4-Hydroxy-2-quinolones 148. Synthesis and antitubercular activity of 1-hydroxy-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid N-R-amides

Article abstract of DOI:10.1007/s10593-008-0139-9

An improved method for the preparation of ethyl 1-hydroxy-3-oxo-6,7- dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate has been proposed and a series of hetarylamides has been synthesized from it. A comparative analysis has been carried out of the antitubercular activities of the synthesized compounds with the active structural analogs 4-hydroxy-2-oxo-1,2-dihydroquinoline-3 and 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxamides studied before.

Full text of DOI:10.1007/s10593-008-0139-9

Chemistry of Heterocyclic Compounds, Vol. 44, No. 8, 2008
4-HYDROXY-2-QUINOLONES
148*. SYNTHESIS AND ANTI-
TUBERCULAR ACTIVITY OF
1-HYDROXY-3-OXO-6,7-DIHYDRO-
3H,5H-PYRIDO[3,2,1-ij]QUINOLINE-
2-CARBOXYLIC ACID N-R-AMIDES
I. V. Ukrainets, A. A. Tkach, and L. A. Grinevich
An improved method for the preparation of ethyl 1-hydroxy-3-oxo-6,7-dihydro-3H,5H-
pyrido[3,2,1-ij]quinoline-2-carboxylate has been proposed and a series of hetarylamides has been
synthesized from it. A comparative analysis has been carried out of the antitubercular activities of the
synthesized compounds with the active structural analogs 4-hydroxy-2-oxo-1,2-dihydroquinoline-3 and
1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxamides studied before.
Keywords: hetarylamides, 4-hydroxy-2-oxoquinoline-3-carboxylic acids, amidation, antitubercular
activity, X-ray structural analysis.
The main problem in the treatment of tuberculosis is the rapid development of resistant pathogens of this
dangerous infection to antimicrobial preparations [2, 3]. According to WHO service multiple medicine resistant
tuberculosis is diagnosed today in an average of 7% of patients which can rapidly seriously destabilize to a
world wide epidemiological situation and develop into a global human threat [4]. Besides improving
prophylactic and diagnostic measures there is now an increase in developing three avenues of research, if not for
a removal agenda of the problem of polyresistant strains then at least to lowering their severity. The first of these
includes the development of strict control schemes via a short course of intensive chemotherapy using a
combination of already existing pharmaceutical agents which significantly inhibits the development of stability
towards it [4, 5]. The second route combines genetic investigation of decoding nucleotides in the
Mycobacterium tuberculosis genome in order to discover the genes responsible for the course of cell mutation
and hence suited to the development of antibiotic resistance [6, 7]. In the future such a route will certainly
permit conceptually novel agents and methods of attack of tuberculosis to develop. However, the value of the
third direction based on an empirical selection of a leading structure from a number of synthesized and then
pharmacologically studied compounds has not been exhausted at the present level of development of science.
_______
* For Communication 147 see [1].
__________________________________________________________________________________________
National University of Pharmacy, Kharkiv 61002, Ukraine; e-mail: uiv@kharkov.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1189-1202, August, 2008. Original article submitted
November 30, 2006.
956
0009-3122/08/4408-0956©2008 Springer Science+Business Media, Inc.

As a particular result of this it is almost impossible to forecast a priori the important parameters for many future
medicines and one substance rather than another can only stand out as the result of a detailed study of a broad
combination of actual properties. This report is a part of such an investigation.
Compounds with high antimicobacterial activity have previously been found by us amongst 1-hydroxy-
3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid heterylamides [8]. On this basis it was of
interest to exchange the trihydropyrrole nucleus annelated to the quinoline ring for a tetrahydropyridine. In
contrast to the completely planar pyrroloquinolone system [9] the pyridoquinolone atom skeleton is unlikely to
have a single planar disposition. Hence such a modification can give extremely useful information as to how the
part of the molecule undergoing structural change interacts with the biological target.
