4-Hydroxy-2-quinolones 138. Synthesis and study of structure-biological activity relationships in a series of 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3, 2,1-ij]quinoline-2-carboxylic acid anilides

Article abstract of DOI:10.1007/s10593-007-0237-0

Two methods are discussed and the synthesis of a series of 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid anilides has been carried out. The antitubercular activity and the effect on the urinary function of the kidney have bee

Full text of DOI:10.1007/s10593-007-0237-0

Chemistry of Heterocyclic Compounds, Vol. 43, No. 12, 2007
4-HYDROXY-2-QUINOLONES
138*. SYNTHESIS AND STUDY OF STRUCTURE –
BIOLOGICAL ACTIVITY RELATIONSHIPS
IN A SERIES OF 1-HYDROXY-3-OXO-5,6-DIHYDRO-
3H-PYRROLO[3,2,1-ij]QUINOLINE-2-CARBOXYLIC
ACID ANILIDES
I. V. Ukrainets, E. V. Mospanova, N. L. Bereznyakova, and O. I. Naboka
Two methods are discussed and the synthesis of a series of 1-hydroxy-3-oxo-5,6-dihydro-3H-
pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid anilides has been carried out. The antitubercular activity
and the effect on the urinary function of the kidney have been studied for the compounds prepared. A
structure-biological activity relationship is discussed.
Keywords: anilides, 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids, diuretics, amidation,
antitubercular activity.
In recent times the attention of synthetic chemists has been drawn to a search for biologically active
substances in order to create from them novel medicinal compounds and it has been ever more attracted to
4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid anilides [2-8]. This is explained not only by the broad
spectrum of pharmaceutical activity of the studied 4-hydroxyquinol-2-ones and their natural occurrence but also
by the ready chemical modification of their basic structure. Directed changes can be introduced into any part of
the basic molecule by quite simple methods guaranteeing the best access to an almost unlimited range of analogs
which, in turn, significantly increases the likelihood of discovering promising structural leads in subsequent
study.
Condensation of primary aromatic amines with triethyl methanetricarboxylate in conventional conditions
gives primarily the methanetricarboxylic acid trianilides. During microwave irradiation the reaction given occurs
somewhat differently and indeed yields 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid anilides [7].
To some extent, the low yields are compensated by the synthesis of the target compounds in a single stage. This
method is certainly of interest although the promising application of it is small since both the quinolone ring and
the anilide fragment are formed from the same aniline.
_______
* For Communication 137 see [1].
__________________________________________________________________________________________
National University of Pharmacy, Kharkiv 61002, Ukraine; e-mail: uiv@kharkov.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1808-1819, December, 2007. Original article submitted
March 23, 2007.
1532
0009-3122/07/4312-1532©2007 Springer Science+Business Media, Inc.

