Discovery of YFJ-36 : Design, Synthesis, and Antibacterial Activities of Catechol-Conjugated β-Lactams against Gram-Negative Bacteria
Cefiderocol is the first approved catechol-conjugated cephalosporin against multidrug-resistant Gram-negative bacteria, while its application was limited by poor chemical stability associated with the pyrrolidinium linker, moderate potency against Klebsiella pneumoniae and Acinetobacter baumannii, intricate procedures for salt preparation, and potential hypersensitivity. To address these issues, a series of novel catechol-conjugated derivatives were designed, synthesized, and evaluated. Extensive structure-activity relationships and structure-metabolism relationships (SMR) were conducted, leading to the discovery of a promising compound 86b (Code no. YFJ-36) with a new thioether linker. 86b exhibited superior and broad-spectrum in vitro antibacterial activity, especially against A. baumannii and K. pneumoniae, compared with cefiderocol. Potent in vivo efficacy was observed in a murine systemic infection model. Furthermore, the physicochemical stability of 86b in fluid medium at pH 6-8 was enhanced. 86b also reduced potential the risk of allergy owing to the quaternary ammonium linker. The improved properties of 86b supported its further research and development.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
|---|---|
| Enthalten in: |
Journal of medicinal chemistry - 67(2024), 8 vom: 25. Apr., Seite 6705-6725 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Liu, Fangjun [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Anti-Bacterial Agents |
|---|
| Anmerkungen: |
Date Completed 25.04.2024 Date Revised 25.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/acs.jmedchem.4c00265 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370862368 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370862368 | ||
| 003 | DE-627 | ||
| 005 | 20240425233710.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240410s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acs.jmedchem.4c00265 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1386.xml |
| 035 | |a (DE-627)NLM370862368 | ||
| 035 | |a (NLM)38596897 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Liu, Fangjun |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of YFJ-36 |b Design, Synthesis, and Antibacterial Activities of Catechol-Conjugated β-Lactams against Gram-Negative Bacteria |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 25.04.2024 | ||
| 500 | |a Date Revised 25.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Cefiderocol is the first approved catechol-conjugated cephalosporin against multidrug-resistant Gram-negative bacteria, while its application was limited by poor chemical stability associated with the pyrrolidinium linker, moderate potency against Klebsiella pneumoniae and Acinetobacter baumannii, intricate procedures for salt preparation, and potential hypersensitivity. To address these issues, a series of novel catechol-conjugated derivatives were designed, synthesized, and evaluated. Extensive structure-activity relationships and structure-metabolism relationships (SMR) were conducted, leading to the discovery of a promising compound 86b (Code no. YFJ-36) with a new thioether linker. 86b exhibited superior and broad-spectrum in vitro antibacterial activity, especially against A. baumannii and K. pneumoniae, compared with cefiderocol. Potent in vivo efficacy was observed in a murine systemic infection model. Furthermore, the physicochemical stability of 86b in fluid medium at pH 6-8 was enhanced. 86b also reduced potential the risk of allergy owing to the quaternary ammonium linker. The improved properties of 86b supported its further research and development | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Anti-Bacterial Agents |2 NLM | |
| 650 | 7 | |a Catechols |2 NLM | |
| 650 | 7 | |a beta-Lactams |2 NLM | |
| 650 | 7 | |a catechol |2 NLM | |
| 650 | 7 | |a LF3AJ089DQ |2 NLM | |
| 650 | 7 | |a Cephalosporins |2 NLM | |
| 700 | 1 | |a Kou, Qunhuan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Hongyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Yangzhi |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Meng |e verfasserin |4 aut | |
| 700 | 1 | |a Meng, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yinyong |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ting |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Yushe |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of medicinal chemistry |d 1963 |g 67(2024), 8 vom: 25. Apr., Seite 6705-6725 |w (DE-627)NLM000006602 |x 1520-4804 |7 nnns |
| 773 | 1 | 8 | |g volume:67 |g year:2024 |g number:8 |g day:25 |g month:04 |g pages:6705-6725 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acs.jmedchem.4c00265 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 67 |j 2024 |e 8 |b 25 |c 04 |h 6705-6725 | ||