O
OH
O
OH
R
NH
OEt
H2N–R
CH(COOEt)3
O
N
O
N
NH
3a–z
2
1
4-(6-methylbenzothiazol-
2-yl)aniline
HN
N
R
Me
N
S
O
O
OH
N
O
OH
N
N
N
H
N
O
R
4
5a–c
3a R = pyridin-4-yl, b = R = pyridin-3-yl, c R = pyridin-2-yl, d R = 3-hydroxypyridin-2-yl,
e R = 3-methylpyridin-2-yl, f R = 4-methylpyridin-2-yl, g R = 5-methylpyridin-2-yl,
h R = 6-methylpyridin-2-yl, i R = pyridimin-2-yl, j R = thiazol-2-yl, k R = 4-methylthiazol-2-yl,
l R = 5-methylthiazol-2-yl, m R = 4-ethoxycarbonylmethylthiazol-2-yl, n R = 4-(1-adamantyl)thiazol-2-yl,
o R = 4-phenylthiazol-2-yl, p R = 4-(4-chlorophenyl)thiazol-2-yl, q R = 4-(4-bromophenyl)thiazol-2-yl,
r R = 5-methyl-1,3,4-thiadiazol-2-yl, s R = 5-ethyl-1,3,4-thiadiazol-2-yl, t R = 5-propyl-1,3,4-thiadiazol-2-yl,
u R = 5-isopropyl-1,3,4-thiadiazol-2-yl, v R = benzothiazol-2-yl, w R = 6-fluorobenzothiazol-2-yl,
x R = 4-chlorobenzothiazol-2-yl, y R = 6-bromobenzothiazol-2-yl, z R = 6-methylbenzothiazol-2-yl;
5a R = Me·HCl, b R = CH2Ph·HCl, c R = CHPh2·HCl.
The synthesis and purification of the starting ethyl 1-hydroxy-3-oxo-6,7-dihydro-3H,5H-pyrido-
[3,2,1-ij]quinoline-2-carboxylate (1) was carried out by treatment of 1,2,3,4-tetrahydroquinoline (2) with an
equimolar ratio of triethoxycarbonylmethane using a known method [10]. Thanks to the additional methylene
unit, the conformational mobility of the reaction centers in the tetrahydroquinoline is undoubtedly greater than
in the indoline. Hence the steric hindrance to acylation, and particularly to subsequent intramolecular
cyclization, must be less. In fact, the pyridoquinoline ester 1 is formed very readily and in high yields while any
anomalies observed in the reaction of triethoxycarbonylmethane with indoline [11] are not seen in this case.
957

TABLE 1. Characteristics of the 1-Hydroxy-3-oxo-6,7-dihydro-3H,5H-
pyrido[3,2,1-ij]quinoline-2-carboxylic Acid N-R-Amides 3-5
Found, %
——————
Calculated, %
Com-
pond
Empirical
formula
mp, °C
Yield, %
C
H
N
3a
3b
3c
3d
3e
3f
C18H15N3O3
67.37
67.28
67.34
67.28
67.25
67.28
64.01
64.09
68.15
68.05
68.13
68.05
68.04
68.05
68.10
68.05
63.26
63.35
58.77
58.70
59.74
59.81
59.73
59.81
58.15
58.10
67.58
67.66
65.55
65.49
60.40
60.34
54.71
54.78
56.16
56.13
57.35
57.29
58.30
58.36
58.45
58.36
63.60
63.65
60.82
60.75
58.38
58.32
52.55
52.64
64.40
64.44
69.42
69.36
59.34
59.42
65.56
65.52
69.76
69.83
4.79
4.71
4.76
4.71
4.66
4.71
4.39
4.48
5.17
5.11
5.18
5.11
5.05
5.11
5.15
5.11
4.30
4.38
4.09
4.00
4.48
4.43
4.39
4.43
4.70
4.63
5.81
5.90
4.20
4.25
3.77
3.68
3.26
3.34
4.04
4.12
4.60
4.53
4.97
4.90
4.88
4.90
4.11
4.01
3.65
3.57
3.36
3.43
3.03
3.09
4.29
4.38
4.60
4.53
6.00
6.09
5.90
5.96
5.77
5.86
13.00
13.08
13.12
13.08
13.02
13.08
12.53
12.46
12.61
12.53
12.64
12.53
12.46
12.53
12.44
12.53
17.29
17.38
12.95
12.84
12.22
12.31
12.36
12.31
10.07
10.16
9.03
9.10
10.48
10.41
9.52
9.60
8.65
8.71
16.30
16.36
15.79
15.72
15.03
15.12
15.17
15.12
11.09
11.13
10.71
10.63
10.27
10.20
9.26
9.21
10.65
10.73
9.05
8.99
11.64
11.55
9.47
9.55
8.03
8.14
183-185
169-171
196-198
191-193
164-166
215-217
226-228
267-269
217-219
203-205
225-227
230-232
184-186
288-290
