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Discovery and Hit-t...
Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold- Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
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- Cotman, Andrej Emanuel (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.,University of Ljubljana, Slovenia
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- Durcik, Martina (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.
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- Tiz, Davide Benedetto (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.;Univ Perugia, Dept Pharmaceut Sci, Via Liceo 1, I-06100 Perugia, Italy.
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- Fulgheri, Federica (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.;Univ Cagliari, Dept Life & Environm Sci, Drug Sect, Via Osped 72, I-09124 Cagliari, Italy.
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- Secci, Daniela (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.;Univ Cagliari, Dept Life & Environm Sci, Drug Sect, Via Osped 72, I-09124 Cagliari, Italy.
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- Sterle, Masa (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.
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- Mozina, Stefan (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.;Lek Pharmaceut, Verovskova Ul 57, Ljubljana 1000, Slovenia.
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- Skok, Ziga (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.;Lek Pharmaceut, Verovskova Ul 57, Ljubljana 1000, Slovenia.
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- Zidar, Nace (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.
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- Zega, Anamarija (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.
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- Ilas, Janez (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.
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- Masic, Lucija Peterlin (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.
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- Tomasic, Tihomir (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.
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- Hughes, Diarmaid, 1956- (author)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi,Institutionen för medicinsk biokemi och mikrobiologi
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- Huseby, Douglas L. (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Uppsala Univ Hosp, Dept Med Sci, S-75185 Uppsala, Sweden.
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- Cao, Sha (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Garoff, Linnea (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Fernandez, Talia Berruga (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Giachou, Paraskevi (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Crone, Lisa (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Simoff, Ivailo (author)
- Uppsala universitet,Institutionen för farmaci,Uppsala Univ, Dept Pharm, Drug Optimizat & Pharmaceut Profiling Platform UDO, S-75123 Uppsala, Sweden.
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- Svensson, Richard (author)
- Uppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab
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- Birnir, Bryndis (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Korol, Sergiy (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Jin, Zhe (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi,Uppsala Univ, Dept Med Cell Biol, S-75123 Uppsala, Sweden.
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- Vicente, Francisca (author)
- Fundac MEDINA, Granada 18016, Spain.
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- Ramos, Maria C. (author)
- Fundac MEDINA, Granada 18016, Spain.
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- de la Cruz, Mercedes (author)
- Fundac MEDINA, Granada 18016, Spain.
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- Glinghammar, Bjorn (author)
- RISE,Bioekonomi och hälsa,RISE Res Inst Sweden, Dept Chem Proc & Pharmaceut Dev, Unit Chem & Pharmaceut Safety, S-15136 Södertälje, Sweden.
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- Lenhammar, Lena (author)
- Uppsala Univ Hosp, Dept Med Sci, S-75185 Uppsala, Sweden.
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- Henderson, Sara R. (author)
- John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England.;Univ Birmingham, Inst Microbiol & Infect, Coll Med & Dent Sci, Birmingham, England.
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- Mundy, Julia E. A. (author)
- John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England.
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- Maxwell, Anthony (author)
- John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England.
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- Stevenson, Clare E. M. (author)
- John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England.
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- Lawson, David M. (author)
- John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England.
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Janssen, Guido V. (author)
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Sterk, Geert Jan (author)
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- Kikelj, Danijel (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.,University of Ljubljana, Slovenia
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Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia University of Ljubljana, Slovenia (creator_code:org_t)
- 2023-01-12
- 2023
- English.
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:2, s. 1380-1425
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Abstract
Subject headings
Close
- We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aerugi-nosa, which are both on the WHO priority list of antibiotic -resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase II alpha, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- antiinfective agent
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Cotman, Andrej E ...
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Durcik, Martina
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Tiz, Davide Bene ...
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Fulgheri, Federi ...
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Secci, Daniela
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Sterle, Masa
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show more...
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Mozina, Stefan
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Skok, Ziga
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Zidar, Nace
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Zega, Anamarija
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Ilas, Janez
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Masic, Lucija Pe ...
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Tomasic, Tihomir
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Hughes, Diarmaid ...
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Huseby, Douglas ...
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Cao, Sha
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Garoff, Linnea
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Fernandez, Talia ...
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Giachou, Paraske ...
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Crone, Lisa
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Simoff, Ivailo
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Svensson, Richar ...
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Birnir, Bryndis
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Korol, Sergiy
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Jin, Zhe
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Vicente, Francis ...
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Ramos, Maria C.
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de la Cruz, Merc ...
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Glinghammar, Bjo ...
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Lenhammar, Lena
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Henderson, Sara ...
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Mundy, Julia E. ...
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Maxwell, Anthony
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Stevenson, Clare ...
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Lawson, David M.
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Janssen, Guido V ...
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Sterk, Geert Jan
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Kikelj, Danijel
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
- Articles in the publication
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Journal of Medic ...
- By the university
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Uppsala University
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RISE