Methods for the synthesis of fluorine-containing derivatives of quinolones, quinazolinones, and benzothiaz- inones based on the interaction of polyfluorobenzoic ...
Pharmaceutical Chemistry Journal
Vol. 42, No. 4, 2008
SYNTHESIS AND TUBERCULOSTATIC ACTIVITY OF FLUORINE-CONTAINING DERIVATIVES OF QUINOLONE, QUINAZOLINONE, AND BENZOTHIAZINONE É. V. Nosova,1 G. N. Liponova,1 M. A. Kravchenko,3 A. A. Laeva,1 and V. N. Charushin2 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 4, pp. 14 – 18, April, 2008. Original article submitted June 15, 2006.
Methods for the synthesis of fluorine-containing derivatives of quinolones, quinazolinones, and benzothiazinones based on the interaction of polyfluorobenzoic acid chloranhydrides with N,N- N,C-, and N,S-dinucleophiles are described. Use of (tetrafluorobenzoyl)isothiocyanate as the fluorine-containing block provides extensive opportunities for the synthesis of 2-substituted benzothiazinones. Some of the fluorinecontaining azaheterocyclic compounds synthesized here had moderate and high activity against Mycobacterium tuberculosis H37Rv.
Interest in the synthesis of polycyclic fluorine-containing derivatives of azaheterocyclic compounds arises because of the wide spectrum of their biological activities. Thus, fluoroquinolones are known as highly active antibacterial agents [1 – 3]. Polycyclic fluoroquinolones include compounds with other types of biological activity [4], including highly effective tuberculostats [5]. We have found compounds with quite high levels of tuberculostatic activity among the bi- and tricyclic fluoroquinolones [6]. A series of condensed quinazolinone derivatives included antibacterial, antitoxoplasma, and antihypertensive agents, phosphodiesterase inhibitors, and compounds with other types of activity [7, 8]. The search for new antituberculous agents remains a current task because of increases in the incidence of tuberculosis and the rapid development of therapeutic resistance to existing tuberculostats. We have previously developed a method for the synthesis of [a]-annealed fluroquinolones [9] and [a]-annealed quinazolinones [10 – 12], as well as 2-substituted benzothiazinones [9] and [b]-annealed benzothiazinones [13]. There is interest in studying their tuberculostatic activity. Synthesis of 6-benzoyl-7H-benzimidazo[3,2-a]quinolones (I) was based on intramolecular cyclization of the 1 2 3
product of the interaction of tetra(penta)fluorobenzoyl chloride with 2-benzoylmethylbenzimidazole [9] with subsequent substitution of the fluorine atom in position 2 by an amine residue. Interaction of tetra(penta)fluorobenzoyl chloride with N,N¢-dinucleophiles (N-N¢-diphenylguanidine, 2-aminoazoles) yielded 2-imino-1,3-diphenylquinazolin-4ones (II) [10], 6H-pyrido[1,2-a]quinazolin-6-ones (III) [11], pyrazolo[1,5-a]-, triazolo[1,5-a]quinazolin-5-ones (IV) [10], and benzthiazolo[3,2-a]quinazolin-4-ones (V) [12]. The reactions of 2-cyanomethyl or 2-benzoylmethylbenzimidazole with polyfluorobenzoylisothiocyanate yielded 1,3-benzothiazinones (VII) [9]. Interaction of imidazolinand benzimidazol-2-thiones with tetra(penta)fluorobenzoylchloride formed derivatives of imidazo-2,1-b][1,3]benzothiazinone (VIII, IX) [13]. [a]-Annealed quinolones (I) have been described in [9], quinazolinones (II, IV) in [10], and [a]-annealed quinazolinones (IIIa, b) in [11]; (V) and (VIa) have been described in [12], 1,3-benzothiazinones (VII) in [9] and (VIII and IX) in [13]. In the present report, we present a method for the synthesis of previously undescribed derivatives (IIIc) and (VIb – m). 2-Substituted 1,3-benzothiazinones (VI) were synthesized from two types of fluorine-containing starting compounds. Thus, heating of polyfluorobenzoylchlorides (X) with thioamides in toluene led to formation of 2-aryl- or 2-(pyridyl-2-yl)benzothiazin-4-ones (VIc, h, i, j) with yields of 62 – 76% (see Scheme 1); the intermediate N-acylated derivatives in these conditions could not be detected.
