4-Hydroxy-2-quinolones. 122. 1-Hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1- ij]-quinoline-2-carboxylic acid hetarylamides as potential antitubercular agents

Article abstract of DOI:10.1007/s10593-007-0137-3

An improved method is reported for the synthesis of a series of 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid hetarylamides. The antitubercular activity of all of the compounds prepared has been studied. The structure-biological activity dependence revealed is discussed.

Full text of DOI:10.1007/s10593-007-0137-3

Chemistry of Heterocyclic Compounds, Vol. 43, No. 7, 2007
4-HYDROXY-2-QUINOLONES. 122*. 1-HYDROXY-
3-OXO-5,6-DIHYDRO-3H-PYRROLO[3,2,1-ij]-
QUINOLINE-2-CARBOXYLIC ACID HETARYLAMIDES
AS POTENTIAL ANTITUBERCULAR AGENTS
I. V. Ukrainets, E. V. Mospanova, and L. V. Sidorenko
An improved method is reported for the synthesis of a series of 1-hydroxy-3-oxo-5,6-dihydro-
3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid hetarylamides. The antitubercular activity of all of the
compounds prepared has been studied. The structure – biological activity dependence revealed is
discussed.
Keywords: hetarylamides, 4-hydroxy-2-oxoquinoline-3-carboxylic acids, amidation, antitubercular
activity.
The tuberculosis epidemic touches the entire world and is becoming a more threatening problem for
contemporary human society. According to World Health Organization data this infection now infects every
third inhabitant of the planet. Every year tuberculosis takes away the lives of more than 3 million human beings,
running ahead of the unfortunate figure for malaria and other infection illnesses [2, 3]. This developing situation
cuts across not just its occurrence in many countries thus worsening their socio-economic conditions but it is
also seen in the appearance and global spread of multiresistant strains of the tubercular micobacterium for which
known agents fail [4, 5]. In this connection the search and development of novel, more active and less toxic
antimicrobacterial preparations has taken on an extreme urgency at this time. For resolution of such problems the
international TAACF program (Tuberculosis Antimicrobial Acquisition and Coordinating Facility) was set up
and under whose terms our current investigation was carried out, the aim being to synthesize and study the
antitubercular properties of the 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]-quinoline-2-carboxylic acid
hetarylamides 1, 2.
It is clear that amidation of the ethyl ester 3 in ethanol (used by us successfully in the synthesis of
1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid alkylamides [1]) did not give the
desired result in the preparation of the heteroanalogs 1 or 2. In addition, the previously [6] proposed length of
refluxing ester 3 with 40% excess hetarylamine in bromobenzene (up to 20 h) is effectively also a complication.
In our view, the 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid hetarylamides 1,
2 can be most conveniently prepared by simple heating of the mixture of ester 3 and the corresponding primary
_______
* For Communication 121 see [1].
__________________________________________________________________________________________
National University of Pharmacy, Kharkiv 61002, Ukraine; e-mail: uiv@kharkov.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1023-1033, July, 2007. Original article submitted March
27, 2006.
0009-3122/07/4307-0863©2007 Springer Science+Business Media, Inc.
863