Removal of this restriction enables amidation of the previously prepared 4-hydroxy-2-oxo-
1,2-dihydroquinoline-3-carboxylic acids and their esters. The lowest alkyl esters of 4-hydroxy-2-oxo-
1,2-dihydroquinoline-3-carboxylic acids are highly reactive [9] and efficiently acylate primary and secondary
amines in the majority of cases. According to the methods frequently met in the literature amidation is brought
about by refluxing the corresponding 3-alkoxycarbonylquinolone and a 40-150% excess of the aniline in a
suitable solvent (pyridine, toluene, xylene, bromobenzene) for 3-36 h with simultaneous distillation of the
alcohol evolved [3, 5, 10, 11]. We have, however, frequently noted the success of carrying out such a reaction
without solvent or in the presence of a small amount of DMF and, very importantly, with an equimolar ratio of
reagents [8, 12]. This method allows a more rational use of the amine and, in addition, shortens the reaction time
to several minutes. Hence it was actually used in the amidation of ethyl 1-hydroxy-3-oxo-5,6-dihydro-
3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylate (1) (method A) to yield a large series of the corresponding anilides
2 and 3.
O
OH
OEt
A. H2N–Ar,
160°C
O
N
O
O
OH
N
1
N
HCl/AcOH
R
H
O
OH
N
B. 1. CDI;
2. H2N–Ar
2a-z, 3 a-i
OH
O
4
2 a R = H; b R = 2-F; c R = 3-F; d R = 4-F; e R = 3,4-F2; f R = 2-Cl; g R = 3-Cl; h R = 4-Cl; i R = 2,3-Cl2;
j R = 2,4-Cl2; k R = 2-Br; l R = 2-Br–4-Me; m R = 3-Br; n R = 4-Br; o R = 2-Me; p R = 3-Me; q R = 4-Me;
r R = 2,3-Me2; s R = 2,4-Me2; t R = 2,5-Me2; u R = 2-OMe; v R = 2-OMe-5-Cl; w R = 3-OMe; x R = 4-OMe;
y R = 4-OEt; z R = 2-CF3; 3 a R = 2-C≡N; b A = 2-COOMe; c R = 2-CONH2; d R = 2-CONHMe;
e R = 4-COOMe; f R = 4-COOEt; g R = 4-COOPr; h R = 4-COOBu; i R = 2-SO2NH2
The acylation of N-alkylanilines by 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids esters
does not always occur smoothly, especially where there are electron-acceptor substituents present in the aniline.
In such cases it is expediently the target esters initially to hydrolyze to the acids and then convert to more
powerful acylating agents: anhydrides, acid chlorides, or mixed anhydrides [3, 5, 10]. N,N'-Dicyclo-
hexylcarbodiimide is also suitable for increasing the electrophilic properties of the carboxyl group carbonyl [10].
In addition, the amine component can be activated by converting it to highly reactive derivatives with
phosphorus trichloride [10]. In this way, many known methods for transformation of carboxylic acids to amides
can be used. It is only necessary to remember that the 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids
in the solution state are distinguished by a very high tendency towards decarboxylation. Thus in DMSO solution
partial decomposition occurs in the course of a day, even at room temperature [13]. For this reason, it is not
possible to use strong heating at the stage of activation of the 4-hydroxy-2-oxo-1,2-dihydroquinoline-
3-carboxylic acids. This specific feature was taken into account by us in developing an alternative method for
synthesizing amides 2, 3 from 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo-[3,2,1-ij]quinoline-2-carboxylic acid
(4). By carrying out the reaction with N,N-carbonyldiimidazole (CDI) at a temperature less than 40ºC the
1533

TABLE 1. Characteristics of the 1-Hydroxy-3-oxo-5,6-dihydro-
3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic Acid Anilides 2a-z, 3a-i
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield*, %
C
3
H
4
N
5
1
2a
2b
2c
2d
2e
2f
2
6
7
93 (88)
86
C18H14N2O3
70.65
70.58
66.78
66.66
66.75
66.66
66.60
66.66
63.07
63.16
63.53
63.44
63.40
63.44
63.51
63.44
57.53
57.62
57.55
57.62
56.19
56.12
57.25
57.16
56.20
56.12
56.10
56.12
71.33
71.24
71.30
71.24
4.70
4.61
4.17
4.04
4.14
4.04
4.09
4.04
3.44
3.53
3.92
3.85
3.88
3.85
3.77
3.85
3.30
3.22
3.14
3.22
3.47
3.40
3.86
3.79
3.49
3.40
3.36
3.40
5.14
5.03
5.12
5.03
9.08
9.15
8.73
8.64
8.56
8.64
8.76
8.64
8.09
8.18
8.30
8.22
8.17
8.22
8.16
8.22
7.58
7.47
7.40
7.47
7.35
7.27
7.11
7.02
7.22
7.27
7.24
7.27
8.66
8.74
8.81
8.74
8.65
8.74
8.30
8.38
8.29
8.38
8.42
8.38
8.39
8.33
7.46
7.55
8.25
8.33
8.39
8.33
8.07
8.00
7.40
7.48
12.76
12.68
7.57
7.69
192-194
181-183
189-191
192-194
217-219
162-164
169-171
226-228
267-269
240-242
167-169
225-227
199-201
236-238
178-180
145-147
202-204
225-227
214-216
227-229
188-190
224-226
163-165
184-186
195-197
219-221
256-258
135-137
293-295
C18H13FN2O3
C18H13FN2O3
C18H13FN2O3
C18H12F2N2O3
C18H13ClN2O3
C18H13ClN2O3
C18H13ClN2O3
C18H12Cl2N2O3
C18H12Cl2N2O3
C18H13BrN2O3
C19H15BrN2O3
C18H13BrN2O3
C18H13BrN2O3
C19H16N2O3
89
90
85
83
2g
2h
2i
88
94
80
2j
82
2k
2l
80
84
2m
2n
2o
2p
2q
2r
2s
87
91
85
C19H16N2O3
89
C19H16N2O3
71.35
71.24
71.77
71.84
71.92
71.84
5.16
5.03
5.35
5.43
5.54
5.43
90
C20H18N2O3
81
C20H18N2O3
84
2t
C20H18N2O3
71.94
71.84
5.51
5.43
82
2u
2v
2w
2x
2y
2z
3a
3b
3c
C19H16N2O4
67.78
67.85
61.67
61.55
67.93
67.85
67.91
67.85
68.47
68.56
60.86
60.97
68.94
68.88
65.82
65.93
4.86
4.79
4.15
4.08
4.70
4.79
4.86
4.79
5.11
5.18
3.43
3.50
3.87
3.95
4.35
4.43
86 (80)
86
C19H15ClN2O4
C19H16N2O4
90 (87)
93 (90)
95
C19H16N2O4
C20H18N2O4
C19H13F3N2O3
C19H13N3O3
80
88
C20H16N2O5
79
C19H15N3O4
65.41
65.32
4.45
4.33
12.12
12.03
81
1534

