4-Hydroxy-2-quinolones 126. 1-Hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1- ij]quinoline-2-carboxylic acid hydrazide and its derivatives

Article abstract of DOI:10.1007/s10593-007-0158-y

A preparative method has been developed for the synthesis of 1-hydroxy-3-oxo-5,6-dihydro-3H pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid hydrazide and its derivatives. The results of a study of the antitubercular activity of the synthesized compounds are

Full text of DOI:10.1007/s10593-007-0158-y

Chemistry of Heterocyclic Compounds, Vol. 43, No. 8, 2007
4-HYDROXY-2-QUINOLONES
126*. 1-HYDROXY-3-OXO-5,6-DIHYDRO-
3H-PYRROLO[3,2,1-ij]QUINOLINE-
2-CARBOXYLIC ACID HYDRAZIDE
AND ITS DERIVATIVES
I. V. Ukrainets, A. A. Tkach, E. V. Mospanova, and E. N. Svechnikova
A preparative method has been developed for the synthesis of 1-hydroxy-3-oxo-5,6-dihydro-
3H pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid hydrazide and its derivatives. The results of a study of
the antitubercular activity of the synthesized compounds are presented.
Keywords: 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids, amidation, hydrazinolysis,
antitubercular activity.
Hydrazine derivatives occupy a special place in the chemotherapy of tuberculosis which is one of the
most dangerous contemporary infectious illnesses. Thus isonicotinic acid hydrazide has been used in medical
practice for more than half a century under the name of isoniazid and it has not lost its value to the present day
[2]. Further, on its basis it has given rise to phthivazid, saluzid, metazid [3] and there continue to be discovered
modified analogs with improved pharmacological properties (e.g. flurenizid [4]). Rifampicin and rifapentin are
amongst the most effective semi-synthetic antitubercular agents and they also contain a hydrazine fragment in
their structure [2].
In continuing our systematic search for potential agents amongst amidated 1-R-4-hydroxy-2-oxo-
1,2-dihydroquinoline-3-carboxylic acids we repeatedly noted the high activity of the corresponding hydrazides
[5], in particular the benzylidenehydrazides [6-8], in relation to the stimulation of tubercular and non-tubercular
micobacteria. Following on in this area and with the aim of revealing a structure biological activity relationship
in the studied series this report concerns tricyclic analogs of 4-hydroxy-2-quinolones and particularly the
1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid derivative.
Ethyl 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylate (1) reacts with
hydrazine hydrate in alcohol solution at room temperature to give the hydrazine 2 in virtually quantitative yield.
An attempt to purify this material by crystallization from DMF led to a very unexpected result. Immediately
_______
* For Communication 125 see [1].
__________________________________________________________________________________________
National University of Pharmacy, Kharkiv 61002, Ukraine; e-mail: uiv@kharkov.ua. US National
Institute of Allergy and Infectious Diseases. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8,
pp. 1196-1203, August, 2007. Original article submitted May 18, 2006.
1014
0009-3122/07/4308-1014©2007 Springer Science+Business Media, Inc.

after reaching the boiling point a copious precipitate began to form from the solution. The solubility of this
material was so low that it was not possible to record the 1H NMR spectrum. Hence to establish its structure we
have used mass spectrometry and this has shown that hydrazide 2 is converted in boiling DMF to the
symmetrical N,N'-di(1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]-2-quinolinoyl)hydrazine (3). Additional
confirmation came from a counter synthesis via reaction of hydrazine 2 with ethyl ester 1.
O
O
O
O
OH
N
OH
N
N
N
H
H
3
DMF, boiling
OH
2, EtOH
O
OH
N
O
O
OEt
.
NHNH2
H2NNH2 H2O
O
N
2
1
O
N
H2N
N
RCHO
R
8a-g
O
O
O
N
OH
N
O
O
OH
R
N
N
N
H
N
H
R
N
7a-g
6a-c
6 a R = 2-Py, b R = 3-Py, c R = 4-Py; 7, 8 a R = Me, b R = Et, c R = Pr,
d R = Bu, e R = C5H11, f R = C6H13, g R = CH2Ph
It was interesting to note that none of the previously studied 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-
3-carboxylic acid hydrazides was characterized by similar properties and crystallization from DMF occurred
without complication and that a similar conversion to N,N'-diacylhydrazines was only possible under much more
forcing pyrolysis conditions [9].