864

865

866

867

or secondary hetarylamine at 160ºC for 3-5 min with an equimolar ratio of reagents. In principle, such reactions
occur quite readily in most cases with high yields without a solvent. However, on a comparatively large scale or
when using amines with high melting points it is advisable to add a small amount of high boiling solvent and this
leads to preparation of the final compounds with higher purity. It should be specially pointed out that the volume
of the added solvent should not be too large: an optimum amount being 1 ml per 0.01 mol otherwise the reaction
rate is significantly lower and the amidation needs several hours.
O
OH
O
OH
NH–R
OEt
H2N–R
HN
O
N
O
N
1a–y
3
N
R
170 oC
O
OH
N
OH
N
N
O
R
O
N
4
2a–c
1 a 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 = pyrimidin-2-yl, j R = pyrazin-2-yl, k R = thiazol-2-yl,
l R = 4-methylthiazol-2-yl, m R = 5-methylthiazol-2-yl, n R = 4-carbethoxymethylthiazol-2-yl,
o R = 4-(adamant-1-yl)thiazol-2-yl, p R = 1,3,4-thiadiazol-2-yl, q R = 5-methyl-1,3,4-thiadiazol-2-yl,
r R = 5-ethyl-1,3,4-thiadiazol-2-yl, s R = 5-propyl-1,3,4-thiadiazol-2-yl, t R = 5-isopropyl-1,3,4-thiadiazol-2-yl,
u R = benzimidazol-2-yl, v R = benzothiazol-2-yl, w R = 6-bromobenzothiazol-2-yl,
x R = 6-methylbenzothiazol-2-yl, y R = 4-(6-methylbenzothiazol-2-yl)phenyl;
2 a R = COOEt, b R = Ме·HCl, c R = CH2Ph·HCl
The tricyclic ester 3 is quite stable to heating and can be held at 215ºC without marked change [7].
However, under amidation conditions, it shows a tendency to partial fission of the ester group to give the
1-hydroxy-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinolin-3-one (4) which can contaminate the target amides 1 and 2.
1
A series of experiments carried out by us at various temperatures and using the H NMR spectra of the
unpurified material showed that, starting at 170ºC, the 2H-derivative 4 was actually formed in quite appreciable
amounts and increased at higher temperature. The 2H-quinolin-3-one 4 can be identified by the characteristic
signal for the H-2 proton at 5.72 ppm. Its good solubility allows a ready removal of this unwanted admixture
after only a single crystallization. None the less, to avoid forming this side product the temperature conditions
should be carefully observed and the reaction mixture not heated above 160ºC.
The 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid hetarylamides 1 and
2 (Table 1) are practically insoluble in water (with the exception of the hydrochlorides 2b,c) as colorless or light
yellow crystalline materials. Their structure was confirmed by 1H NMR spectroscopy, superposition of signals in
which was very rare and this allowed identification of all of the proton containing functional groups (Table 2).
868

The antitubercular activities of the synthesized hetarylamides 1 and 2 were studied by a radiometric
method [8, 9] using the BACTEC 12B culture medium [10]. The results of a primary microbiological screening
(the first level of the investigation) showed that many of the tested substances at initial concentration 6.25 µg/ml
in vitro showed clear antitubercular activity and inhibited the growth of Mycobacterium tuberculosis H37Rv
ATCC 27294 by 98-100% (Table 1). Compounds showing activity not less than 90% at this stage were carried
on to the next screening level to determine the actual minimum inhibitory concentration (MIC). Based on this
value (Table 1) the group of samples of interest for further study was reduced to five 1r-v since samples with an
MIC ≤ 1 µg/ml are generally considered as promising.
Comparison of the results for the microbiological investigation with the nature of the amide fragment
present on the heterocycle revealed that the series of 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]-
quinoline-2-carboxylic acid hetarylamides 1, 2 shows about the same structure – biological activity relationship
as seen in the 1R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid amides with the smallest (C(1) to C(3))
alkyl substituents on the quinolone ring nitrogen atom. Hence in the series of isomeric pyridylamides 1a-c the
dependence of the antitubercular activity on the position of the nitrogen atom in the pyridine ring (in the order
4 > 3 >>2) can be clearly traced whereas a hydroxyl or methyl group in a pyrid-2-ylamide residue (amides 1d-h)
deactivates the molecule. An analogous effect has also been seen in the corresponding 1R-4-hydroxy-2-oxo-
1,2-dihydroxyquinoline-3-carboxamides [11, 12]. In the case of the diazahetarylamide pyrazine derivatives
(amide 1j) the activity is always more than the isomeric pyrimidines (amide 1i) while the strength of the
antimicrobial activity of the thiadiazol-2-ylamides 1r-t is governed by the C(5) alkyl-substituent. Amongst the
thiazole derivatives (amides 1k-o) the antitubercular effect is also markedly strengthened by the presence of an
alkyl substituent at position 5. However, the reliability of this conclusion only refers to a methyl group since it is
known [13] that a long chain tetradecyl radical leads to total loss of the effect on the microbacterial cell. All of
the benzothiazol-2-ylamides, as do their analogous 1R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid
derivatives, actively inhibit the growth of the tuberculosis microbacterium. But if in the former, as judged by
their MIC values, the activity falls in the series of introduced substituents H > 6-Br > 6-CH3, then a completely
different pattern is seen in the latter [14]. At the same time, the role of the phenyl ring situated between the
quinoline-3-carbamide and the 6-methylbenzothiazole fragment (in amide 1y) is identical in all cases and it
totally eliminates any kind of antimicrobial properties [14]. The aza biostere of the benzothiazol-2-ylamide 1v
(benzimidazol-2-ylamide 1u) is of special interest. It was found experimentally that exchanging the sulfur atom
for a nitrogen atom led to a two fold lowering of the MIC and can therefore be considered as very favourable. In
the 4-substituted piperazin-1-ylamides 2a-c the tuberculosis bacterium proves completely immune although, e.g.
in fluoroquinolone antibiotics the presence of this heterocycle is considered as a structurally helpful fragment
[15].
EXPERIMENTAL
1H NMR Spectra for the compounds synthesized were recorded on a Bruker WM-360 instrument (360
MHz) for DMSO-d6 solvent and TMS internal standard. Ethyl 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]-
quinoline-2-carboxylate (3) was prepared as described in [7].
1-Hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic
Acid
Hetarylamides
(1a-y, 2a) (General Method). A mixture of ester 3 (2.59 g, 0.01 mol), the corresponding hetarylamine (0.01
mole), in DMF (1 ml) was stirred and held for 3-5 min at 160ºC. The reagents initially dissolved and then a
vigorous evolution of ethanol was observed. After this the amide product began to crystallize from the reaction
mixture. After cooling, ethanol 10-15 ml) was added and the product was triturated thoroughly. The precipitated
amides 1a-y or 2a were filtered off, washed with alcohol, dried, and crystallized from DMF.
869