241-243
267-269
286-288
210-212
177-179
173-175
195-197
294-296
329-331
345-347
303-305
296-298
277-279
261-263
236-238
217-219
93
94
89
80
81
92
95
95
82
90
88
89
85
91
94
90
95
84
82
86
88
95
90
89
96
92
90
80
77
83
C18H15N3O3
C18H15N3O3
C18H15N3O4
C19H17N3O3
C19H17N3O3
3g
3h
3i
C19H17N3O3
C19H17N3O3
C17H14N4O3
3j
C16H13N3O3S
C17H15N3O3S
C17H15N3O3S
C20H19N3O5S
C26H27N3O3S
C22H17N3O3S
C22H16ClN3O3S
C22H16BrN3O3S
C16H14N4O3S
C17H16N4O3S
C18H18N4O3S
C18H18N4O3S
C20H15N3O3S
C20H14FN3O3S
C20H14ClN3O3S
C20H14BrN3O3S
C21H17N3O3S
C27H21N3O3S
C18H21N3O3·HCl
C24H25N3O3·HCl
C30H29N3O3·HCl
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
3y
3z
4
5a
5b
5c
958

In the presence of a small amount of DMF (ensuring better mixing of the reagents and preventing local
superheating of the reaction mixture) ester 1 is amidated by primary and secondary amines at 160ºC in the
course of several minutes to give the 1-hydroxy-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-if]quinoline-
2-carboxylic acid N-R-amides 3-5 in good yields (Table 1).
All of the N-R-amides 3-5 are colorless, crystalline materials with sharp melting points and, with the
1
exception of the hydrochlorides 5a-c, are virtually insoluble in water. The overall H NMR spectra of the N-R-
amides 3-5 are extremely similar to the spectra of the corresponding 1-hydroxy-3-oxo-5,6-dihydro-3H-
pyrrolo[3,2,1-ij]quinoline-2-carboxylic acids [8]. The only significant difference is the two proton quintet at
high field (~ 2.0 ppm) due to the protons of the 6-methylene group in the pyridoquinolone ring (Table 2).
In the case of the 4-(1-adamantyl)thiazolyl-2-amide 3n an X-ray structural analytical study (see Fig. 1
and Tables 3 and 4) has confirmed the proposal above that the change from pyrroloquinolones to
pyridoquinolone has to cause a conformational restructuring of the molecule.
Fig. 1. The structure of the amide 3n molecule with atom numeration.
It was found that two molecules (A and B) exist in the independent part of the unit cell differing in some
geometric parameters. As in the case of the 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-
2-carboxylic acid amides [9], the quinolone fragment and atoms O(1}, C(10}, C(12}, O(2}, C(13}, O(3}, N(2}, and C(14}
lie in a single plane in both conformers to within 0.03 Å. This is likely due to the presence of the two
intramolecular hydrogen bonds: O(2)–H(2O)···O(3) (H···O 1.72 in A and 1.53 Å in B, O–H···O 160º in A and 150º
in B) and N(2)–H(2N)···O(1) (H···O 1.89 in A and 1.91 Å in B, N–H···O 140º in A and B). The formation of the
intramolecular hydrogen bonds also leads to lengthening of the bonds O(1)–C(9) to 1.245(4) in A and 1.254(5) in
B and O(3)–C(13) to 1.238(5) in A and 1.259(5) in B when compared to their mean value of 1.210 Å [12]. A
shortened intramolecular contact H(5a)···O(2) of 2.42 Å is found in the A molecule (sum of van der Waal radii
2.46 Å [13]). At the same time the "additional" C(11) atom deviates as expected from the mean square place
passing through the remaining ring atoms by 0.51 in molecule A and by -0.56 Å in B.
