Metal [beta]-lactamase inhibitor cyclo-amidodithioformate derivative and preparation method of same
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A cyclic aminodithioformate and lactamase technology, applied in organic chemistry, antibacterial drugs, etc., can solve the problems of difficult treatment, wide drug resistance spectrum, poor sensitivity, etc., to achieve Develop promising effects
Active Publication Date: 2016-12-14
ZHENGZHOU UNIV
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In 2009, the first superbacteria producing NDM-1 metallo-β-lactamase was discovered in New Delhi, India. This bacterium is only sensitive to a few antibacterial drugs such as colistin, has a wide spectrum of drug resistance, and is difficult to treat (The Lancet Infectious Diseases2010, 10, 597.)
In 2015, Yang Kewu's research group at Northwest Un
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Embodiment 1
[0042] The preparation of embodiment 1 compound 1a
[0043] At room temperature, take the compound anhydrous piperidine (100mg, 1.16mmol) and sodium hydroxide (93mg, 2.32mmol) into a 10mL single-necked bottle, add 2mL of ethanol, stir at room temperature, the system is not completely dissolved; add carbon disulfide (169μL, 2.79 mmol), the system turns golden white and turbid, and the reaction stops in about half an hour. The solvent was distilled off under reduced pressure, an appropriate amount of ethyl acetate was added, the solid adhering to the bottle wall was scraped off with a spoon, filtered with suction, the filter cake was rinsed with ethyl acetate again, and vacuum-dried to obtain 325 mg of white solid with a yield of 99%.
[0044] m.p.: >300°C; 1 H NMR (400MHz,D 2 O)δ4.38(s,1H). 13 C NMR (100MHz,D 2 O) δ209.13,50.21.
Embodiment 2
[0045] The preparation of embodiment 2 compound 2a
[0046] At room temperature, the compound 1,4,7-triazacyclononane was taken in a solvent, and the preparation was the same as that of the compound 1a in Example 1 to obtain 36 mg of white crystals with a yield of 15%.
[0047]m.p.:174-176℃; 1 H NMR (400MHz, CDCl 3 )δ4.78–3.85(m,12H),2.64(s,9H). 13 CNMR (100MHz, CDCl 3 )δ201.42, 29.71, 20.49. HR-MS (ESI) Calcd for C 12 h 21 N 3 S 6 [M+Na]+:421.9957,found:421.9957.
Embodiment 3
[0048] The preparation of embodiment 3 compound 3a
[0049] At room temperature, take compound 1, 4, 7, 10-tetraazacyclododecane in a solvent, and prepare 327 mg of white solid with a yield of 99% according to the preparation of compound 1a in Example 1
[0050] m.p.:278-280℃ 1 H NMR (400MHz,D 2 O) δ4.70. 13 C NMR (100MHz,D 2 O) δ55.01.
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Abstract
The invention belongs to the field of medical chemistry and discloses a metal [beta]-lactamase inhibitor cyclo-amidodithioformate derivative and a preparation method of the same. The compound is represented as the structural formulas 1, 2 or 3 as follows, wherein R is sodium, a methyl group, an n-hexyl group, an n-decyl group or an n-dodecyl group. The inhibitor is combined with a carbapenem antibiotic (e.g. meropenem) to achieve the inhibition activity of metal [beta]-lactamase, so that the sensitivity to the carbapenem antibiotic of a bacterial strain having drug resistance against the carbapenem is recovered. The inhibitor has significant effects on a bacterial strain producing NDM-1 enzyme and having drug resistance against the carbapenem. A red blood cell haemolytic test and a cytotoxicity test prove that the compound is low in toxicity. The series of the compounds is hopeful to serve as a potential candidate medicine of the metal [beta]-lactamase inhibitor.
Description
technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a metal β-lactamase inhibitor cyclic aminodithioformate derivative with potential application value and a preparation method thereof. Background technique [0002] Since the use of antibiotics in the clinical treatment of bacterial infections, the problem of bacterial resistance has become increasingly serious. There are many reasons for bacterial drug resistance, among which drug hydrolytic enzymes that can spread horizontally are an important reason for bacteria to acquire drug resistance. In 2009, the first superbacteria producing NDM-1 metallo-β-lactamase was discovered in New Delhi, India. This bacterium is only sensitive to a few antibacterial drugs such as colistin, has a wide spectrum of drug resistance, and is difficult to treat (The Lancet Infectious Diseases 2010, 10, 597.). Since the discovery of the NDM-1 enzyme-producing strain, it has been prevalent in more than ...
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