Urals State Technical University, Ekaterinburg. I. Ya. Postovskii Institute of Organic Synthesis, Urals Branch, Russian Academy of Sciences, Ekaterinburg. State Science Research Institute “Ftiziopul’monologiya,” Ministry of Health of the Russian Federation, Ekaterinburg.
169 0091-150X/08/4204-0169 © 2008 Springer Science+Business Media, Inc.
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É. V. Nosova et al. Y
O
O
O
F
F
Ph
R
N
N
R
NH
N
F
II
Y = R = F (a), Y = H, R = pyrrolidin-1-yl (b), Y = H, R = morpholin-4-yl (c)
R = morpholin-4-yl (a), 4-methylpiperidin-1-yl (b)
O F
O F
N
R
NH
Ph
F
I
Ph
N
Y F
NH
F
N
F
N
R
X
N
F
O
N
S
F 1
1
V III
R
IV
R
V
1 X = CH, R = H (a), Ph (b), R = morpholin-4-yl, 1 X = N, R = CF3 (c) 1 R = H (a), CH3 (b), 1 R = 4-ethoxycarbonylpiperazin-1-yl, R = CH3 (c)
Synthesis of thioamides was in some cases difficult, which restricted variation in the substituents at position 2 of benzothiazin-4-one. Wider possibilities were made available by using (polyflourobenzoyl)isothiocyanate (XI) as the fluorine-containing block, this being prepared from polyfluorobenzoylchloride (X). The reaction of cycloalkylimines with
Y
O
F
Y N
1
S
R
F
O
F R
N R
S
F F
VI
VII
HN
NH
1
R
R = F, Y = R 1 = H (a), Y = H, R 1 = OCH3 (b), Y = R = pyrrolidin-1-yl, 1 R = OCH3 (c)
solutions of compound (XI) with heating in the presence of triethylamine yielded 2-cycloalkylimino[1,3]-benzothiazepin-4-ones (VIk – m) with yields of 70 – 75% without detection of intermediate thioureas. Attachment of 2-aminopyridine and 2-aminopyrimidine to (polyfluorobenzoyl)isothiocyanates (XI) occurred smoothly in acetonitrile at room temperature to form compounds (XII). Cyclization of thiourea (XII) to form [1, 3]-benzothiazin-4-one occurred with boiling in toluene in the presence of triethylamine for 3 h or in dimethylsulfoxide (DMSO) for 3 min with yields of 87 – 90%. Heating of 2-hydrazino-4,6-dimethylpyrimidine with (tetrafluorobenzoyl)isothiocyanate in acetonitrile for 1 h led to the formation of compound (VIb) (see Scheme 1). The structures of 2-R-benzothiazin-4-ones (VIb – m) were confirmed by 1H and 13F NMR spectroscopy and mass spectrometry (see Chemical Methods).
O
CHEMICAL METHODS
F
CH3
N S
R
N 1
R
F
N
VIII
O 1
R
F
N
N H3C
S F IX
N
2-Methyl-8,10-difluoro-9-(4-ethoxycarbonylpiperazin1-yl)-6H-pyrido[1,2-a]quinazolin-6-one (IIIc). 1-Ethoxycarbonylpiperazine (1.6 ml, 10 mmol) was added to 0.6 g of 2-methyl-8,9,10-trifluoro-6H-pyrido[1,2-a]quinazolin-6-one (2.4 mmol) in 5 ml of dimethylformamide. The reaction mix was boiled for 5 h; after cooling, the precipitate of derivative (IIIc) was collected by filtration and recrystallized from ethanol. The yield was 0.66 g (67.8%). The melting point was 112 – 114°C. The 1H NMR spectrum (DMSO-d6), d, ppm, was: 1.22, t (3H, CH3); 2.3, d (3H, CH3, J4 0.9 Hz); 3.33, t
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Scheme 1 Y
O
Y
F
Cl
F
F F
O
F
N=C=S
F X
F
CH3
XI
F
N
NH S R
Het-NH2
Y
S
O NHHet
N H
F N
F
NHNH2
S
O
O
F
N
NH2
F Y
H 3C
F
N
F
S
F XII
F
CH3
N
F VI b
R
N N H H
N CH3
F VI c,h – m
Y
O
F
N S
F
NHHet
F VI d – g
