2026-10-13T12:33:55Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34036718 2026-09-30T19:19:42Z category_4 category_146 category_8 category_19 category_21 category_873 category_46 category_734 category_64 category_128 category_132 portal_63 item_type_6 month_year_09_2026

Fluorinated Aliphatic Thiols in the Design of Cephalosporin Conjugates for Metallo-β-Lactamase Inhibition Alexandra Kondratieva (25145939) Philip Rainsford (11510092) Perwez Bakht (20356711) Ranjana Pathania (384841) Annette Bayer (1696084) Biochemistry Space Science Microbiology Pharmacology Biotechnology Chemical Sciences not elsewhere classified Immunology Biological Sciences not elsewhere classified Cancer Hematology Infectious Diseases thus incompletely resolved serious clinical threat leaving group properties leaving group ability designed compounds consist fluorinated aliphatic thiols aliphatic thiols compared cephalosporin core linked trifluoromethylated aliphatic thiol 19 </ sup new delhi metallo based mbl inhibitors aliphatic thiol cephalosporin conjugates based inhibitors aromatic thiol unsolved challenges selective release rapid spread producing bacteria nonfluorinated control mediated hydrolysis hydrolysis monitoring fluorination improves findings highlight f nmr conjugate containing catalytic activity alternative method Antibiotic resistance is a major global health challenge, with the rapid spread of metallo-β-lactamase (MBL)-expressing bacteria presenting a serious clinical threat. In this study, we synthesized and investigated a series of novel cephalosporin conjugates envisioned to release MBL inhibitors upon MBL-mediated hydrolysis. The designed compounds consist of a cephalosporin core linked to trifluoromethylated aliphatic thiol-based MBL inhibitors. Conjugates releasing aliphatic thiols upon hydrolysis by the New Delhi Metallo-β-lactamase-1 (NDM-1) were identified, confirming that fluorination improves the leaving group properties of some aliphatic thiols compared to a nonfluorinated control. However, when comparing with a conjugate containing an aromatic thiol, fluorinated aliphatic thiol release appeared slower and mechanistically more complex, thus incompletely resolved. The conjugates exhibited potent inhibitory activity against several subclass B1 MBLs. In addition, the utility of ¹⁹F NMR as an alternative method for hydrolysis monitoring was exemplified. The findings highlight the potential, but also some unsolved challenges, of altering the leaving group ability of aliphatic thiol-based inhibitors to exploit the catalytic activity of NDM-1 for the selective release of inhibitors in MBL-producing bacteria. 2026-09-30T00:00:00Z Text Journal contribution 10.1021/acsomega.6c07917.s001 https://figshare.com/articles/journal_contribution/Fluorinated_Aliphatic_Thiols_in_the_Design_of_Cephalosporin_Conjugates_for_Metallo-_-Lactamase_Inhibition/34036718 CC BY-NC 4.0