The reason for this phenomenon is likely due to a specific effect of the pyrrole ring which leads to some
increase in the electrophilic properties of the carbonyl carbon atom in the hydrazide fragment when compared
with normal hydrazides, i.e. of 1-N-alkyl-substituted 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids.
As a result it appears reasonable for the reaction to occur by a reamidation transformation mechanism of
hydrazide 2 to diacylhydrazine 3 under relatively mild conditions. This proposal is supported by the dissociation
1015

TABLE 1. Characteristics of Compounds 2,6 and 7
Found, %
Calculated, %
Antitubercular activity
Inhibition
——————
Com-
pound
Empirical
formula
Yield,
%
mp, оС
MIC*2,
of growth of
M. Tuberculosis,
%*
C
H
N
µg/ml
2
C12H11N3O3
C18H14N4O3
C18H14N4O3
C18H14N4O3
C21H16N4O4
C22H18N4O4
C23H20N4O4
C24H22N4O4
C25H24N4O4
C26H26N4O4
C27H20N4O4
58.63 4.40 17.22 236-238
58.77 4.52 17.13
64.54 4.28 16.85 252-254
64.67 4.22 16.76
64.76 4.14 16.64 257-259
64.67 4.22 16.76
64.77 4.16 16.80 281-283
64.67 4.22 16.76
64.81 4.22 14.51 315-317
64.94 4.15 14.43
65.56 4.49 13.88 255-257
65.67 4.51 13.92
66.25 4.72 13.52 218-220
66.34 4.84 13.45
66.89 5.21 13.10 174-176
66.97 5.15 13.02
97
86
89
93
85
84
81
87
84
80
89
16
80
100
100
17
14
8
—
—
6a
6b
6c
7a
7b
7c
7d
7e
7f
6.25
6.25
—
—
—
5
—
67.64 5.50 12.53 170-172
67.56 5.44 12.60
68.02 5.81 12.17 199-201
68.11 5.73 12.22
69.90 4.44 12.13 180-182
69.82 4.34 12.06
0
–
0
3.13
0.78
7g
99
___________
* Concentration of material studied 6.25 µg/ml.
*2 MIC – minimum inhibitory concentration.
constants (pKa) for the carboxyl group of the 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-
2-carboxylic acid (4) and its acyclic analog 1-ethyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid
(5). A comparison of these values shows that closing the pyrrole ring for the same length N-alkyl substituent
actually leads to an increase in the reactivity of the carboxyl group.
O
O
OH
OH
OH
OH
O
N
O
N
Et
5
4
pKa = 7.53 + 0.05
pKa = 7.20 + 0.03
Bearing in mind the instability of hydrazide 2 in refluxing DMF the synthesis of the derived
pyridylmethylidenehydrazides 6 was carried out in ethanol. This places limits on the method of preparing the
2-alkyl-4-oxoquinazolin-3-ylamides 7 (Table 1). In particular it is clear that the reaction of hydrazide 2 with
2-R-4H-3,1-benzoxazin-4-ones is known in this case to be unacceptable since, to avoid the formation of acyclic
compounds, the syntheses are carried out in strictly anhydrous and high boiling solvents [10]. From several other
theoretically possible variants of the synthesis of this class of compound we have used a method avoiding an
ambiguous reaction route, i.e. the amidation of ester 1 by the previously synthesized 3-amino-2-R-quinazolin-
4(3H)-ones 8a-g.