As a result of annelation with the quinolone ring the tetrahydropyridine ring takes on a chair type
conformation (folding parameters [14]: S = 0.58, θ = 39.6º, ψ = 7.3º for A and S = 0.68, θ = 36.1º, ψ = 1.9º for
B). A shortened intramolecular contact H(10b)···O(1) of 2.35 in A and 2.36 Å in B (2.46 Å) arises. The five
membered thiazole heterocycle is somewhat noncoplanar with the planar fragment (torsional angle C(130–N(20–
C(14)–S(1) -11.0(6) in A and 11.0(6)º in B and this is likely due to a repulsion between the carbonyl group oxygen
atom and the sulfur atom [shortened intramolecular contact S(1)···O(3) 2.77 Å in A and B (3.13 Å)]. The
adamantane substituent is placed in such a way that the C(18)–C(17) bond is virtually coplanar with the plane of
the thiazole ring (torsional angle C(18)–C(17)–C(15)–C(16) -11.1(6) in A and 10.0(6)º in B).
959

960

961

TABLE 3. Bond Lengths (l) in the Amide Structure 3n
Bond
S(1A)–C(14A)
l, Å
Bond
S(1A)–C(16A)
l, Å
1.706(5)
1.370(4)
1.462(5)
1.392(5)
1.386(5)
1.327(5)
1.393(5)
1.372(6)
1.402(7)
1.410(5)
1.403(5)
1.487(6)
1.514(7)
1.512(5)
1.536(6)
1.517(6)
1.543(7)
1.513(6)
1.527(6)
1.521(7)
1.726(4)
1.423(5)
1.319(5)
1.298(5)
1.254(5)
1.260(5)
1.428(6)
1.476(6)
1.370(6)
1.416(6)
1.435(6)
1.466(7)
1.347(6)
1.525(5)
1.558(5)
1.517(6)
1.519(6)
1.543(5)
1.568(6)
1.727(5)
1.391(4)
1.367(5)
1.285(5)
1.246(4)
1.238(5)
1.396(5)
1.492(6)
1.346(6)
1.437(5)
1.458(5)
1.482(7)
1.381(6)
1.510(6)
1.556(5)
1.520(7)
1.525(6)
1.535(6)
1.532(6)
1.710(4)
1.369(6)
1.491(5)
1.389(5)
1.397(5)
1.323(5)
1.400(6)
1.398(6)
1.364(6)
1.408(6)
1.376(5)
1.465(6)
1.455(7)
1.492(6)
1.542(6)
1.525(6)
1.522(7)
1.540(6)
1.496(6)
1.515(8)
N(1A)–C(1A)
N(1A)–C(10A)
N(2A)–C(14A)
N(3A)–C(15A)
O(2A)–C(7A)
C(1A)–C(6A)
C(2A)–C(3A)
C(3A)–C(4A)
C(5A)–C(6A)
C(7A)–C(8A)
C(8A)–C(13A)
C(11A)–C(12A)
C(15A)–C(17A)
C(17A)–C(24A)
C(18A)–C(19A)
C(19A)–C(26A)
C(21A)–C(23A)
C(23A)–C(25A)
C(25A)–C(26A)
S(1B)–C(14B)
N(1B)–C(1B)
N(2B)–C(13B)
N(3B)–C(14B)
O(1B)–C(9B)
O(3B)–C(13B)
C(1B)–C(2B)
C(2B)–C(12B)
C(4B)–C(5B)
C(6B)–C(7B)
C(8B)–C(9B)
C(10B)–C(11B)
C(15B)–C(16B)
C(17B)–C(22B)
C(17B)–C(18B)
C(19B)–C(20B)
C(20B)–C(21B)
C(21B)–C(22B)
C(24B)–C(25B)
N(1A)–C(9A)
N(2A)–C(13A)
N(3A)–C(14A)
O(1A)–C(9A)
O(3A)–C(13A)
C(1A)–C(2A)
C(2A)–C(12A)
C(4A)–C(5A)
C(6A)–C(7A)
C(8A)–C(9A)
C(10A)–C(11A)
C(15A)–C(16A)
C(17A)–C(18A)
C(17A)–C(22A)
C(19A)–C(20A)
C(20A)–C(21A)
C(21A)–C(22A)
C(24A)–C(25A)
S(1B)–C(16B)
N(1B)–C(9B)
N(1B)–C(10B)
N(2B)–C(14B)
N(3B)–C(15B)
O(2B)–C(7B)
C(1B)–C(6B)
C(2B)–C(3B)
C(3B)–C(4B)
C(5B)–C(6B)
C(7B)–C(8B)
C(8B)–C(13B)
C(11B)–C(12B)
C(15B)–C(17B)
C(17B)–C(24B)
C(18B)–C(19B)
C(19B)–C(26B)
C(21B)–C(23B)
C(23B)–C(25B)
C(25B)–C(26B)
All of the synthesized amides 3-5 underwent microbiological screening towards Mycobacterium
tuberculosis H37Rv ATCC 27294 using a radiometric method [15, 16]. It was found that some of the substances
tested at a concentration of 6.25 µg/ml in vitro showed high antitubercular activity and inhibited the tuberculosis
micobacterium growth by 99-100% (Table 5).
