Preparation and use of 2-substituted-(S)-(3-mercapto-2-methylpropanoyl)-glycine derivatives

A technology of methacryl and derivatives, which is applied in the field of new pan-MBL inhibitors, can solve problems such as spreading, and achieve the effects of good reversal, low energy consumption and high yield

Inactive Publication Date: 2018-06-05
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

More seriously, due to the exchange / transfer of MBL genes between the same or different pathogenic bacteria in recent years, super bacteria (such as K. pneumoniaeIR8, E. cloacae ST231, E. coli IR60 and other strains) with dual expression of MBL / SBL have emerged continuously / spread

Method used

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  • Preparation and use of 2-substituted-(S)-(3-mercapto-2-methylpropanoyl)-glycine derivatives
  • Preparation and use of 2-substituted-(S)-(3-mercapto-2-methylpropanoyl)-glycine derivatives
  • Preparation and use of 2-substituted-(S)-(3-mercapto-2-methylpropanoyl)-glycine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1, Synthesis of (R)-2-(4-fluorophenyl)-2-((S)-3-thiomethyl-2-methylpropionamido)acetic acid (1)

[0029]

[0030] As shown in the synthesis diagram above, first, add D-p-fluorophenylglycine (200mg, 1.18mmol) into a 50ml double-necked bottle, add 15ml of methanol to dissolve, and slowly add SOCl dropwise at 0°C 2 (129μL, 1.77mmol), after dropping, after 10min, transfer to 75°C and heat to reflux for 2h. TLC monitored the completion of the reaction, and directly spin-dried to obtain 249mg of gray solid, with a yield of 96.4%.

[0031] Then, the product obtained in the first step (200mg, 1.09mmol) was dissolved in 4ml DMF, and then HOBT (301mg, 2.18mmol), EDCI (417mg2.18mmol), DIEA (569μL, 3.27mmol), (S)-2 -Methylacetylated mercaptopropionic acid (177mg, 1.09mmol) was stirred at room temperature for 12h, and the reaction was completed. Add saturated NH 4 Cl solution, EA extracted three times, the combined organic layer was washed once with saturated brine, drie...

Embodiment 2

[0034] Example 2, Synthesis of (S)-2-(4-fluorophenyl)-2-((S)-3-thiomethyl-2-methylpropionamido)acetic acid (2)

[0035]

[0036] The synthesis method was similar to Example 1, and the target compound 2 was obtained, and the total yield of the three steps was 46.0%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.83 (s, 1H), 8.66 (d, J = 7.4 Hz, 1H), 7.44 (d, J= 5.2 Hz, 2H), 7.21 (t, J = 8.4 Hz, 2H), 5.37 (d, J = 7.1 Hz, 1H), 2.63 (d, J = 7.3 Hz, 2H),2.47-2.37 (m, 1H), 2.08 (t, J = 7.4 Hz, 1H), 1.08 (d, J = 5.3 Hz, 3H) ppm; 13 CNMR (150 MHz, DMSO- d 6 ) δ 174.31, 172.23, 133.79, 133.60, 130.20, 130.14, 115.77, 115.63, 55.91, 43.22, 27.69, 17.61 ppm. LC-MS: m / z 270.1 [M - H] - .

Embodiment 3

[0037] Example 3, Synthesis of (R)-2-(4-hydroxyphenyl)-2-((S)-3-thiomethyl-2-methylpropionamido)acetic acid (3)

[0038]

[0039] The synthesis method was similar to Example 1, and the target compound 3 was obtained, and the total yield of the three steps was 49.2%. 1 H NMR (400 MHz, CDCl 3 ) δ 12.57 (s, 1H), 9.50 (s, 1H), 8.50 (d, J = 7.0 Hz, 1H), 7.18 (d, J =8.2 Hz, 2H), 6.76 (d, J = 8.0 Hz, 2H), 5.17 (d, J = 7.1 Hz, 1H), 2.75-2.57(m, 2H), 2.41-2.38 (m, 1H), 2.19 (t, J = 7.5 Hz, 1H), 1.02 (d, J = 6.4 Hz,3H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 178.98, 177.57, 162.32, 134.04, 133.84,132.35, 120.36,120.31, 60.97, 47.74, 32.80, 22.11 ppm. LC-MS: m / z 268.1 [M-H] - .

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Abstract

The invention provides a 2-substituted-(S)-(3-mercapto-2-methylpropanoyl)-glycine derivative with a structural formula represented by a formula I (shown in the description). The invention further provides a preparation process and use of the 2-substituted-(S)-(3-mercapto-2-methylpropanoyl)-glycine derivative. Pharmacodynamic tests prove that compounds has relatively good inhibitory activity to various metal beta lactamases (MBL), and particularly, a compound 3 has the optimal inhibitory activity and is remarkably superior to certain MBL small-molecule inhibitors such as captopril reported at present. X-ray crystal structure researches of compounds prove that the action mechanism between the compounds of the invention and MBL is characterized in that mercapto groups of the compounds are chelated with zinc ions at MBL active sites. Besides, antimicrobial activity tests prove that the compounds of the invention have very good bacteriostatic effect to multiple clinically separated superbacteria strains when being combined with beta-lactam antibiotic for use. The 2-substituted-(S)-(3-mercapto-2-methylpropanoyl)-glycine derivative has a clear and definite action mechanism and a remarkable pesticide effect, and new drug selection is likely to be provided for clinic.

Description

technical field [0001] The invention belongs to the field of compound drugs, and in particular relates to a novel pan-MBL inhibitor and its application in reversing drug resistance of superbugs. Background technique [0002] β-lactam antibiotics (such as cephalosporins, carbapenems, etc.) are currently the most widely used antibiotics in clinical practice, with the advantages of good curative effect, low toxicity, and wide indications. However, the current global situation of β-lactam antibiotic resistance is extremely severe. For example, carbapenem-resistant Enterobacteriaceae bacteria (the "last line of defense" for β-lactam-resistant bacteria) that have emerged in recent years can cause fatal septic shock. The most important mechanism leading to β-lactam antibiotic resistance is the production of β-lactamase by pathogenic bacteria; from the catalytic mechanism, β-lactamase can be divided into two categories, namely, metallo-lactamase (MBL) and Serine β-lactamase (SBL)....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/52C07C319/02A61K31/198A61P31/04
CPCC07C323/52C07B2200/07C07C227/18C07C319/02C07C327/06C07C229/36
Inventor 吴勇李国菠海俐景丽刘莎于竹君
Owner SICHUAN UNIV
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