1016

TABLE 2. 1H NMR Spectra of Synthesized Compounds 6 and 7
Com-
pound
Chemical shiftsи, δ, ppm. (J, Hz)
6a
16.10 (1H, s, ОH); 13.43 (1H, s, NH); 8.68 (1Н, d, J = 4.8, Н-6'); 8.39 (1Н, s, CH=N);
7.99 (1Н, d, J = 7.7, Н-3'); 7.87 (1Н, t, J = 7.5, Н-4'); 7.71 (1H, d, J = 8.0, Н-9);
7.60 (1H, d, J = 7.2, Н-7); 7.42 (1Н, t, J = 5.8, Н-5'); 7.26 (1Н, t, J = 7.4, Н-8);
4.40 (2H, t, J = 8.1, 5-СН2); 3.43 (2Н, t, J = 8.0, 6-СН2)
6b
16.23 (1H, s, ОH); 13.45(1H, s, NH); 8.91 (1Н, s, Н-2'); 8.64 (1Н, d, J = 4.9, Н-6');
8.50 (1Н, s, CH=N); 8.15 (1Н, d, J = 7.9, 4'-Н); 7.74 (1H, d, J = 8.1, Н-9);
7.60 (1H, d, J = 7.1, Н-7); 7.46 (1H, t, J = 7.7, Н-5'); 7.27 (1Н, t, J = 7.5, Н-8);
4.37 (2H, t, J = 8.0, 5-СН2); 3.44 (2Н, t, J = 8.0, 6-СН2)
6c
7a
16.25 (1H, s, ОH); 13.50 (1H, s, NH); 8.71 (2Н, d, J = 5.3, Н-2',6'); 8.43 (1Н, s, CH=N);
7.78 (1H, d, J = 8.1, Н-9); 7.69 (2H, d, J = 5.3, Н-3',5'); 7.58 (1H, d, J = 7.3, Н-7);
7.26 (1Н, t, J = 7.6, Н-8); 4.40 (2H, t, J = 8.1, 5-СН2); 3.43 (2Н, t, J = 8.1, 6-СН2)
15.35 (1H, s, ОH); 12.30 (1H, s, NH); 8.13 (1Н, d, J = 7.6, Н-8');
7.81 (1Н, t, J = 8.0, Н-7'); 7.74 (1Н, d, J = 8.0, Н-9); 7.61 (2Н, m, Н-5' + Н-7);
7.49 (1H, t, J = 7.6, Н-6'); 7.26 (1H, t, J = 7.7, Н-8); 4.43 (2H, t, J = 8.2, 5-СН2);
3.47 (2Н, t, J = 8.1, 6-СН2); 2.47 (3Н, s, СН3)
7b
7c
15.28 (1H, s, ОH); 12.36 (1H, s, NH); 8.12 (1Н, d, J = 7.7, Н-8');
7.80 (1Н, t, J = 8.0, Н-7'); 7.75 (1Н, d, J = 7.9, Н-9); 7.63 (2Н, m, Н-5' + Н-7);
7.47 (1H, t, J = 7.6, Н-6'); 7.20 (1H, t, J = 7.7, Н-8); 4.42 (2H, t, J = 8.0, 5-СН2);
3.44 (2Н, t, J = 8.0, 6-СН2); 2.77 (2Н, q, J = 7.2, СН2CH3); 1.10 (3Н, t, J = 7.1, СН3)
15.30 (1H, s, ОH); 12.33 (1H, s, NH); 8.17 (1Н, d, J = 7.8, Н-8');
7.82 (1Н, t, J = 7.9, Н-7'); 7.74 (1Н, d, J = 8.0, Н-9); 7.65 (2Н, m, Н-5' + Н-7);
7.48 (1H, t, J = 7.5, Н-6'); 7.22 (1H, t, J = 7.8, Н-8); 4.44 (2H, t, J = 8.1, 5-СН2);
3.45 (2Н, t, J = 8.0, 6-СН2); 2.80 (2Н, m, СН2-Et); 1.88 (2H, m, СН2СН3);
1.07 (3Н, t, J = 7.3, СН3)
7d
7e
7f
15.33 (1H, s, ОH); 12.27 (1H, s, NH); 8.14 (1Н, d, J = 7.7, Н-8');
7.84 (1Н, t, J = 7.9, Н-7'); 7.76 (1Н, d, J = 8.1, Н-9); 7.63 (2Н, m, Н-5' + Н-7);
7.45 (1H, t, J = 7.4, Н-6'); 7.23 (1H, t, J = 7.9, Н-8); 4.45 (2H, t, J = 8.0, 5-СН2);
3.48 (2Н, t, J = 7.9, 6-СН2); 2.79 (2Н, m, СН2-Pr); 1.80 (2H, q, J = 7.7, СН2-Et);
1.46 (2H, m, СН2СН3); 0.97 (3Н, t, J = 7.1, СН3)
15.26 (1H, s, ОH); 12.21 (1H, s, NH); 8.13 (1Н, d, J = 7.9, Н-8');
7.80 (1Н, t, J = 8.0, Н-7'); 7.77 (1Н, d, J = 8.0, Н-9); 7.62 (2Н, m, Н-5' + Н-7);
7.46 (1H, t, J = 7.6, Н-6'); 7.20 (1H, t, J = 7.7, Н-8); 4.42 (2H, t, J = 8.0, 5-СН2);
3.46 (2Н, t, J = 8.0, 6-СН2); 2.81 (2Н, m, СН2-Bu); 1.84 (2H, q, J = 7.3, СН2-Pr);
1.42 (4H, m, (СН2)2СН3); 0.93 (3Н, t, J = 7.0, СН3)
15.30 (1H, s, ОH); 12.25 (1H, s, NH); 8.16 (1Н, d, J = 8.1, Н-8');
7.82 (1Н, t, J = 8.0, Н-7'); 7.74 (1Н, d, J = 8.1, Н-9); 7.60 (2Н, m, Н-5' + Н-7);