(4H, N(CH2)2); 3.53, m (4H, N(CH2)2); 4.08, q (2H, OCH2); 7.48, d (1H, J3 9.2 Hz, 4-H); 7.63, dd (1H, J3 9.3 Hz, J4 1.9 Hz, 3-H); 7.72, dd (1H, J3 12.1 Hz, J5 1.6 Hz, 7-H); 8.56, s (1H, 1-H). The atomic formula was C20H20F2N4O3. 2-(4,6-Dimethylpyrimidin-2-yl)hydrazino-6,7,8-triflu oro[1,3]benzothiazin-4-one (VIb). A solution of 8 mmol of tetrafluorobenzoylisothiocyanate in acetonitrile was added to a suspension of 0.55 g (4 mmol) of 2-hydrazino-4,6-dimethylpyrimidine in 10 ml of anhydrous acetonitrile. The reaction mixture was held at room temperature for 30 min and was then boiled for 1 h, after which it was evaporated to one quarter of its volume. The resulting precipitate of benzothiazinone (VIb) was collected by filtration and recrystallized from DMSO. The yield was 0.85 g (67.3%) and the melting temperature was > 250°C. The 1H NMR spectrum, d, ppm, was: 2.28, s (6H, 2CH3); 6.58, s (1H, 5¢-H); 7.94, ddd (1H, J3 10.0 Hz, J4 7.8 Hz, J5 2.0 Hz, 5-H); 11.0, broad s (1H, NH); 11.9, broad s (1H, NH). The 19F NMR spectrum, dF, ppm, was: 9.48, m (1F); 26.70, m (1F); 26.93, m (1F). The mass spectrum, m/z (Irel, %), was: 353 [M+] (85), 191 (30), 190 (20), 164 (10), 163 (100), 162 (21), 123 (35), 109 (12), 108 (40), 107 (15), 96 (15), 93 (14), 67 (30), 66 (11). The atomic formula was C14H10F3N5OS. 6,7,8-Trifluoro-2-phenyl[1,3]benzothiazin-4-one (VIc). The chloranhydride of tetrafluorobenzoic acid (1.6 ml, 7 mmol) was added to 0.5 g (3.6 mmol) of benzthioamide in 8 ml of dry toluene. The reaction mix was boiled for 3 h and then cooled. The resulting precipitate of derivative (VIc) was collected by filtration and recrystallized from DMSO. The yield was 0.8 g (76.4%) and the melting point was 160 – 162°C. The 1H NMR spectrum, d, ppm, was: 7.62, m,
(2H); 7.73, m (1H); 8.15, ddd (1H, J3 10.3 Hz, J4 7.4 Hz, J5 2.2 Hz, 5-H); 8.19, m (2H). The 19F NMR spectrum (DMSO-d6), dF, ppm, was: 151.84, ddd (1F, J3 22.5 Hz, J3 21.5 Hz, J4 7.4 Hz, 7-F); 135.10, ddd (1F, J3 21.5 Hz, J4 6.2 Hz, J5 2.2 Hz, 8-F); 132.50, ddd (1F, J3 22.5 Hz, J3 10.3 Hz, J4 6.2 Hz, 6-F). The mass spectrum, m/z (Irel, %), was: 293 [M+] (11), 190 (100), 162 (30). The atomic formula was C14H6F3NOS. Compounds (VIh – k) were synthesized by the same method. 6,7,8-Trifluoro-2-(pyridin-2-yl)[1,3]benzothiazin-4-one (VIh). The yield was 76.5% and the melting point was 166 – 168°C. The 1H NMR spectrum, d, ppm, was: 7.75, dd (1H, J3 8.0 Hz, J3 4.0 Hz, 5¢-H); 8.10, td (1H, J3 8.0 Hz, J4 1.8 Hz, 4¢-H); 8.13, ddd (1H, J3 10.4 Hz, J4 7.4 Hz, J5 2.2 Hz, 5-H); 8.38, d (1H, J3 8.0 Hz, 3¢-H); 8.79, dd (1H, J3 4.0 Hz, J4 1.8 Hz, 6¢-H). The 19F NMR spectrum, dF, ppm, was: 11.05, ddd (1F, J3 22.5 Hz, J3 21.1 Hz, J4 7.4 Hz, 7-F); 27.36, ddd (1F, J3 21.1 Hz, J4 6.2 Hz, J5 2.2 Hz, 8-F); 30.30, ddd (1F, J3 22.5 Hz, J3 10.4 Hz, J4 6.2 Hz, 6-F). The atomic formula was C13H5F3N2OS. 5,6,7,8-Tetrafluoro-2-(4-chlorophenyl)[1,3]benzothiazin-4-one (VIi). The yield was 62.6% and the melting point was 186 – 188°C. The 1H NMR spectrum, d, ppm, was: 7.66, d (2H, J3 8.8 Hz, 3¢,5¢-H); 8.20, d (2H, J3 8,8 Hz, 2¢,6¢-H). The atomic formula was C14H4F4NOSCl. 6,7,8-Trifluoro-2-( p-tolyl)[1,3]benzothiazin-4-one (VIj). The yield was 71.2% and the melting point was 184 – 186°C. The 1H NMR spectrum, d, ppm, was: 2.46, s (3H, CH3); 7.43, d (2H, J3 8.0 Hz, 3¢,5¢-H); 8.09, d (2H, J3 8.0 Hz,
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É. V. Nosova et al.
