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The extracellular zinc metalloprotease collagenase H (ColH) from <jats:italic>Clostridium histolyticum<\/jats:italic> is a virulence factor that catalyses tissue damage, leading to improved host invasion and colonisation. Besides the major role of ColH in pathogenicity, its extracellular localisation makes it a highly attractive target for the development of new antivirulence agents. Previously, we had found that a highly selective and potent thiol prodrug (with a hydrolytically cleavable thiocarbamate unit) provided efficient ColH inhibition. We now report the synthesis and biological evaluation of a range of zinc\u2010binding group (ZBG) variants of this thiol\u2010derived inhibitor, with the mercapto unit being replaced by other zinc ligands. Among these, an analogue with a phosphonate motif as ZBG showed promising activity against ColH, an improved selectivity profile, and significantly higher stability than the thiol reference compound, thus making it an attractive candidate for future drug development.<\/jats:p>","DOI":"10.1002\/cmdc.202000994","type":"journal-article","created":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T21:59:40Z","timestamp":1611784780000},"page":"1257-1267","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Phosphonate as a Stable Zinc\u2010Binding Group for \u201cPathoblocker\u201d Inhibitors of Clostridial Collagenase H (ColH)"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5224-9690","authenticated-orcid":false,"given":"Katrin","family":"Voos","sequence":"first","affiliation":[{"name":"Department of Pharmacy Pharmaceutical and Medicinal Chemistry Saarland University  Campus C2 3 66123 Saarbr\u00fccken Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2625-9446","authenticated-orcid":false,"given":"Esther","family":"Sch\u00f6nauer","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Christian Doppler Laboratory for Innovative Tools for Biosimilar Characterization Division of Structural Biology University of Salzburg  Billrothstrasse 11 5020 Salzburg Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8192-6574","authenticated-orcid":false,"given":"Alaa","family":"Alhayek","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Optimization Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI)  Campus E8 1 66123 Saarbr\u00fccken Germany"},{"name":"Department of Pharmacy Saarland University  Campus E8 1 66123 Saarbr\u00fccken Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3991-2800","authenticated-orcid":false,"given":"J\u00f6rg","family":"Haupenthal","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Optimization Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI)  Campus E8 1 66123 Saarbr\u00fccken Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasia","family":"Andreas","sequence":"additional","affiliation":[{"name":"Department of Microbial Natural Products Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI)  Campus E8 1 66123 Saarbr\u00fccken Germany"},{"name":"Department of Pharmacy Saarland University  Campus E8 1 66123 Saarbr\u00fccken Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1042-5665","authenticated-orcid":false,"given":"Rolf","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Microbial Natural Products Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI)  Campus E8 1 66123 Saarbr\u00fccken Germany"},{"name":"Department of Pharmacy Saarland University  Campus E8 1 66123 Saarbr\u00fccken Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5871-5231","authenticated-orcid":false,"given":"Rolf W.","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Optimization Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI)  Campus E8 1 66123 Saarbr\u00fccken Germany"},{"name":"Department of Pharmacy Saarland University  Campus E8 1 66123 Saarbr\u00fccken Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6089-3045","authenticated-orcid":false,"given":"Hans","family":"Brandstetter","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Christian Doppler Laboratory for Innovative Tools for Biosimilar Characterization Division of Structural Biology University of Salzburg  Billrothstrasse 11 5020 Salzburg Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8734-4663","authenticated-orcid":false,"given":"Anna K. 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