7.43 (1H, t, J = 7.5, Н-6'); 7.21 (1H, t, J = 7.8, Н-8); 4.44 (2H, t, J = 8.1, 5-СН2);
3.49 (2Н, t, J = 8.1, 6-СН2); 2.73 (2Н, m, СН2-С5Н11); 1.82 (2H, q, J = 7.8, СН2-Bu);
1.44 (2H, q, J = 7.0, СН2-Pr); 1.35 (4Н, m, (СН2)2СН3); 0.88 (3Н, t, J = 7.0, СН3)
7g
15.09 (1H, s, ОH); 12.20 (1H, s, NH); 8.17-7.16 (12Н, m, Н arom.);
4.45 (2H, t, J = 8.0, 5-СН2); 4.13 (2Н, s, СН2-Ph); 3.48 (2Н, t, J = 8.0, 6-СН2)
1
Amongst the specific features of the H NMR spectra of the hydrazide 2 we noted a broad two proton
singlet for the free amino group at 4.59 ppm (Table 2). Distinctive features of the pyridylmethylidene derivatives
6a-c are the azomethine proton singlets at 8.39-8.50 ppm. At lower field there are only observed the OH and
CONH group protons and the aromatic protons in the pyridine rings next to the nitrogen atom. Characteristic
signals for the protons in the amides 7a-g are found in the aliphatic part of the spectrum and these correspond to
the alkyl substituents in position 2 of the quinazolone fragments.
The ability of the synthesized compound to inhibit the growth of tuberculosis bacteria was studied
radiometrically [11, 12]. Experimental data for primary microbiological screening has shown high activity
towards Mycobacterium tuberculosis H37Rv ATCC 27294 only for the 3- and 4-pyridylmethylidenehydrazides
6b,c (Table 1). At the same time, a comparative analysis of the biological properties of these compounds and
their structural analogs with open 1-N-alkyl chains shows that annelation of a quinolone ring with a pyrrole
overall causes some lowering of the antimicrobial activity; the MIC increasing with this modification from 3.13
to 6.25 µg/ml.
1017

EXPERIMENTAL
1
The H NMR spectra of the synthesized compounds were recorded on a Bruker WM-360 (360 MHz)
instrument using DMSO-d6 solvent and TMS internal standard. The mass spectrum of the diacylhydrazine 3 was
recorded on a Finnigan MAT Incos 50 quadrupole spectrometer with full scanning in the range 33-700 m/z, EI
ionization of 70 eV, direct sample introduction, and heating rate of about 5ºC/s. The acid-base equilibria were
measured using method [13] with 80% aqueous dioxane solvent. For preparation of the mixed solvent it was
freshly doubly distilled and freed from CO2 and the dioxane for UV spectroscopy was supplied by the company
Labscan. The 0.01 mol·l-1 aqueous KOH titrant was freed from CO2. The concentration of the titrated solutions
was 0.0005 mol·l-1 at the half neutralization point. The potentiometric titration was performed on a steady state
SevenEasy S-20-K Mettler Toledo pH meter with an InLab 413 combination electrode at 25ºC. The accuracy of
the results obtained was calculated by mathematical statistics [14]. Ethyl 1-hydroxy-3-oxo-4,5-dihydro-
3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylate (1) was prepared by the method in [15] and 2-R-3-aminoquinazolin-
4(3H)-ones 8a-b by that in [9].
