https://doi.org/10.1021/acs.jmedchem.1c01407

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Abstract

Herein, we report the design and synthesis of inhibitors of Mycobacterium tuberculosis (Mtb) phospho-MurNAc-pentapeptide translocase I (MurX), the first membrane-associated step of peptidoglycan synthesis, leveraging the privileged structure of the sansanmycin family of uridylpeptide natural products. A number of analogues bearing hydrophobic amide modifications to the pseudo-peptidic end of the natural product scaffold were generated that exhibited nanomolar inhibitory activity against Mtb MurX and potent activity against Mtb in vitro. We show that a lead analogue bearing an appended neopentylamide moiety possesses rapid antimycobacterial effects with a profile similar to the frontline tuberculosis drug isoniazid. This molecule was also capable of inhibiting Mtb growth in macrophages where mycobacteria reside in vivo and reduced mycobacterial burden in an in vivo zebrafish model of tuberculosis.

Item Type: Journal Article
Divisions: Faculty of Science > Life Sciences (2010- )
SWORD Depositor: Library Publications Router
Journal or Publication Title: Journal of Medicinal Chemistry
Publisher: American Chemical Society
ISSN: 1520-4804
Official Date: 9 December 2021
Dates:
DateEvent
9 December 2021Published
30 November 2021Available
30 November 2021Accepted
Volume: 64
Number: 23
Page Range: pp. 17326-17345
DOI: 10.1021/acs.jmedchem.1c01407
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
Copyright Holders: Copyright © 2021 American Chemical Society

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