A comparative analysis of the antimicobacterial properties of amides 3-5 and their structural analogs (the
corresponding 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2- and 1-R-4-hydroxy-2-oxo-1,2-
dihydroquinoline-3-carboxylic acid hetarylamides with the smallest N1 alkyl substituents in the quinolone ring
showed the same dependence of observed antimicrobial activity on the heterocycle chemical structure in the
amide fragment of the molecule. Hence the pyridyl-4-amides are always more active than their 3-analogs and
these, in turn, markedly exceed in strength the antitubercular effect of the 2-isomers. Amongst the 3-hydroxy
series and some monomethyl-substituted pyridyl-2-amides the transition to the pyridoquinoline-
962

TABLE 4. Valence Angles (ω) in the Amide Structure 3n
Angle
1
ω, deg
2
Angle
3
ω,deg.
4
C(14A)–S(1A)–C(16A)
C(1A)–N(1A)–C(10A)
C(13A)–N(2A)–C(14A)
N(1A)–C(1A)–C(6A)
C(6A)–C(1A)–C(2A)
C(3A)–C(2A)–C(12A)
C(2A)–C(3A)–C(4A)
C(4A)–C(5A)–C(6A)
C(1A)–C(6A)–C(7A)
O(2A)–C(7A)–C(8A)
C(8A)–C(7A)–C(6A)
C(7A)–C(8A)–C(13A)
O(1A)–C(9A)–N(1A)
N(1A)–C(9A)–C(8A)
C(10A)–C(11A)–C(12A)
O(3A)–C(13A)–N(2A)
N(2A)–C(13A)–C(8A)
N(3A)–C(14A)–S(1A)
C(16A)–C(15A)–N(3A)
N(3A)–C(15A)–C(17A)
C(18A)–C(17A)–C(15A)
C(15A)–C(17A)–C(24A)
C(15A)–C(17A)–C(22A)
C(17A)–C(18A)–C(19A)
C(18A)–C(19A)–C(26A)
C(19A)–C(20A)–C(21A)
C(23A)–C(21A)–C(22A)
C(21A)–C(22A)–C(17A)
C(25A)–C(24A)–C(17A)
C(26A)–C(25A)–C(24A)
C(25A)–C(26A)–C(19A)
C(9B)–N(1B)–C(1B)
C(1B)–N(1B)–C(10B)
C(14B)–N(3B)–C(15B)
C(6B)–C(1B)–C(2B)
C(3B)–C(2B)–C(1B)
C(1B)–C(2B)–C(12B)
C(3B)–C(4B)–C(5B)
C(1B)–C(6B)–C(5B)
C(5B)–C(6B)–C(7B)
O(2B)–C(7B)–C(6B)
C(7B)–C(8B)–C(9B)
C(9B)–C(8B)–C(13B)
O(1B)–C(9B)–C(8B)
C(11B)–C(10B)–N(1B)
C(11B)–C(12B)–C(2B)
O(3B)–C(13B)–C(8B)
N(3B)–C(14B)–N(2B)
N(2B)–C(14B)–S(1B)
C(16B)–C(15B)–C(17B)
C(15B)–C(16B)–S(1B)
C(15B)–C(17B)–C(24B)
C(15B)–C(17B)–C(18B)
89.3(2)
120.2(3)
122.8(4)
120.7(3)
116.4(3)
119.3(4)
122.1(4)
118.9(4)
118.6(3)
120.8(4)
120.8(4)
119.1(4)
118.4(3)
117.4(3)
114.7(4)
123.6(4)
115.3(4)
116.4(3)
114.7(4)
118.2(4)
112.1(4)
111.4(3)
108.5(3)
112.4(4)
106.7(4)
108.8(4)
110.4(4)
110.3(3)
109.9(3)
108.1(4)
109.9(4)
122.1(4)
122.1(4)
111.0(4)
123.9(4)
115.9(4)
121.0(4)
120.4(4)
115.2(4)
125.1(4)
114.5(4)
120.3(4)
123.0(4)
121.2(4)
111.0(4)
112.5(4)
122.6(4)
120.9(4)
123.3(3)
128.0(4)
113.5(3)
110.0(3)
112.1(3)
C(1A)–N(1A)–C(9A)
C(9A)–N(1A)–C(10A)
C(14A)–N(3A)–C(15A)
N(1A)–C(1A)–C(2A)
C(3A)–C(2A)–C(1A)
C(1A)–C(2A)–C(12A)
C(5A)–C(4A)–C(3A)
C(1A)–C(6A)–C(5A)
C(5A)–C(6A)–C(7A)
O(2A)–C(7A)–C(6A)
C(7A)–C(8A)–C(9A)
C(9A)–C(8A)–C(13A)
O(1A)–C(9A)–C(8A)