TABLE 1. Tuberculostatic Activity of [a]-Annealed Fluoroquinolones (I), Quinazolinones (II), and [a]-Annealed Quinazolinones (III – V) Compound
MIC, mg/ml
Ia Ib Ic IIa IIb IIIa IIIb IIIc IVa IVb IVc Va Vb Vc
6.25 1.56 12.5 > 12.5 > 12.5 3.12 1.56 0.3 0.62 12.5 12.5 12.5 12.5 12.5
2¢,6¢-H); 8.14, ddd (1H, J3 10.0 Hz, J4 7.5 Hz, J5 2.3 Hz, 5-H). The atomic formula was C15H8F3NOS. 6,7,8-Trifluoro-2-(pyridin-2-yl)[1,3]benzothiazin-4-one (VIk). The yield was 77.1% and the melting point was 182 – 184°C. The 1H NMR spectrum, d, ppm, was: 7.76, ddd (1H, J3 8.0 Hz, J3 4.8 Hz, J4 0.8 Hz, 5¢-H); 8.10, td (1H, J3 8.0 Hz, J4 1.8 Hz, 4¢-H); 8.36, dd (1H, J3 8.0 Hz, J3 0.8 Hz, 3¢-H); 8.79, dd (1H, J3 4.8 Hz, J4 1.8 Hz, 6¢-H). The atomic formula was C13H4F4N2OS. 6,7,8-Trifluoro-2-(pyridin-2-yl)amino[1,3]benzothiazin4-one (VId). A solution of 0.3 g (0.9 mmol) of thiourea (IIIa) in 3 ml of DMSO was boiled for 3 min and the resulting precipitate of VId was collected by filtration and recrystallized from DMSO. The yield was 0.25 g (90.2%) and the melting point was 202 – 204°C. The 1H NMR spectrum, d, ppm, was: 7.16, ddd (1H, J3 8.0 Hz, J3 5.0 Hz, J4 0.5 Hz, 5¢-H); 7.29, dd (1H, J3 8.0 Hz, J4 0.5 Hz, 3¢-H); 7.81, td (1H, J3 8.0 Hz, J4 1.5 Hz, 4¢-H); 7.97, ddd (J3 9.8 Hz, J4 7.5 Hz, J5 2.3 Hz, 5-H); 8.41, dd (1H, J3 5.0 Hz, J4 1.5 Hz, 6¢-H); 12.2. broad s (1H, NH). The 19F NMR spectrum, dF, ppm, was: 10.12, m (1F); 26.20, m (1F); 27.37, m (1F). The mass spectrum, m/z (Irel, %), was: 309 [M+] (30), 308 (19), 190 (19), 162 (23), 119 (100), 78 (35). The atomic formula was C13H6F3N3OS. Compounds (VId – g) were synthesized by the same method. 6,7,8-Trifluoro-2-(pyrimidin-2-yl)(amino[1,3]benzothiazin-4-one (VIe). The yield was 89.1% and the melting point was 262 – 264°C. The 1H NMR spectrum, d, ppm, was: 7.27, t (1H, J3 4.9 Hz, 5¢-H), 8.02, ddd (1H, J3 10.0 Hz, J4 7.7 Hz, J5 2.2 Hz, 5-H), 8.78, d (1H, J3 4.9 Hz, 4¢-H), 12.5, broad s (1H, NH). The 19F NMR spectrum, dF, ppm, was: 10.09, m (1F), 27.35, m (1F), 27.92, m (1F). The mass spectrum, m/z
