5-nitrofurfurylidene 2-chloro-5,6,7,8 - tetrahydroquinolin-4-carboxylic acid, which has antimicrobial activity


(57) Abstract:

The invention relates to 5-nitrofurfurylidene 2-chloro-5,6,7,8-tetrahydroquinolin-4-carboxylic acid with bacteriostatic activity against Staphylococcus aureus with MIC of 1 µg/l and E. coli was 3.9 µg/ml at LD50more than 500 MK/kg 1 tab.

The connection relates to the field of organic chemistry, class 5,6,7,8-tetrahydroquinolin-4-carboxylic acid, namely to new biologically active 5-nitrofurfurylidene 2-chloro-5,6,7,8-tetrahydroquinolin-4-carboxylic acid of the formula II

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which can find application as antimicrobial drug drug.

The closest structural analogue of the claimed compound is a hydrazide 5,6,7,8-tetrahydroquinolin-4-carboxylic acid of the formula

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studied for the presence of anti-tuberculosis activity, but not showing it. About anti-inflammatory activity of this compound is not known. [Isber O. , H. Gutmann , O. Straub et al. Helv. Chim.acta. 38(4) 1033-1046 (1955)].

Known and used in medical practice antimicrobial drug of ethacridine lactate, which is taken as a benchmark comparison of antimicrobial action /Masciello of the present invention is to obtain a previously undescribed 5-nitrofurfurylidene 2 chloro-5,6,7,8-tetrahydroquinolin-4-carboxylic acid, possessing antimicrobial activity. This goal is achieved by obtaining the hydrazide 2-chloro-5,6,7,8-tetrahydroquinolin-4-carboxylic acid (I) by the interaction of the methyl ester [1] 2-chloro-5,6,7,8-tetrahydroquinolin-4-carboxylic acid with hydrazine hydrate

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The example of receiving compound I: To a solution 2,11 g (0.01 mol) of the methyl ester of 2-chloro-5,6,7,8-tetrahydroquinolin-4-carboxylic acid in 30 ml of ethanol was added a 1.5-fold excess of 60% hydrazine hydrate and boiled for 5 hours, the Reaction mixture is cooled, poured into cold water, the residue is filtered off, washed with hot water until neutral, dried and crystallized from ethanol. The output of 1.34 g (58,4%). So pl. 185-187oC. Found: N 18,75; Hal 15,61%. C10H12ClN3O. Calculated: N 18,63; Hal 15,74%.

5-nitrofurfurylidene II is obtained by reaction of a hydrazide and I 5-nitrofurfural

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Example obtain the claimed compound 5-nitrofurfurylidene 2-chloro-5,6,7,8-tetrahydroquinolin-4-carboxylic acid: to a solution of 2.25 g (0.01 mole) of the hydrazide 1 in 15 ml of acetic acid was added to 1.41 g (0.01 mol) of 5-nitrofurfural, incubated at room temperature for 1 day. The precipitation is filtered off,crystallized from acetic Cl 10,17%.

The inventive compound is a light yellow crystalline substance, soluble in DMF, acetic acid. The IR spectrum (Specord suspension in vaseline oil) there is an absorption band at 1630 cm-1(CO).

The study of the bacteriostatic activity of the compound was carried out at the Department of Microbiology and acute toxicity - at the Department of pharmacology pharmaceutical Academy, Perm.

To determine the bacteriostatic activity (Pershin, N. Methods of experimental chemotherapy. M , S. 109-111, 456-460 (1959). The order of the USSR Ministry of health N 250 from 13.03.75 About unification of the methods of determining the sensitivity of microorganisms to chemotherapeutic drugs. M., 1975.) took out a portion of 0.05 g and was dissolved in 5 ml of the corresponding solvent. A dilution of 1:100. Source drug dilution were prepared on mesopatamia broth (BCH) in a dilution of 1: 500 by mixing (1 ml dilution of 1:100 and 4 ml BCH). For experience took a series of test tubes containing 2 ml of the BCH. The method used twofold serial dilutions by transferring 2 ml of liquid from one tube to another. As control was used tubes with the medium without drug. Studies were performed regarding Locke. Daily agar culture test microbes were washed in isotonic solution of sodium chloride and brought on the optical standard to a concentration of 500 million microbial cells in ml of Standard breeding bred contents 5 million microbial cells in 1 ml After the addition of the microbial suspension tubes were incubated at 37oC. analysis was performed at 18 to 20 h in the presence of bacterial growth (turbidity environment) or in his absence due to the antibacterial action of the drug. Indicator antibacterial activity of chemical compounds is the minimum inhibitory concentration (MIC) of the drug (μg/ml) inhibits the growth of the appropriate test organism in the standard experiment.

Was determined acute toxicity (LD50) of compound II on white mice weighing 21 - 26 g after a single intraperitoneal injection of 2% starch mucus. Each pair was injected dose in ascending order. The death of animals were recorded within 1 day. LD50the size of the fluctuations calculated by the Express-method at p = 0.05 [5].

Compared acute toxicity LD50, antimicrobial activity against Staphylococcus aureus, Escherichia coli, and the value of the ratio MICK studied Na lactate [5].

The test results presented in the table.

According to the classification of the toxicity of drugs by compound II belongs to the class of low-toxic drugs, it is 7.1 times less toxic than ethacridine lactate.

As can be seen from table investigational compound for antimicrobial activity against Staphylococcus 500 times and in relation to E. coli is 126 times more active compared with ethacridine lactate. The ratio of MIC (μg/mg) toxicity LD50(mg/kg) is for Staphylococcus - 0,002 and for Escherichia coli 0,0078.

Thus, 5-nitrofurfurylidene 2-chloro-5,6,7,8-tetrahydroquinolin-4-carboxylic acid (II) exerts pronounced antibacterial activity and is low toxic. Therefore, the claimed compound II can be used in medicine as an antimicrobial drug.

Izmerov of the Imperial family and other Parameters toxicometric industrial poisons in a single exposure. M, Medicine, S. 197 (1977)

5-Nitrofurfurylidene 2-chloro-5,6,7,8-tetrahydroquinolin-4-carboxylic acid of the formula

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possessing antimicrobial activity.


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16 cl, 1 tbl, 86 ex