TABLE 1. (continued)
1
2
3
4
5
6
7
3d
C20H17N3O4
C20H16N2O5
C21H18N2O5
C22H20N2O5
C23H22N2O5
C18H15N3O5S
66.02
66.11
65.98
65.93
66.57
66.66
67.25
67.34
67.90
67.97
56.02
56.10
4.64
4.72
4.47
4.43
4.70
4.79
5.03
5.14
5.35
5.46
3.81
3.92
11.46
11.56
7.72
7.69
7.49
7.40
7.22
7.14
6.97
6.89
10.83
10.90
268-270
249-251
195-197
178-180
151-153
257-259
77
89
90
88
94
73
3e
3f
3g
3h
3i
_______
* Yield using method A. For compounds 2a,u,w,x the yields are given
in brackets for method B.
imidazolide of acid 4 can be converted to the anilides 2 and 3 without any kind of complication (method B). It
should be noted that method B can hardly be justified for the acylation of the majority of primary aromatic
amines, in particular those used in the synthesis of anilides 2 and 3. The introduction into the synthetic scheme
of additional stages of hydrolysis of the ester function and subsequent activation of the carboxyl group is
advisable only in those cases where hindrance to the use of method A occurs, e.g. in the acylation of thermally
unstable anilines.
All of the synthesized 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1,-ij]quinoline-2-carboxylic acid
anilides 2 and 3 (Table 1) are light-yellow crystalline materials and at room temperature are virtually insoluble in
water, slightly soluble in alcohol, and moderately soluble in DMF and DMSO. 1H NMR spectroscopy was used
to confirm the chemical structure of the compounds obtained (Table 2).
The antitubercular activity of anilides 2 and 3 was studied in vitro by a radiometric method [14, 15]
relative to Mycobacterium tuberculosis H37Rv ATCC 27294 at an initial concentration of 6.25 µg/ml. Primary
microbiological experimental screening data showed that in contrast to our previous reports of 1-hydroxy-3-oxo-
5,6-dihydro-3H-pyrrolo[3,2,1-ij]-2-carboxylic acid heterylamides [12], which demonstrated a similarity in
biological properties to the corresponding 1R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides with the
lowest (C(1)–C(3)) alkyl substituents on the quinolone ring nitrogen atom, the anilides 2 and 3 showed an opposite
trend in many respects. Hence, for example, if the absence of antitubercular activity in the unsubstituted anilide
2a and its alkyl- and alkoxy-substituted analogs 2o-y was fully expected, then the failure of inhibition of growth
of the tubercular mycobacteria in the majority of the remaining compounds even to some degree was
unexpected. It was found that exchange of a quinolone ring for pyrroloquinolone fully deactivates the normally
highly active monofluoroanilides [16]. At the same time, in the case of 3,4-difluoro(2e)- and ortho-
trifluoromethyl(2z)-substituted derivatives the indicated modification, conversely, slightly increases the
antimycobacterial properties. In all of the group of synthesized materials only a single compound (the meta-
chloroanilide 2g) can be picked out as having 100% inhibition of the growth of the test strain in the first level of
screening studies. However, the minimum inhibitory concentration (MIC) found at the subsequent step was
6.25 µg/ml for this compound which rules out any prospect of becoming a future antitubercular medicine (the
MIC for such compounds should not exceed 1µg/ml).
The previously discovered [17] high level of diuretic activity shown by several 1-hydroxy-3-oxo-
5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid cyclo-alkylamides served as the theoretic reason for
studying the effect of the synthesized compounds on the urinary function of the kidney. With the
1535

