Hrast, Martina, Jukič, Marko, Patin, Delphine, Tod, Julie, Dowson, Christopher G., Roper, David I., Barreteau, Hélène and Gobec, Stanislav (2018) In silico identification, synthesis and biological evaluation of novel tetrazole inhibitors of MurB. Chemical Biology & Drug Design, 91 (6). pp. 1101-1112. doi:10.1111/cbdd.13172 ISSN 1747-0285.

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Abstract

In the context of antibacterial drug discovery resurgence, novel therapeutic targets and new compounds with alternative mechanisms of action are of paramount importance. We focused on UDP-N- acetylenolpyruvylglucosamine reductase (i.e. MurB), an underexploited target enzyme that is involved in early steps of bacterial peptidoglycan biosynthesis. On the basis of the recently reported crystal structure of MurB in complex with NADP+ , a pharmacopohore model was generated and used in a virtual screening campaign with combined structure-based and ligand-based approaches. In order to explore chemical space around hit compounds, further similarity search and organic synthesis was employed to obtain several compounds with micromolar IC50 values on MurB. The best inhibitors in the reported series of 5-substituted tetrazol-2-yl acetamides were compounds 13, 26 and 30 with IC50 values of 34, 28 and 25 µM, respectively. None of the reported compounds possessed in vitro antimicrobial activity against S. aureus and E. coli.

Item Type:	Journal Article
Subjects:	Q Science > QR Microbiology R Medicine > RM Therapeutics. Pharmacology
Divisions:	Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH):	Peptidoglycans, Biosynthesis, Tetrazoles, Tetrazoles -- Synthesis, Antibacterial agents
Journal or Publication Title:	Chemical Biology & Drug Design
Publisher:	Wiley-Blackwell Publishing, Inc.
ISSN:	1747-0285
Official Date:	June 2018
Dates:	Date Event June 2018 Published 24 January 2018 Available 13 January 2018 Accepted
Volume:	91
Number:	6
Page Range:	pp. 1101-1112
DOI:	10.1111/cbdd.13172
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Date of first compliant deposit:	12 February 2018
Date of first compliant Open Access:	24 January 2019
RIOXX Funder/Project Grant:	Project/Grant ID RIOXX Funder Name Funder ID L1-6745 Javna Agencija za Raziskovalno Dejavnost RS http://dx.doi.org/10.13039/501100004329 J1-6743 Javna Agencija za Raziskovalno Dejavnost RS http://dx.doi.org/10.13039/501100004329 Z1-8158 Javna Agencija za Raziskovalno Dejavnost RS http://dx.doi.org/10.13039/501100004329

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