1-Hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic Acid Hydrazide (2).
Hydrazine hydrate (0.011 mol, calculated from the actual content) was added to a solution of ester 1 (2.59 g,
0.01 mol) in ethanol (15 ml). After 2 h the reaction mixture was diluted with cold water. The precipitated
1
hydrazide 2 was filtered off, washed with water, and dried. Yield 2.38 g (97%); mp 236-238ºC (ethanol). H
NMR spectrum, δ, ppm (J, Hz): 16.68 (1H, s, OH); 10.90 (1H, s, CONH); 7.68 (1H, d, J = 8.1, H-9); 7.46 (1H,
d, J = 7.0, H-7); 7.16 (1H, t, J = 7.9, H-8); 4.59 (2H, br. s, NNH2); 4.34 (2H, t, J = 8.0, 5-CH2); 3.42 (2H, t,
J = 8.0, 6-CH2).
N,N’-Di(1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]-2-quinolinoyl)hydrazine (3). A mixture
of the hydrazide 2 (2.45 g, 0.01 mol) and DMF (15 ml) was heated. The material initially dissolved and then
began to form a precipitate on reaching reflux temperature. It was then refluxed for 20 min and cooled. The
precipitated diacylhydrazine 3 was filtered off, washed with alcohol, and dried. Yield 2.06 g (90%); mp
395-397ºC. Mass spectrum, m/z (Irel, %): 458 [M]+ (2), 245 (68), 214 (100), 187 (12), 145 (7). Found, %:
C 62.96; H 4.05; N 12.12. C24H18N4O6. Calculated, %: C 62.88; H 3.96; N 12.22.
1-Hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic Acid (4). Ester (2.59 g,
0.01 mol) was added to a solution of HCl in acetic acid (20 ml) with a low water content prepared as in the
method [16] and the product was held at 60ºC for 5 h. It was then cooled and the precipitated crystals of acid 4
were filtered off, washed with alcohol and then water, and dried. Yield 1.92 g (83%); mp 260-262ºC (decomp.,
1
sealed capillary). H NMR spectrum, δ, ppm (J, Hz): 15.90 (1H, s, OH); 14.37 (1H, s, COOH); 7.78 (1H, d,
J = 8.3, H-9); 7.70 (1H, d, J = 7.4, H-7); 7.36 (1H, t, J = 7.7, H-8); 4.40 (2H, t, J = 7.8, 5-CH2); 3.44 (2H, t,
J = 7.8, 6-CH2). Found, %: C 62.41; H 3.88; N 6.11. C12H9NO4. Calculated, %: C 62.34; H 3.92; N 6.06.
4-Hydroxy-2-oxo-1-ethyl-1,2-dihydroquinoline-3-carboxylic Acid (5) was prepared from the
corresponding ethyl ester [17] using the method reported above. Yield 1.75 g (75%); mp 133-135ºC (decomp.,
sealed capillary). 1H NMR spectrum, δ, ppm (J, Hz): 15.97 (1H, s, 4-OH); 14.36 (1H, s, COOH); 8.12 (1H, dd,
J = 8.1 and 1.5, H-5); 7.81 (1H, td, J = 7.8 and 1.5, H-7); 7.45 (1H, d, J = 8.3, H-8); 7.18 (1H, t, J = 7.5, H-6);
4.22 (2H, q, J = 7.2, NCH2); 1.21 (3H, t, J = 7.2, CH3). Found, %: C 61.86; H 4.84; N 5.94. C12H11NO4.
Calculated, %: C 61.80; H 4.75; N 6.01.
1-Hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic Acid Pyridylmethyli-
denehydrazides 6a-c (General Method). The corresponding pyridylaldehyde (0.011 mol) was added to a
solution of the hydrazide 2 (2.45 g, 0.01 mol) in hot ethanol (50 ml) and refluxed for 1 h. The product was
cooled and the precipitated crystals of the pyridylmethylidenehydrazide 6a-c were filtered off, washed with
alcohol, and dried. They were recrystallized from a mixture of DMF and ethanol.