1-Hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic Acid Piperazin-1-ylamide
hydrochlorides (2b,c). The piperazin-1-ylamides 2b,c obtained by the previous method were suspended in
ethanol (15 ml), gaseous HCl in ethanol was added to pH 3 (the precipitate dissolved) and the product was then
left for several hours in an ice bath. The crystals of the piperazin-1-ylamide hydrochlorides 2b,c were filtered
off, washed with ether, and dried.
The authors thank the US National Institute for Allergy and Infectious Diseases for carrying out this
study of the antitubercular properties of the compounds synthesized in accord with the TAACF (Tuberculosis
Antimicrobial Acquisition & Coordinating Facility) program (contract No. 01-A1-45246).
REFERENCES
1.
I. V. Ukrainets, N. L. Bereznyakova, and E. V. Mospanova, Khim. Geterotsikl. Soedin., 1015 (2007).
[Chem. Heterocycl. Comp., 43, 856 (2007)].
2.
3.
4.
5.
6.
7.
WHO Web Site. Links for an Overview of Tuberculosis Worldwide. http://www.who.int/tb/en/
L. S. Efferen, Curr. Opin. Pulm. Med., 3, 131 (1997).
A. Fraser, M. Paul, A. Attamna, and L. Leibovici, Int. J. Tuberc. Lung. Dis., 10, 19 (2006).
A. Faustini, A. J. Hall, and C. A. Perucci, Thorax, 61, 158 (2006).
A. Kutyrev and T. Kappe, J. Heterocycl. Chem., 34, 969 (1997).
I. V. Ukrainets, L. V. Sidorenko, O. V. Gorokhova, E. V. Mospanov, and O. V. Shishkin, Khim.
Geterotsikl. Soedin., 718 (2006). [Chem. Heterocycl. Comp., 42, 631 (2006)].
L. B. Heifets, in: L. B. Heifets (editor), Drug Susceptibility in the Chemotherapy 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.
8.
9.
10.
11.
S. H. Siddiqui, in: H. D. Isenberg (editor), Clinical Microbiology Procedures Handbook, Vol. 1,
American Society for Microbiology, Washington D.C. (1992), p. 5.14.2
I. V. Ukrainets, S. A. El Kayal, O. V. Gorokhova, L. V. Sidorenko, and T. V. Alexeeva, Visnyk
Farmatsii, No. 1 (37), 12 (2004).
12.
13.
14.
15.
I. V. Ukrainets, S. A. El Kayal, O. V. Gorokhova, and L. V. Sidorenko, Farm. Zhurn., No. 4, 47 (2004).
L. A. Petrushova, Dissertation of Candidates in Pharm. Sci., Kharkiv (2006).
Amjad Aby Sharkh, Dissertation of Candidates in Pharm. Sci., Kharkiv (2003).
G. A. Mokrushina, V. N. Charushin, and O. N. Chupakhin, Khim. –Farm. Zh., 29, No. 9, 5 (1995).
870