Antimycobacterial N-pyridinylsalicylamides, isosters of salicylamides

Article abstract of DOI:10.1016/j.farmac.2004.02.003

The series of derivatives of substituted N-pyridinylsalicylamides were synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium avium and two strains of Mycobacterium kansasii. In the quantitative structure activity relationships analysis (QSAR), the Free-Wilson and Hansch approaches were used but the analysis was not significant. (The standard deviations of regression coefficients were greater than the values of the coefficients). The molecules were separated the heterocyclic and salicyl moiety in the molecules, and the study of influences of substituents on salicyl moiety was used, as well. 5-Chloro-pyridin-2-yl, and the substitution of the salicyl moiety by chlorine in position 4 or 5 had the strongest influence on the increase in antimycobacterial activity.

Full text of DOI:10.1016/j.farmac.2004.02.003

IL FARMACO 59 (2004) 615–625
www.elsevier.com/locate/farmac
Antimycobacterial N-pyridinylsalicylamides, isosters of salicylamides
Karel Waisser a,*, Katerˇina Dražková a, Jirˇí Kuneš a, Veˇra Klimešová a, Jarmila Kaustová b
a Department of Inorganic and Organic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovsky Strasse 1203,
Hradec Kralove 50005, Czech Republic
b Department for the Diagnostics of Mycobacteria, Regional Institute of Public Health, Partyánské nán. 7, 72892 Ostrava, Czech Republic
Received 22 December 2003; accepted 19 February 2004
Available online 11 May 2004
Abstract
The series of derivatives of substituted N-pyridinylsalicylamides were synthesized. The compounds were evaluated for in vitro antimyco-
bacterial activity against Mycobacterium avium and two strains of Mycobacterium kansasii. In the quantitative structure activity relationships
analysis (QSAR), the Free–Wilson and Hansch approaches were used but the analysis was not significant. (The standard deviations of
regression coefficients were greater than the values of the coefficients). The molecules were separated the heterocyclic and salicyl moiety in the
molecules, and the study of influences of substituents on salicyl moiety was used, as well. 5-Chloro-pyridin-2-yl, and the substitution of the
salicyl moiety by chlorine in position 4 or 5 had the strongest influence on the increase in antimycobacterial activity.
© 2004 Elsevier SAS. All rights reserved.
Keywords: N-pyridinylsalicylamide; Tuberculostatics; Antimycobacterial activity; Mycobacterium
1. Introduction
Search for new antimycobacterial compounds is one of the
most challenging tasks of current medicinal chemistry. In
particular, the study of antimycobacterial properties of sali-
cylanilides [1,2] is of great interest, as salicylanilides can
inhibit the bacterial two-component systems [3,4], which can
also be important in mycobacteria. In our previous papers,
we systematically studied isosters of salicylanilides, i.e.
3-hydroxypicolinanilides [5], 2-sulfanylbenzanilides [5] and
N-benzylsalicylamides [6]. The goal of this paper was to
study the antimycobacterial activity of N-pyridinylsa-
licylamides. In the 20th century, the development of antimy-
cobacterial agents was directed towards antituberculotics and
antileprotics. However, while the diseases caused by poten-
tially pathogenic mycobacterial strains are rare in the human
population, they usually end up in a fatal way. Our attention
is thus concentrated on the potentially pathogenic mycobac-
terial strains as well [7].
Fig. 1. Synthesis of N-pyridinyl-2-hydroxy-benzamides (i.e. N-pyridinyl-
salicylanilides).
were prepared by the treatment of phenyl salicylates with
substituted amino pyridines. The structural assignment is
based on 1H NMR, 13C NMR and IR spectra. An overview of
the compounds under study is in Fig. 2.
2. Chemistry
3. Results and discussion
The synthetic pathway leading to N-pyridinylsali-
cylanilides is depicted in Fig. 1. N-pyridinylsalicylanilides
For the purpose of an initial investigation of structure–
activity relationships, we used the Free–Wilson and Hansch
approaches. We separated the molecules on heterocyclic and
* Corresponding author.
E-mail address: waisser@faf.cuni.cz (K. Waisser).
© 2004 Elsevier SAS. All rights reserved.
doi:10.1016/j.farmac.2004.02.003