1536

1537

arylalkylamides the diuretic effect is more strongly expressed while it has been shown experimentally that the
benzylamides always appear more active than their 2-arylethyl and 3-arylpropyl analogs, i.e. exchange from a
methylene separating the aromatic ring and the amide nitrogen atom to a chain of two or three methylenes leads
to a marked lowering in activity. The question of how removal of a designated methylene group from the
molecule reflects on the biological properties can only be answered experimentally. Interest in the testing of
anilides close in structure to the arylalkylamides mentioned (2 and 3) is a result of this.
The studies were carried out by a known method [18] using white nonpedigree rats of weight 180-200 g.
The results obtained in this way show that the transition from benzylamides to 1-hydroxy-3-oxo-5,6-dihydro-
3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid anilides with the same substituents in the aromatic amide ring is
generally accompanied by a marked increase in diuretic effects. As a rule, m-isomers proved more active than
their o- and p-substituted analogs. For example, amongst the three monofluoroanilides 2b-d an increase in
diuresis is only caused by the m-fluoro derivative 2c whereas the isomeric o- and p-fluoroanilides 2b,d show no
overall effect on urinary excretion. The same pattern has been observed by us before for monofluoro-
benzylamides. It was interesting that the strength of the diuretic effect caused by the 3,4-difluoroanilide 2e and
its 3-fluoro-substituted precursor 2c were identical. This fact gives us a basis for identifying the presence of a
fluorine in the p-position of the anilide fragment as unwanted since its presence (or conversely absence) has no
influence on the diuretic properties. An even more weighty argument supporting this conclusion is the well
known dependence found when developing fluoroquinolone antibiotics: an increase in the number of fluorine
atoms in the molecule causing an inherent increase in the toxicity of the chemical material [19].
In the series of 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid anilides
with electron-acceptor substituents (which have acidic properties or are able to be converted to them in vivo) a
moderate increase in diuresis in experimental animals is only brought about by the 2-sulfamoyl derivative 3i.
The anilides 3a-h, prepared from nitriles, amides, and esters of aromatic carboxylic amino acids, not only do not
possess diuretic properties but, in several cases, e.g. the 2-carbamoyl anilide 3c, even markedly depress urinary
excretion.
EXPERIMENTAL
1H NMR spectra for the synthesized compounds were recorded on a Bruker WM-360 (360 MHz)
instrument for DMSO-d6 solutions and with TMS as internal standard. 1-Hydroxy-3-oxo-5,6-dihydro-3H-
pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid (4) and its ethyl ester 1 were prepared by the methods [20] and [21]
respectively. Anhydrous DMF for peptide synthesis and N,N-carbonyldiimidazole from the Fluka company were
used in the synthesis of the amides 2 and 3 by method B.
1-Hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic Acid Anilides 2a-z, 3a-i.
A. A mixture of ester 1 (2.59 g, 0.01 mol), the corresponding aniline (0.01 mol) and DMF (1 ml) was held in a
metal bath for 3-5 min at 160ºC. When the heating was complete the hot reaction mixture was treated with
ethanol (15-20 ml) (Care ! The solution may boil over vigorously) and carefully triturated. This process stopped
solidification of the reaction mass and significantly eased the separation and subsequent purification of the final
product. The precipitated anilides 2a-z or 3a-i were filtered, washed with alcohol, dried, and crystallized from
DMF.
B. N,N-Carbonyldiimidazole (1.78 g, 0.011 mol) was added to a solution of acid 4 (2.31 g, 0.01 mol) in
anhydrous DMF (30 ml) protected from atmospheric moisture by a CaCl2 tube and held at a temperature not
greater than 40ºC until CO2 evolution ceased (~ 5 h). The corresponding aniline (0.01 mol) was added, the
reaction mixture heated to 90ºC, held at this temperature for 2 h, cooled, and diluted with acidified HCl water.
The precipitated anilides 2 or 3 were filtered off, washed with water, and dried.
1538

The identical nature of anilides 2 or 3 prepared by the different methods were proved by the absence of
melting point depression for mixed samples and from their 1H NMR spectra.
The authors thank the National Institute for Allergic and Infectious Diseases (USA) for carrying out a
study of the antitubercular properties of the compounds synthesized by us under the TAACF (Tuberculosis
Antimicrobial Acquisition and Coordination Facility) program (contract No. 01-AI-45246).
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