(Irel, %), was: 310 [M+] (40), 191 (13), 190 (100), 162 (43), 120 (25). The atomic formula was C12H5F3N4OS. 5,6,7,8-Tetrafluoro-2-(pyrimidin-2-yl)amino[1,3]benzothiazin-4-one (VIf). The yield was 87.4% and the melting point was 279 – 281°C. The 1H NMR spectrum, d, ppm, was: 7.25, t (1H, J3 5.0 Hz, 5¢-H); 8.75, d (1H, J3 5.0 Hz, 4¢-H); 12.4, broad s (1H, NH). The 19F NMR spectrum, dF, ppm, was: 6.05, m (1F); 13.78, m (1F); 21.19, m (1F); 25.52, m (1F). The mass spectrum, m/z (Irel, %), was: 328 [M+] (40), 209 (12), 208 (100), 180 (38), 148 (12), 120 (54). The atomic formula was C12H4F4N4OS. 5,6,7,8-Tetrafluoro-2-(pyridin-2-yl)amino[1,3]benzothiazin-4-one (VIg). The yield was 88.4% and the melting point was 220 – 222°C. The 1H NMR spectrum, d, ppm, was: 7.14, ddd (1H, J3 7.8 Hz, J3 5.0 Hz, J4 0.8 Hz, 5¢-H); 7.29, dd (1H, J3 7.8 Hz, J4 0.8 Hz, 3¢-H); 7.79, td (1H, J3 7.8 Hz, J4 1.5 Hz, 4¢-H); 8.38, dd (1H, J3 5.0 Hz, J4 1.5 Hz, 6¢-H); 12.2, broad s (1H, NH). The 19F NMR spectrum, dF, ppm, was: 5.52, m (1F); 13.11, m (1F); 20.97, m (1F); 25.40, m (1F). The mass spectrum, m/z (Irel, %), was: 327 [M+] (28), 326 (15), 208 (21), 180 (22), 120 (12), 119 (100), 78 (56), 51 (12). The atomic formula was C13H5F4N3OS. 5,6,7,8-Tetrafluoro-2-(morpholin-4-yl)[1,3]benzothiazin-4-one (VIm). A solution of 0.35 g (4.5 mmol) of NH4SCN in 5 ml of acetone was added to a solution of 0.86 g (4.5 mmol) of pentafluorobenzoylchloride in 1.5 ml of toluene. The mixture was kept at 40°C for 5 min and NH4Cl was removed by filtration. The filtrate was supplemented with a solution of 0.39 ml (4.5 mmol) of morpholine in 5 ml of acetone. The reaction mixture was held at room temperature for 3 h and then evaporated. The residue was supplemented with 15 ml of toluene and 1.25 ml (0.91 g, 9 mmol) of Net3. The reaction mixture was boiled for 3 h; after cooling, the precipitate of compound (VIm) was collected by filtration and recrystallized from ethanol. The yield was 68.4% and the melting point was 153 – 155°C. The 1H NMR spectrum, d, ppm, was: 3.71, m (4H, N(CH2)2); 3.82, m (4H, O(CH2)2). The mass spectrum, m/z (Irel, %), was: 320 [M+], (14), 208 (100), 180 (21), 209 (11). The atomic formula was C12H8F4N2OS. 6,7,8-Trifluoro-2-(4-ethoxycarbonylpiperazin-1-yl)[1,3]benzothiazin-4-one (VIl). The yield was 75.3% and the melting point was 131 – 133°C. The 1H NMR spectrum, d, ppm, was: 1.21, t (3H, CH3), 3.54, m (4H, N(CH2)2), 3.87, m (4H, N(CH2)2), 4.09 q (2H, OCH2), 8.05, ddd (1H, J3 10.2 Hz, J4 7.2 Hz, J5 2.1 Hz, 5-H). The mass spectrum, m/z (Irel, %), was: 373 [M+], (17), 190 (94), 258 (70), 162 (30), 128 (81), 56 (100). The atomic formula was C15H14F3N3O3S. Elemental analysis data for all the compounds synthesized corresponded to calculated values.
