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FältnamnIndikatorerMetadata
00009047naa a2200817 4500
001oai:DiVA.org:uu-497765
003SwePub
008230308s2023 | |||||||||||000 ||eng|
009oai:DiVA.org:ri-63982
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4977652 URI
0247 a https://doi.org/10.1021/acs.jmedchem.2c015972 DOI
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:ri:diva-639822 URI
040 a (SwePub)uud (SwePub)ri
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Cotman, Andrej Emanuelu Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.,University of Ljubljana, Slovenia4 aut
2451 0a Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold- Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
264 c 2023-01-12
264 1b American Chemical Society (ACS),c 2023
338 a electronic2 rdacarrier
500 a Funding details: Wellcome Trust, WT, 110072/Z/15/Z, BB/P012523/1; Funding details: Biotechnology and Biological Sciences Research Council, BBSRC, BB/J014524/1; Funding details: Javna Agencija za Raziskovalno Dejavnost RS, ARRS, J1-3030, J1-3031, P1-0208; Funding details: Seventh Framework Programme, FP7, FP7/2007-2013; Funding details: Innovative Medicines Initiative, IMI, 115583; Funding text 1: The research presented in this paper was conducted as part of the ND4BB ENABLE Consortium and has received support from the Innovative Medicines Initiative Joint Undertaking under grant no. 115583, resources of which are comprised of financial contributions from the European Union’s seventh framework program (FP7/2007-2013) and EFPIA companies’ in-kind contribution. The views expressed in this article are the views of the authors, and neither IMI nor the European Union or EFPIA is responsible for any use that may be made of the information contained herein. Financial support from the Slovenian Research Agency (grant nos. P1-0208, J1-3030, J1-3031) was gratefully acknowledged. S.R.H. was supported by an iCASE studentship funded by BBSRC and Redx Pharma Plc (BB/J014524/1). Work in A.M.’s lab was supported by an Investigator Award from the Wellcome Trust (110072/Z/15/Z) and by a BBSRC Institute Strategic Programme Grant (BB/P012523/1). The authors thank Diamond Light Source for access to beamlines I03, I04, I04-1, and I24 under proposals MX18565 and MX25108.
520 a 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.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Läkemedelskemi0 (SwePub)301032 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Medicinal Chemistry0 (SwePub)301032 hsv//eng
653 a antiinfective agent
7001 a Durcik, Martinau Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.4 aut
7001 a Tiz, Davide Benedettou Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.;Univ Perugia, Dept Pharmaceut Sci, Via Liceo 1, I-06100 Perugia, Italy.4 aut
7001 a Fulgheri, Federicau Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.;Univ Cagliari, Dept Life & Environm Sci, Drug Sect, Via Osped 72, I-09124 Cagliari, Italy.4 aut
7001 a Secci, Danielau Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.;Univ Cagliari, Dept Life & Environm Sci, Drug Sect, Via Osped 72, I-09124 Cagliari, Italy.4 aut
7001 a Sterle, Masau Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.4 aut
7001 a Mozina, Stefanu Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.;Lek Pharmaceut, Verovskova Ul 57, Ljubljana 1000, Slovenia.4 aut
7001 a Skok, Zigau Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.;Lek Pharmaceut, Verovskova Ul 57, Ljubljana 1000, Slovenia.4 aut
7001 a Zidar, Naceu Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.4 aut
7001 a Zega, Anamarijau Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.4 aut
7001 a Ilas, Janezu Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.4 aut
7001 a Masic, Lucija Peterlinu Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.4 aut
7001 a Tomasic, Tihomiru Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.4 aut
7001 a Hughes, Diarmaid,d 1956-u Uppsala universitet,Institutionen för cell- och molekylärbiologi,Institutionen för medicinsk biokemi och mikrobiologi4 aut0 (Swepub:uu)diarhugh
7001 a Huseby, Douglas L.u Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Uppsala Univ Hosp, Dept Med Sci, S-75185 Uppsala, Sweden.4 aut0 (Swepub:uu)douhu661
7001 a Cao, Shau Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi4 aut0 (Swepub:uu)shaca305
7001 a Garoff, Linneau Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi4 aut
7001 a Fernandez, Talia Berrugau Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi4 aut
7001 a Giachou, Paraskeviu Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi4 aut
7001 a Crone, Lisau Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi4 aut
7001 a Simoff, Ivailou Uppsala universitet,Institutionen för farmaci,Uppsala Univ, Dept Pharm, Drug Optimizat & Pharmaceut Profiling Platform UDO, S-75123 Uppsala, Sweden.4 aut0 (Swepub:uu)ivasi192
7001 a Svensson, Richardu Uppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab4 aut0 (Swepub:uu)ricsv977
7001 a Birnir, Bryndisu Uppsala universitet,Institutionen för medicinsk cellbiologi4 aut0 (Swepub:uu)brybi979
7001 a Korol, Sergiyu Uppsala universitet,Institutionen för medicinsk cellbiologi4 aut0 (Swepub:uu)serko922
7001 a Jin, Zheu Uppsala universitet,Institutionen för medicinsk cellbiologi,Uppsala Univ, Dept Med Cell Biol, S-75123 Uppsala, Sweden.4 aut0 (Swepub:uu)zheji315
7001 a Vicente, Franciscau Fundac MEDINA, Granada 18016, Spain.4 aut
7001 a Ramos, Maria C.u Fundac MEDINA, Granada 18016, Spain.4 aut
7001 a de la Cruz, Mercedesu Fundac MEDINA, Granada 18016, Spain.4 aut
7001 a Glinghammar, Bjornu RISE,Bioekonomi och hälsa,RISE Res Inst Sweden, Dept Chem Proc & Pharmaceut Dev, Unit Chem & Pharmaceut Safety, S-15136 Södertälje, Sweden.4 aut
7001 a Lenhammar, Lenau Uppsala Univ Hosp, Dept Med Sci, S-75185 Uppsala, Sweden.4 aut
7001 a Henderson, Sara R.u John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England.;Univ Birmingham, Inst Microbiol & Infect, Coll Med & Dent Sci, Birmingham, England.4 aut
7001 a Mundy, Julia E. A.u John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England.4 aut
7001 a Maxwell, Anthonyu John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England.4 aut
7001 a Stevenson, Clare E. M.u John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England.4 aut
7001 a Lawson, David M.u John Innes Ctr, Dept Biochem & Metab, Norwich NR4 7UH, England.4 aut
7001 a Janssen, Guido V.4 aut
7001 a Sterk, Geert Jan4 aut
7001 a Kikelj, Danijelu Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.,University of Ljubljana, Slovenia4 aut
7102 a Univ Ljubljana, Fac Pharm, Ljubljana 1000, Slovenia.b University of Ljubljana, Slovenia4 org
7730 t Journal of Medicinal Chemistryd : American Chemical Society (ACS)g 66:2, s. 1380-1425q 66:2<1380-1425x 0022-2623x 1520-4804
8564 u https://doi.org/10.1021/acs.jmedchem.2c01597y Fulltext
8564 u https://uu.diva-portal.org/smash/get/diva2:1742239/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-497765
8564 8u https://doi.org/10.1021/acs.jmedchem.2c01597
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:ri:diva-63982

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