Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, 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 IIα, 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
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| Enthalten in: |
Journal of medicinal chemistry - 66(2023), 2 vom: 26. Jan., Seite 1380-1425 |
| Sprache: |
Englisch |
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| Links: |
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| Themen: |
Anti-Bacterial Agents |
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| Anmerkungen: |
Date Completed 27.01.2023 Date Revised 07.02.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.2c01597 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM351453032 |
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| 041 | |a eng | ||
| 100 | 1 | |a Cotman, Andrej Emanuel |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 27.01.2023 | ||
| 500 | |a Date Revised 07.02.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, 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 IIα, 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 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Topoisomerase II Inhibitors |2 NLM | |
| 650 | 7 | |a Anti-Bacterial Agents |2 NLM | |
| 650 | 7 | |a Benzothiazoles |2 NLM | |
| 650 | 7 | |a DNA Gyrase |2 NLM | |
| 650 | 7 | |a EC 5.99.1.3 |2 NLM | |
| 700 | 1 | |a Durcik, Martina |e verfasserin |4 aut | |
| 700 | 1 | |a Benedetto Tiz, Davide |e verfasserin |4 aut | |
| 700 | 1 | |a Fulgheri, Federica |e verfasserin |4 aut | |
| 700 | 1 | |a Secci, Daniela |e verfasserin |4 aut | |
| 700 | 1 | |a Sterle, Maša |e verfasserin |4 aut | |
| 700 | 1 | |a Možina, Štefan |e verfasserin |4 aut | |
| 700 | 1 | |a Skok, Žiga |e verfasserin |4 aut | |
| 700 | 1 | |a Zidar, Nace |e verfasserin |4 aut | |
| 700 | 1 | |a Zega, Anamarija |e verfasserin |4 aut | |
| 700 | 1 | |a Ilaš, Janez |e verfasserin |4 aut | |
| 700 | 1 | |a Peterlin Mašič, Lucija |e verfasserin |4 aut | |
| 700 | 1 | |a Tomašič, Tihomir |e verfasserin |4 aut | |
| 700 | 1 | |a Hughes, Diarmaid |e verfasserin |4 aut | |
| 700 | 1 | |a Huseby, Douglas L |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Sha |e verfasserin |4 aut | |
| 700 | 1 | |a Garoff, Linnéa |e verfasserin |4 aut | |
| 700 | 1 | |a Berruga Fernández, Talía |e verfasserin |4 aut | |
| 700 | 1 | |a Giachou, Paraskevi |e verfasserin |4 aut | |
| 700 | 1 | |a Crone, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Simoff, Ivailo |e verfasserin |4 aut | |
| 700 | 1 | |a Svensson, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Birnir, Bryndis |e verfasserin |4 aut | |
| 700 | 1 | |a Korol, Sergiy V |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Zhe |e verfasserin |4 aut | |
| 700 | 1 | |a Vicente, Francisca |e verfasserin |4 aut | |
| 700 | 1 | |a Ramos, Maria C |e verfasserin |4 aut | |
| 700 | 1 | |a de la Cruz, Mercedes |e verfasserin |4 aut | |
| 700 | 1 | |a Glinghammar, Björn |e verfasserin |4 aut | |
| 700 | 1 | |a Lenhammar, Lena |e verfasserin |4 aut | |
| 700 | 1 | |a Henderson, Sara R |e verfasserin |4 aut | |
| 700 | 1 | |a Mundy, Julia E A |e verfasserin |4 aut | |
| 700 | 1 | |a Maxwell, Anthony |e verfasserin |4 aut | |
| 700 | 1 | |a Stevenson, Clare E M |e verfasserin |4 aut | |
| 700 | 1 | |a Lawson, David M |e verfasserin |4 aut | |
| 700 | 1 | |a Janssen, Guido V |e verfasserin |4 aut | |
| 700 | 1 | |a Sterk, Geert Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Kikelj, Danijel |e verfasserin |4 aut | |
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