N(1A)–C(10A)–C(11A)
C(2A)–C(12A)–C(11A)
O(3A)–C(13A)–C(8A)
N(3A)–C(14A)–N(2A)
N(2A)–C(14A)–S(1A)
C(16A)–C(15A)–C(17A)
C(15A)–C(16A)–S(1A)
C(18A)–C(17A)–C(24A)
C(18A)–C(17A)–C(22A)
C(24A)–C(17A)–C(22A)
C(18A)–C(19A)–C(20A)
C(20A)–C(19A)–C(26A)
C(23A)–C(21A)–C(20A)
C(20A)–C(21A)–C(22A)
C(21A)–C(23A)–C(25A)
C(26A)–C(25A)–C(23A)
C(23A)–C(25A)–C(24A)
C(16B)–S(1B)–C(14B)
C(9B)–N(1B)–C(10B)
C(13B)–N(2B)–C(14B)
C(6B)–C(1B)–N(1B)
N(1B)–C(1B)–C(2B)
C(3B)–C(2B)–C(12B)
C(4B)–C(3B)–C(2B)
C(4B)–C(5B)–C(6B)
C(1B)–C(6B)–C(7B)
O(2B)–C(7B)–C(8B)
C(8B)–C(7B)–C(6B)
C(7B)–C(8B)–C(13B)
O(1B)–C(9B)–N(1B)
N(1B)–C(9B)–C(8B)
C(12B)–C(11B)–C(10B)
O(3B)–C(13B)–N(2B)
N(2B)–C(13B)–C(8B)
N(3B)–C(14B)–S(1B)
C(16B)–C(15B)–N(3B)
N(3B)–C(15B)–C(17B)
C(15B)–C(17B)–C(22B)
C(22B)–C(17B)–C(24B)
C(22B)–C(17B)–C(18B)
123.4(3)
116.4(3)
110.5(3)
122.9(3)
120.2(4)
120.5(4)
119.1(4)
123.1(4)
118.3(4)
118.4(4)
119.1(4)
121.8(4)
124.2(3)
115.0(4)
111.2(4)
121.1(4)
119.0(4)
124.6(3)
126.8(4)
109.1(4)
108.5(4)
106.9(4)
109.3(3)
110.6(4)
110.3(5)
108.2(4)
109.7(4)
110.9(4)
108.1(4)
111.2(4)
87.3(2)
115.6(4)
128.1(4)
118.5(4)
117.6(4)
123.1(4)
122.0(4)
122.6(4)
119.6(4)
124.9(4)
120.6(4)
116.7(4)
120.2(4)
118.6(4)
114.7(5)
118.6(4)
118.8(4)
115.8(3)
112.1(4)
119.9(3)
108.6(3)
107.9(3)
109.4(3)
963

TABLE 4 (continued)
1
2
3
4
C(24B)–C(17B)–C(18B)
C(20B)–C(19B)–C(26B)
C(26B)–C(19B)–C(18B)
C(20B)–C(21B)–C(23B)
C(23B)–C(21B)–C(22B)
C(25B)–C(23B)–C(21B)
C(23B)–C(25B)–C(26B)
C(26B)–C(25B)–C(24B)
108.7(4)
108.4(4)
112.9(4)
110.7(4)
107.8(4)
109.3(4)
110.5(4)
109.9(5)
C(19B)–C(18B)–C(17B)
C(20B)–C(19B)–C(18B)
C(19B)–C(20B)–C(21B)
C(20B)–C(21B)–C(22B)
C(17B)–C(22B)–C(21B)
C(17B)–C(24B)–C(25B)
C(23B)–C(25B)–C(24B)
C(25B)–C(26B)–C(19B)
108.8(4)
108.5(4)
110.5(4)
108.3(4)
110.9(3)
109.5(3)
109.2(4)
109.1(4)
2-carboxylic acid derivative 3d-g unexpectedly led to a slight overall increase in activity. The effect of a methyl
group in position 6 of the pyridyl-2-amide residue was to fully deactivate the molecule in all cases
independently of the structure of the quinolone part. Amidation of the hydroxyquinoline carboxylic acids by
2-aminopyrimidine was also unhelpful since the specific activity of the compounds obtained in this way never
exceeded 20-25%. On the other hand, the thiazol-2-yl amides showed much higher and stable results. It was
found that substituents in position 4 or 5 of the thiazole generally increased the activity but they should not be
sterically bulky. Introduction of a second nitrogen atom into the five-membered ring (the 1,3,4-thiadiazolyl-
