4-Alkyl-1,2,4-triazole-3-thione analogues as metallo-β-lactamase inhibitors

Abstract

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1,2,4‐Triazole‐3‐Thione Analogues with a 2‐Ethylbenzoic Acid at Position 4 as VIM‐type Metallo‐β‐Lactamase Inhibitors

“…Its effect might be indirect through its higher rigidity and/or the displacement of water molecules, which would contribute a favorable entropic stabilization energy. [45] Finally, replacing the phenyl ring by a cyclohexyl group (i. e. 50) led to a large decrease in inhibitory potency, confirming the importance of an aromatic group at this position.…”

“…However, although similar inhibitory activities were measured, this series was of limited interest because these compounds did not behave more favorably in microbiological assays. In parallel, we developed another series of stable compounds possessing diversely substituted alkyl chains at position 4 and found that an alkanoic chain was favourable to VIM‐type MBL inhibition (Figure 1C) [45] . Most importantly, some compounds showed antibiotic potentiation activity on VIM‐producing K. pneumoniae clinical isolates.…”

“…Unfortunately, these compounds were characterized by a narrower inhibition spectrum as they were poorly or not active against NDM-1 and Figure 1. Structure of previously reported 1,2,4-triazole-3-thione compounds with a carboxylic group on the 4-substituent and their inhibitory potency on selected MBLs: (A) Schiff base analogue, [38] (B) reduced Schiff base analogue, [44] (C) alkanoic analogue; [45] (D) general structure of synthesized analogues with a 2-ethylbenzoic acid substituent at position 4. NI: no inhibition.…”

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

“…1,2,4-triazole-3-thione (TZT) derivatives: TZT was identified as a potential motif that interacted with the two zinc ions of MBL (L1) through one of the three nitrogen atoms, and sulfur atom, at the same time. An initial crystal structure evaluation of the analogous compound in complex with the L1 enzyme [132] led to synthesis [133][134][135][136][137][138][139][140] (Scheme 36) and enzymatic inhibition studies on a variety of compounds with variable substituents at positions 4 and 5 of TZT. A number of selected compounds exhibited IC 50 values in the micro-molar range against representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1 and CphA); however, limited success was observed in the microbiological assays [134][135][136][137]139,140].…”

“…An initial crystal structure evaluation of the analogous compound in complex with the L1 enzyme [132] led to synthesis [133][134][135][136][137][138][139][140] (Scheme 36) and enzymatic inhibition studies on a variety of compounds with variable substituents at positions 4 and 5 of TZT. A number of selected compounds exhibited IC 50 values in the micro-molar range against representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1 and CphA); however, limited success was observed in the microbiological assays [134][135][136][137]139,140]. In addition to the antimicrobial activity against class B β-lactamases, a series of compounds was assessed in vitro against KPC-2 as well.…”