Synthesis and Tuberculostatic Activity of Fluorine-containing Derivatives
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TABLE 2. Tuberculostatic Activity of Fluorine-Containing Benzothiazinones (VI, VII) and [b]-Annealed Benzothiazinones (VIII, IX) Compound
R
R1
Y
MIC, mg/ml
VIa VIb VIc VId VIe VIf VIg VIh VIi VIj VIk VIl VIm VIIa VIIb VIICc VIId VIIIa VIIIb VIIIc IX
morpholin-4-yl (4,6-dimethylpyrimidin-2-yl)hydrazino Ph (pyridin-2-yl)amino (pyrimidin-2-yl)amino (pyrimidin-2-yl)amino (pyridin-2-yl)amino pyridin-2-yl n-ClC6H4 n-CH3C6H4 pyridin-2-yl 4-ethoxycarbonylpiperazin-1-yl morpholin-4-yl CN COPh CN COPh morpholin-4-yl 4-ethoxycarbonylpiperazin-1-yl pyrrolidin-1-yl 4-methylpiperidin-1-yl
morpholin-4-yl F F F F F F F F F F F F – – – – – – – F
H H H H H F F H F H F H F H F F H – – – 4-methylpiperidin-1-yl
0.36 12.5 50 12.5 12.5 12.5 12.5 0.3 6.25 > 12.5 > 12.5 12.5 12.5 0.36 6.25 12.5 12.5 0.1 50 50 3.12
BIOLOGICAL METHODS MIC values were measured at the Science Research Institute of Phthysiopulmonology by the absolute concentrations method on “Novaya” medium using the laboratory strain of Mycobacterium tuberculosis H37Rv. Samples of cultures of the laboratory strains were placed in sterile porcelain jars and ground to homogeneity, gradually adding sterile physiological saline. The resulting culture suspension was standardized in terms of a bacterial turbidity standard corresponding to 500 million cells (5 State Control Institute units). Agent samples (10 mg) were placed in tubes and dissolved in 1 ml of DMSO followed by addition of 9 ml of water. Study substance conditions (12.8, 6.4, 3.2, 1.6, 0.8, 0.4, 0.3, 0.2, and 0.1 mg/ml) were prepared using distilled water. Media were kept in the inclined position for 20 min at 85°C and were then seeded with M. tuberculosis (0.2 ml), sealed with rubber bungs, and placed in an incubator the inclined position at 37°C. The effects of each agent concentration on M. tuberculosis were studied in three parallel series. Results were recorded every 10 days. The reference agent was isoniazid at concentrations of 1 and 5 mg/ml. RESULTS AND DISCUSSION The data presented in Table 1 show that among the [a]-annealed quinolone and quinazolinone derivatives, hig-
her levels of tuberculostatic activity were found with 6H-pyrido[1,2-a]quinazolin-4-ones (III) and pyrazolo[1,5-a]quinazolin-5-one (IVa). In the series of compounds (III), activity depended on the nature of the R and R1 substituents. The greatest activity (MIC 0.3 mg/ml) was seen with compound (IIIc), which had a methyl group at position 2 and a 4-ethoxycarbonylpiperazine moiety at position 9. A similar MIC value (0.62 mg/ml) was obtained with compound (IVa). Less active compounds were [a]-annealed quinolone derivatives (I), though activity in this series of compounds depended on the R substituent at position 10. Compound (Ib), with a pyrrolidine fragment at this position, was more active. The series of 2-substituted and [b]-annealed benzothiazinone derivatives included several compounds with high tuberculostatic activity (Table 2). Thus, fluorine-containing derivatives of quinolone, quinazolinone, and benzothiazinone showed marked tuberculostatic activity and potential for further searches for antituberculous substances. This study was supported by the Russian Foundation for Basic Research (Project Nos. 06-03-32747, 04-03-96107Ural, and 04-03-96011-Ural), the Ministry of Education, and the CRDF, Annex BF4MO5, EK-005-X2[REC-005], “BRHE 2004 Post-Doctoral Fellowship Award” Y2-C-05-01, and grants from the President of the Russian Federation, No. MK-1492.2005.03 and NSh-9178.2006.3.
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