Search: WFRF:(Birnir Bryndis) >
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
-
- Cotman, Andrej Emanuel (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.,University of Ljubljana, Slovenia
-
- Durcik, Martina (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.
-
- Tiz, Davide Benedetto (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.;Univ Perugia, Dept Pharmaceut Sci, Via Liceo 1, I-06100 Perugia, Italy.
-
show more...
-
- 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.
-
- 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.
-
- Sterle, Masa (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.
-
- Mozina, Stefan (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.;Lek Pharmaceut, Verovskova Ul 57, Ljubljana 1000, Slovenia.
-
- Skok, Ziga (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.;Lek Pharmaceut, Verovskova Ul 57, Ljubljana 1000, Slovenia.
-
- Zidar, Nace (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.
-
- Zega, Anamarija (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.
-
- Ilas, Janez (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.
-
- Masic, Lucija Peterlin (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.
-
- Tomasic, Tihomir (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.
-
- Hughes, Diarmaid, 1956- (author)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi,Institutionen för medicinsk biokemi och mikrobiologi
-
- Huseby, Douglas L. (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Uppsala Univ Hosp, Dept Med Sci, S-75185 Uppsala, Sweden.
-
- Cao, Sha (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
-
- Garoff, Linnea (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
-
- Fernandez, Talia Berruga (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
-
- Giachou, Paraskevi (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
-
- Crone, Lisa (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
-
- Simoff, Ivailo (author)
- Uppsala universitet,Institutionen för farmaci,Uppsala Univ, Dept Pharm, Drug Optimizat & Pharmaceut Profiling Platform UDO, S-75123 Uppsala, Sweden.
-
- Svensson, Richard (author)
- Uppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab
-
- Birnir, Bryndis (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
-
- Korol, Sergiy (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
-
- Jin, Zhe (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi,Uppsala Univ, Dept Med Cell Biol, S-75123 Uppsala, Sweden.
-
- Vicente, Francisca (author)
- Fundac MEDINA, Granada 18016, Spain.
-
- Ramos, Maria C. (author)
- Fundac MEDINA, Granada 18016, Spain.
-
- de la Cruz, Mercedes (author)
- Fundac MEDINA, Granada 18016, Spain.
-
- Glinghammar, Bjorn (author)
- RISE,Bioekonomi och hälsa,RISE Res Inst Sweden, Dept Chem Proc & Pharmaceut Dev, Unit Chem & Pharmaceut Safety, S-15136 Södertälje, Sweden.
-
- Lenhammar, Lena (author)
- Uppsala Univ Hosp, Dept Med Sci, S-75185 Uppsala, Sweden.
-
- 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.
-
- Mundy, Julia E. A. (author)
- John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England.
-
- Maxwell, Anthony (author)
- John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England.
-
- Stevenson, Clare E. M. (author)
- John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England.
-
- Lawson, David M. (author)
- John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England.
-
Janssen, Guido V. (author)
-
Sterk, Geert Jan (author)
-
- Kikelj, Danijel (author)
- Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.,University of Ljubljana, Slovenia
-
show less...
-
Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia University of Ljubljana, Slovenia (creator_code:org_t)
- 2023-01-12
- 2023
- English.
-
In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:2, s. 1380-1425
- Related links:
-
https://doi.org/10.1...
-
show more...
-
https://uu.diva-port... (primary) (Raw object)
-
https://urn.kb.se/re...
-
https://doi.org/10.1...
-
https://urn.kb.se/re...
-
show less...
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)
Find in a library
To the university's database
- By the author/editor
-
Cotman, Andrej E ...
-
Durcik, Martina
-
Tiz, Davide Bene ...
-
Fulgheri, Federi ...
-
Secci, Daniela
-
Sterle, Masa
-
show more...
-
Mozina, Stefan
-
Skok, Ziga
-
Zidar, Nace
-
Zega, Anamarija
-
Ilas, Janez
-
Masic, Lucija Pe ...
-
Tomasic, Tihomir
-
Hughes, Diarmaid ...
-
Huseby, Douglas ...
-
Cao, Sha
-
Garoff, Linnea
-
Fernandez, Talia ...
-
Giachou, Paraske ...
-
Crone, Lisa
-
Simoff, Ivailo
-
Svensson, Richar ...
-
Birnir, Bryndis
-
Korol, Sergiy
-
Jin, Zhe
-
Vicente, Francis ...
-
Ramos, Maria C.
-
de la Cruz, Merc ...
-
Glinghammar, Bjo ...
-
Lenhammar, Lena
-
Henderson, Sara ...
-
Mundy, Julia E. ...
-
Maxwell, Anthony
-
Stevenson, Clare ...
-
Lawson, David M.
-
Janssen, Guido V ...
-
Sterk, Geert Jan
-
Kikelj, Danijel
-
show less...
- About the subject
-
- MEDICAL AND HEALTH SCIENCES
-
MEDICAL AND HEAL ...
-
and Basic Medicine
-
and Medicinal Chemis ...
- Articles in the publication
-
Journal of Medic ...
- By the university
-
Uppsala University
-
RISE