Carbamylmethyl Mercaptoacetate Thioether: A Novel Scaffold for the Development of L1 Metallo-β-lactamase Inhibitors

Abstract

Given the clinical importance of metallo-β-lactamases (MβLs), a new scaffold, N-substituted carbamylmethyl mercaptoacetate thioether, was constructed. The obtained molecules - inhibited MβLs from all three subclasses, but preferentially L1 from subclass B3. Compound with a-carboxyphenyl substituent exhibited the broadest spectrum with at least 70% inhibition of enzymes from all subclasses at 100 μM, while compound with a-methylphenyl substituent was the most potent inhibitor of any individual enzyme, with 97% inhibition at 100 μM and an IC value of 0.41 μM against L1. Isothermal titration calorimetry assays corroborate findings from UV-vis spectrophotometric assays that the inhibition of L1 by is dose-dependent. Docking studies suggest that the carboxyl group, the sulfide atom, and the carbonyl group of the carbamyl coordinate Zn2 in a chelating fashion. Using cells expressing L1, and were able to decrease cefazolin minimum inhibitory concentration 8-fold.

β-lactam/β-lactamase inhibitor combinations: an update

“…133,134 Substituted amide derivatives of mercaptoacetic acid (mercaptoacetamides, 41) are also prominent in a number of recent studies: Arjomandi and co-workers reported a series of amino acid conjugates of mercaptoacetamide and some longer chain homologs (mercaptpropionamide and mercaptobutyramide) which display IMP-1 inibition. 135 Other studies employed mercaptoacetamide thioethers containing acetate 136 and azolyl ring [137][138][139][140] substituents. The diverse library of thiolcontaining MBL-inhibitors also include thiomethylbenzoic acids, 141 bisthiazolidines, 142,143 rhodanines and its related thioenolates, [144][145][146][147] cysteine-containing oligopeptides, 148,149 phosphonate and tetrazole bioisosters of mercaptoacids 150 and thiones.…”

Approaches for the discovery of metallo‐β‐lactamase inhibitors: A review

“…McGeary synthesizes a series of 2‐aminopyrrole‐1‐benzyl‐4,5‐diphenyl‐1H‐pyrrole‐3‐carbonitrile derivatives that can inhibit MBLs extensively as a good example (). Finally, some thioesters and ester thioethers, as well as thione derivatives, have recently been reported, some of which also show broad‐spectrum inhibition of related MBLs (Chang et al., ; Liu, Shi, Kang, Oelschlaeger, & Yang, ; Sevaille et al., ).…”

Addressing Antimicrobial Resistance through New Medicinal and Synthetic Chemistry Strategies

“…The metal-chelating thioether-based MBL inhibitor ( 34 ; Fig. 5 ; IC 50 value of 0.41 µM against L1 MBL) has been reported 137 to restore the antimicrobial properties of cefazolin to that of susceptible, non–MBL-producing E. coli cells. Virtual screening methodologies 138,139 have also been applied for identification of non–β-lactam BML inhibitors, including nonmetal chelating structures, in addition to the use of a recombinant NDM-1 strategy.…”