2-amides) proved even more favourable to antitubercular activity and almost always retained the ability to block
the growth of the tubercular micobacteria by 90-100% at low minimum inhibitory concentration (MIC). On the
other hand the structure of the quinolone fragment proved to have a more marked influence on the activity of the
benzothiazole derivatives. If the complete absence of antimicobacterial properties of a 4-(6-methyl-
benzothiazol-2-yl)anilide (4) was quite predictable the comparatively low activity of the benzothiazol-2-yl
amide 3v and also its halo (3w-y) and methyl (3z) analogs proved somewhat unexpected.
TABLE 5. Antitubercular Activity of Compounds 3-5
Inhibition
of the growth of M.
tuberculosis, %
Inhibition
of the growth of M.
tuberculosis, %
Com-
pound
Com
pound
MIC*, µg/ml
MIC*, µg/ml
3a
3b
3c
3d
3e
3f
100
57
14
17
58
13
15
0
6.25
—
3p
3q
3r
3s
3t
73
63
100
100
100
100
9
—
—
—
3.13
0.78
1.56
3.13
—
—
—
—
3u
3v
3w
3x
3y
3z
4
3g
3h
3i
—
—
39
25
100
20
0
—
20
99
100
100
100
18
32
—
—
3j
6.25
3.13
3.13
6.25
—
6.25
—
3k
3l
—
3m
3n
3o
5a
5b
5c
0
0
—
—
—
0
—
_______
* According to the criteria adopted in the TAACF (Tuberculosis
Antimicrobial Acquisition and Coordinating Facility), the actual MIC only
being determined for compounds showing activity not less than 90% in the
first stage.
964

In summarising our investigation it should be noted that annelation of the quinolone ring with the
tetrahydropyridine ring generally did not cardinally affect the antitubercular properties. In this case we can
conclude that the N(1)-alkyl substituents in the 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid
hetarylamides (in common with the trihydropyrrole or tetrahydropyridine fragments in the corresponding 1-hydroxy-
3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2- and 1-hydroxy-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quino-
line 2-carboxylic acid derivatives) did not play a direct role in the binding to the biological target. Most likely,
in some degree, it affects the ability to interact with receptors via one of the key functional groups (the carbonyl
at position 2 of the quinolone ring). The second such center is evidently the NH grouping in the amide fragment.
Confirmation of this comes from the repeated observation of full loss of activity in the secondary amides of
type 5.
EXPERIMENTAL
Commercial 1,2,3,4-tetrahydroquinoline and triethoxycarbonylmethane were obtained from the Fluka
company. 1H NMR spectra for the synthesized compounds were recorded on a Bruker WM-360 instrument (360
MHz) using DMSO-d6 and with TMS as internal standard.
