Metal binding pharmacophore click-derived discovery of new broad-spectrum metallo-β-lactamase inhibitors

Yan, Yu‐Hang; Ding, Hu; Zhu, Kai-Rong; Mu, Binsong; Yang, Zheng; Huang, Meng-Yi; Zhou, Cong; Li, Wenfang; Wang, Zhenling; Wu, Yong; Li, Guobo

doi:10.1016/j.ejmech.2023.115473

Cited by 4 publications

(27 citation statements)

References 36 publications

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“…1 H NMR (400 MHz, DMSOd 6 ) δ: 12.91 (s br, 1H), 8.87 (s, 1H), 7.30−7.18 (m, 5H), 3.50 (t, J = 8.0 Hz, 2H), 2.94 (t, J = 8.0 Hz, 2H) ppm. 13 2-Acetamido-5-benzylthiazole-4-carboxylic Acid (5). 1d (200 mg, 0.81 mmol) was dissolved in DCM.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.12 (dd, J = 13.2 Hz, J = 7.2 Hz, 4H), 4.40 (s, 2H), 2.25 (s, 3H) ppm. 13 2-Amino-5-(4-hydroxybenzyl)thiazole-4-carboxylic Acid (16). To a solution of methyl 2-amino-5-(4-methoxybenzyl)thiazole-4-carboxylate (15d, 278 mg, 1.00 mmol) in dry DCM was added BBr 3 (751 mg, 3.00 mmol) at 0 °C.…”

Section: -Amino-5-(3-bromobenzyl)thiazole-4-carboxylic Acidmentioning

confidence: 99%

“…1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.92 (s, 1H), 7.37−7.27 (m, 5H), 7.05 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 4.50 (s, 2H), 4.23 (s, 2H) ppm. 13 (27). A suspension of 13d (327 mg, 1.00 mmol), 4-pyridylboronic acid (366 mg, 3.00 mmol), tetrakis(triphenylphosphine)palladium (116 mg, 0.10 mmol), and cesium carbonate (978 mg, 3.00 mmol) in 1,4-dioxane was stirred for 4 h at 110 °C under argon.…”

Section: -Amino-5-(4-(trifluoromethyl)benzyl)thiazole-4-carboxylic Ac...mentioning

confidence: 99%

“…1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.08 (s, 1H), 6.96− 6.94 (m, 3H), 6.66 (d, J = 8.0 Hz, 1H), 4.48 (t, J = 8.4 Hz, 2H), 4.23 (s, 2H), 3.12 (t, J = 8.4 Hz, 2H) ppm. 13 (44). The target compound was obtained using a method similar to that for 1, 63% yield for two steps, 96.7% HPLC purity.…”

Section: -Amino-5-(4-(trifluoromethyl)benzyl)thiazole-4-carboxylic Ac...mentioning

confidence: 99%

“…The target compound was obtained using a method similar to that for 1, 50% yield for two steps, 99.5% HPLC purity. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.16 (d, J = 8.0 Hz, 2H), 6.95 (s, 1H), 6.86 (d, J = 8.4 Hz, 2H), 4.26 (s, 2H), 3.72 (s, 3H) ppm 13. C NMR (101 MHz, DMSO-d 6 ) δ: 164.85, 164.08, 158.35, 137.29, 137.16, 132.82, 129.80, 114.36, 55.49, 31.81 ppm.…”

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Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-β-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding

Yan,

Zhang,

et al. 2023

J. Med. Chem.

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Metallo-β-lactamases (MBLs) are zinc-dependent enzymes capable of hydrolyzing all bicyclic β-lactam antibiotics, posing a great threat to public health. However, there are currently no clinically approved MBL inhibitors. Despite variations in their active sites, MBLs share a common catalytic mechanism with carbapenems, forming similar reaction species and hydrolysates. We here report the development of 2-aminothiazole-4-carboxylic acids (AtCs) as broad-spectrum MBL inhibitors by mimicking the anchor pharmacophore features of carbapenem hydrolysate binding. Several AtCs manifested potent activity against B1, B2, and B3 MBLs. Crystallographic analyses revealed a common binding mode of AtCs with B1, B2, and B3 MBLs, resembling binding observed in the MBL-carbapenem product complexes. AtCs restored Meropenem activity against MBL-producing isolates. In the murine sepsis model, AtCs exhibited favorable synergistic efficacy with Meropenem, along with acceptable pharmacokinetics and safety profiles. This work offers promising lead compounds and a structural basis for the development of potential drug candidates to combat MBL-mediated antimicrobial resistance.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: -Amino-5-(3-bromobenzyl)thiazole-4-carboxylic Acidmentioning

confidence: 99%