Halogen-Substituted Triazolethioacetamides as a Potent Skeleton for the Development of Metallo-β-Lactamase Inhibitors

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Antimicrobial Resistance

Background:

• Metallo-β-lactamases (MβLs) are critical enzymes conferring resistance to β-lactam antibiotics.
• Currently, no effective MβL inhibitors are available for clinical use, necessitating the development of novel therapeutic agents.
• Antibiotic resistance poses a significant global health threat, driving the urgent need for new antimicrobial strategies.

Purpose of the Study:

• To design and synthesize novel halogen-substituted triazolethioacetamides as potential inhibitors of MβLs.
• To evaluate the inhibitory activity of synthesized compounds against key MβL enzymes, including ImiS, NDM-1, and VIM-2.
• To elucidate the mechanism of inhibition and explore the binding interactions within the MβL active site.

Main Methods:

• Synthesis of thirteen halogen-substituted triazolethioacetamide derivatives.
• In vitro enzymatic assays to determine IC₅₀ values against various MβLs (ImiS, NDM-1, VIM-2, L1).
• Enzyme kinetics studies to characterize inhibition mechanisms (e.g., mixed inhibition).
• Molecular docking simulations to predict binding modes and interactions within the CphA active site.

Main Results:

• All synthesized compounds, except compound 7, demonstrated inhibitory activity against ImiS, with IC₅₀ values ranging from 0.032 to 15.64 μM.
• Chlorine-substituted compounds (1, 2, 3) showed potent inhibition against NDM-1 (IC₅₀ < 0.96 μM).
• Fluorine-substituted compounds 12 and 13 exhibited significant inhibition against VIM-2 (IC₅₀ = 38.9 and 2.8 μM, respectively).
• Compounds 9 and 13 acted as mixed inhibitors of ImiS with low K_i values (0.074 and 0.27 μM).
• Docking studies revealed favorable binding interactions for compounds 1 and 9 within the CphA active site, mimicking substrate binding.

Conclusions:

• Halogen-substituted triazolethioacetamides represent a promising scaffold for developing novel MβL inhibitors.
• Specific substitution patterns confer selectivity and potency against different MβL enzymes.
• The findings provide a basis for further optimization of these compounds as potential therapeutic agents against MBL-producing bacteria.