Ethyl 1-hydroxy-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate (1). 1,2,3,4-
Tetrahydroquinoline (2) (12.5 ml, 0.1 mol) was added dropwise with stirring to triethoxycarbonylmethane
(21.1 ml, 0.1 mol) heated to 215ºC such that the reaction mixture temperature did not change outside the range
±5ºC from the initial value. The ethanol evolved in the process could be liberated via a fractionating column
without increasing the starting reagents. After the addition of all of the 1,2,3,4-tetrahydroquinoline the reaction
mixture was held for 10-15 min at the same temperature and then cooled to about 100ºC. Aqueous Na2CO3
solution (10%, 300 ml) was added and heated to 70-80ºC. The obtained solution of the 1-O-sodium salt of ester
1 was purified with carbon and filtered. After cooling, the filtrate was acidified with dilute (1:1) HCl to pH
4.5-5. The precipitated ester 1 was filtered off, washed with water, and dried. Yield 26.23 g (96%). Colorless
1
needles with mp 102-104ºC (hexane). According to data in [17] yellow needles with mp 101ºC. H NMR
spectrum, δ, ppm (J, Hz): 13.10 (1H, s, OH); 7.88 (1H, d, J = 8.0, H-10); 7.49 (1H, d, J = 7.3, H-8); 7.18 (1H, d,
J = 7.5, H-9); 4.33 (2H, q, J = 7.0, OCH2); 3.99 (2H, t, J = 5.6, NCH2); 2.94 (2H, t, J = 6.1, 7-CH2); 2.00 (2H,
quin, J = 6.0, 6-CH2); 1.32 (3H, t, J = 7.0, OCH2CH3).
1-Hydroxy-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic Acid N-R-amides 3a-z,
4 (General Method). A mixture of ester 1 (2.73 g, 0.01 mol), the corresponding primary amine (0.01 mol), and
DMF (1 ml) was stirred and held at 160ºC for 3-5 min. The starting reagents initially dissolved and then began
to crystallize out to the final amide after vigorous evolution of ethanol. Ethanol (10-15 ml) was added to the
uncooled reaction mixture (beware of sudden effervescence) and the product was thoroughly triturated. The
precipitated hetarylamide 3 or anilide 4 was filtered off, washed with alcohol, dried, and crystallized from DMF.
1-Hydroxy-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic Acid 4-R-piperazin-
1-ylamide Hydrochlorides 5a-c. The 4-R-piperazin-1-ylamide bases (0.01 mol) obtained by in the preceding
experiment were suspended in ethanol (10 ml) and a solution of gaseous HCl in ethanol was added to pH 3 (the
precipitate dissolved) after which it was left for several hours in an ice chest. The separated 4-R-piperazin-
1-ylamide hydrochloride crystals 5a-c were filtered off, washed with ether, and dried.
X-ray Crystallographic Study. Crystals of amide 3n are triclinic (DMF), at 20ºC: a = 7.293(1),
b = 11.298(1), c = 26.995(3) Å, α = 91.20(1)º, β = 91.74(1)º, γ = 90.06(1)º, V = 2222.8(4) Å3, Mr = 462.57,
Z = 4, space group P , dcalc = 1.382 g/cm3, µ(MoKα) = 0.181 mm-1, F(000) = 980. The unit cell parameters and
1
intensities of 18142 reflections (7800 independent, Rint = 0.057) were measured on an Xcalibur-3 diffractometer
(MoKα radiation, CCD detector, graphite monochromator, ω-scanning to 2θmax = 50º).
965

The structure was solved by a direct method using the SHELXTL program package [18]. The positions
of the hydrogen atoms were revealed from electron density difference synthesis and refined using the "riding"
model with Uiso = nUeq for a non-hydrogen atom bound to the given hydrogen (n = 1.5 for the hydroxyl group
and n = 1.2 for all remaining hydrogen atoms). The structure was refined in F2 full matrix least squares analysis
in the anisotropic approximation for non-hydrogen atoms to wR2 = 0.215 for 7609 reflections (R1 = 0.082 for
3121 reflections with F > 4σ (F), S = 1.080). The full crystallographic information has been placed in the
Cambridge structural data base (reference No. CCDC631476). The interatomic distances and valence angles are
given in Tables 3 and 4.
The authors thank the National Institute for Allergic Infectious Diseases (USA) for carrying out the
study within the TAACF program of the antitubercular properties of the compounds synthesized by us (contract
No. 01-A1-45246).
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