1018

1-Hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid 2-R-4-oxo-4H-quin-
azolin-3-ylamides 7a-g (General Method). A mixture of ester 1 (2.59 g, 0.01 mol), the corresponding 3-amino-
2-R-quinazolin-4(3H)-one 8a-g (0.01 mol), and DMF (1 ml) was stirred and held for 3-5 min at 160ºC. The
product was cooled, ethanol (10-15 ml) added, and thoroughly triturated. The precipitated amide 7a-g was
filtered off, washed with alcohol, dried, and recrystallized from DMF.
The authors than the US National Institute of Allergy and Infectious Diseases for carrying out this study
of the antitubercular properties of the synthesized compounds within the TAACF (Tuberculosis Antimicrobial
and Coordinating Facility) program (contract No. 01-AI-45246).
REFERENCES
1.
I. V. Ukrainets, L. V. Sidorenko, and O. S. Golovchenko, Khim. Geterotsikl. Soedin., 1189 (2007).
[Chem. Heterocycl. Comp., 43, 1008 (2007)].
2.
3.
4.
5.
http://www.taacf.org/about-TB-current-drugs.htm
M. D. Mashkovskii, Drugs [in Russian], Vol. 2, Torsing, Kharkiv (1997), p. 334.
L. I. Petrukh, M. N. Kovalenko, and O. I. Mikhalik, Farmakom, No. 2, 9 (1999).
I. V. Ukrainets, Jaradat Nidal Amin, P. O. Bezugly, O. V. Gorokhova, L. V. Sidorenko, and
I. V. Porokhnyak, Fisiologichno Aktyvni Rechovyny, No. 1 (27), 21 (1999).
I. V. Ukrainets, Jaradat Nidal Amin, P. O. Bezuglii, O. V. Gorokhova, and L. V. Sidorenko, Visnyk
Farmatsii, No. 1 (21), 13 (2000).
I. V. Ukrainets, O. S. Prokopenko, L. V. Sidorenko, and O. V. Gorokhova, Visnyk Farmatsii, No. 3 (39),
3 (2004).
I. V. Ukrainets, L. V. Sidorenko, O. S. Prokopenko, V. B. Rybakov, and V. V Chernyshev, Zhurn. Org.
Farm. Khim., 2, No. 4 (8), 17 (2004).
6.
7.
8.
9.
10.
Jaradat Nidal Amin, Dissertation of Candidates in Pharm. Chem., Kharkiv (2000).
I. V. Ukrainets, O. V. Gorokhova, S. G. Taran, P. A. Bezugly, and A. V. Turov, Khim. Geterotsikl.
Soedin., 229 (1994). [Chem. Heterocycl. Comp., 30, 208 (1994)].
11.
12.
13.
14.
15.
16.
17.
L. B. Heifets, in: L. B. Heifets (editor), Drug Susceptibility in the Chemistry of Mycobacterial Infections,
CRC Press, Boca Raton (1991), p. 89.
C. B. Inderleid and K. A. Nash, in: V. Lorian (editor), Antibiotics in Laboratory Medicine, Williams and
Wilkins, Baltimore (1996), p. 127.
A. Albert and E. P. Sergeant, Ionization Constants of Acids and Bases [in Russian] Khimiya, Moscow
(1964).
E. N. L’vovskii, Statistical Methods for Deriving Empirical Formulae [in Russian] Higher School,
Moscow (1988), p. 41.
I. V. Ukrainets, L. V. Sidorenko, O. V. Gorokhova, E. V. Mospanova, and O. V. Shishkin, Khim.
Geterotsikl. Soedin., 718 (2006). [Chem. Heterocycl. Comp., 42, 631 (2006)].
S. Jönsson, G. Andersson, T. Fex, T. Fristedt, G. Hedlund, K. Jansson, L. Abramo, I. Fritzson,
O. Pekarski, A. Runström, H. Sandin, I. Thuvesson, and A. Björk, J. Med. Chem., 47, 2075 (2004).
I. V. Ukrainets, O. V. Gorokhova, S. G. Taran, P. A. Bezugly, A. V. Turov, N. A. Marusenko, and
O. A. Evtifeeva, Khim. Geterotsikl. Soedin., 958 (1994). [Chem. Heterocycl. Comp., 30, 829 (1994)].
1019