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K. Waisser et al. / IL FARMACO 59 (2004) 615–625
salicyl moiety. We studied the influence of the substituents on
the heterocyclic and salicyl moieties. 5-Chloro-pyridin-2-yl,
and the substitution of the salicyl moiety by chlorine in
position 4 or 5 have the strongest influence on the increase in
antimycobacterial activity. The quantitative structure–anti-
mycobacterial activity was not statistically significant. (The
standard deviations of regression coefficients were greater
than the values of the coefficients.)
N-Pyridinylsalicylamides constitute a new group of po-
tential antituberculotics. Some compounds under study are
more active than INH against potentially pathogenic strains
(e.g. 4f, 5i, 6i, 7e, 7i, 7j).
J = 4.95 Hz, J = 0.97 Hz, H5′), 7.04 (dd, 1H, J = 8.11 Hz,
J = 1.37 Hz, H3), 7.02–6.95 (m, 1H, H5). 13C NMR
(75 MHz): d 164.3, 156.8, 151.8, 148.4, 138.6, 134.1, 131.0,
120.1, 120.0, 118.4, 117.3, 114.2.
4.1.1.2. N-(Pyridin-3-yl)-2-hydroxy-benzamide (1b). Pink
crystals. Yield 67%, m.p. 227–228 °C [8] 224–228°C. IR
(KBr): m (C=O) 1667 cm–1. 1H NMR (300 MHz): d 10.53 (bs,
1H, OH), 8.86 (d, 1H, J = 2.33 Hz, H2′), 8.33 (dd, 1H,
J = 4.67 Hz, J = 1.51 Hz, H6′), 8.15 (ddd, 1H, J = 8.24 Hz,
J = 2.33 Hz, J = 1.51 Hz, H4′), 7.93 (dd, 1H, J = 7.97 Hz,
J = 1.65 Hz, H6), 7.48–7.36 (m, 2H, H4, H5′), 7.03–6.92 (m,
2H, H3, H5). 13C NMR (75 MHz): d 167.1, 158.5, 145.2,
142.6, 135.2, 134.1, 129.5, 128.2, 123.9, 119.4, 117.8, 117.5.
4. Experimental
4.1.1.3. N-(Pyridin-4-yl)-2-hydroxy-benzamide (1c). Yellow
crystals. Yield 72%, m.p. 234–236 °C, IR (KBr): m (C=O)
1
1676 cm–1. H NMR (300 MHz): d 10.65 (bs, 1H, NH),
4.1. Chemistry
8.52–8.42 (m, H2′, H6′), 7.86 (dd, 1H, J = 7.70 Hz,
J = 1.65 Hz, H6), 7.75–7.70 (m, 2H, H3′, H5′), 7.47–7.39 (m,
1H, H4), 7.03–6.92 (m, 2H, H3, H5). 13C NMR (75 MHz): d
167.0, 157.8, 150.6, 145.5, 134.0, 129.9, 119.4, 118.8, 117.3,
114.4.
The melting points (m.p.) were determined on a Kofler
apparatus. The samples for analysis and antimycobacterial
tests were dried over phosphorous pentoxide at 61 °C and at
pressure 66 Pa for 24 h. Elemental analyses (C, H, N) were
performed on a CHNS–O CE elemental analyzer (Fisons EA
1110, Milano) and were within 0.4% of the theoretical
values. The IR spectra were measured in KBr pellets on a
Nicolet Impact 400 apparatus; the wave numbers are given in
cm–1. The bonding vibrations of the C=O group [m (C=O)]
were found in the region 1641–1691 cm–1.
4.1.1.4.
N-(5-Chloro-pyridin-2-yl)-2-hydroxy-benzamide
(1d). Yellow crystals. Yield 61%, m.p. 209–211 °C [8] 209–
211°C. IR (KBr): m (C=O) 1656 cm–1. 1H NMR (300 MHz,):
d 11.74 (bs, 1H, NH), 11.00 (bs, 1H, OH), 8.38 (d, 1H,
J = 2.61 Hz, H6′), 8.29 (d, 1H, J = 8.93 Hz, H3′), 8.01 (dd,
1H, J = 7.97 Hz, J = 1.92 Hz, H6), 7.95 (dd, 1H, J = 8.93 Hz,
J = 2.61 Hz, H4′), 7.49–7.41 (m, 1H, H4), 7.06–6.95 (m, 2H,
H3, H5). 13C NMR (75 MHz, DMSO): d 164.3, 156.8, 150.4,
146.8, 138.4, 134.3, 131.0, 125.7, 120.1, 118.2, 117.3, 115.2.
TLC was performed on silica gel plates precoated with a
fluorescent indicator Silufol UV 254 + 366 (Kavalier, Votice
Czech Republic), with petrolether/acetone (3:1) as the mo-
1
bile phase. The H NMR and 13C NMR spectra of new
compounds were recorded in DMSO-d6 solution at ambient
temperature on a Varian Mercury-Vx BB 300 spectrometer
operating at 300 MHz. Chemical shifts were recorded as d
values in parts per millions (ppm) and were indirectly refer-
enced to tetramethylsilane via the solvent signal (2.49 for 1H
or 39.7 for 13C).
4.1.1.5.
N-(4-Methyl-pyridin-2-yl)-2-hydroxy-benzamide
(1e). White crystals.Yield 58%, m.p. 202–204 °C, IR (KBr):
m (C=O) 1684 cm–1. 1H NMR (300 MHz): d 11.71 (bs, 1H,
NH), 10.85 (bs, 1H, OH), 8.18 (d, 1H, J = 5.22 Hz, H6′), 8.12
(s, 1H, H3′), 8.03 (dd, 1H, J = 8.10 Hz, J = 1.38 Hz, H6),
7.49–7.39 (m, 1H, H4), 7.04 (dd, 1H, J = 8.10 Hz,
J = 1.38 Hz, H3), 7.01–6.95 (m, 2H, H5, H5′), 2.34 (s, 3H,
CH3). 13C NMR (75 MHz): d 164.2, 156.8, 151.9, 149.4,
148.0, 134.1, 130.9, 121.0, 120.0, 118.4, 117.3, 114.7, 21.2.
4.1.1. Synthesis of N-pyridinylsalicylamides: general
procedure
A mixture of an amine (1 g) and phenyl salicylate
(1.2 equivalents) was melted at 190–210 °C for 90 min under
an air condenser. The reaction mixture was then heated at
reflux with ethanol for 10 min, filtered off and the product
was crystallized from the same solvent (yields 55–89%).
4.1.1.6.
N-(5-Methyl-pyridin-2yl)-2-hydroxy-benzamide
(1f). White crystals. Yield 55%, m.p. 218–220 °C, IR (KBr):
m (C=O) 1670 cm–1. 1H NMR (300 MHz): d 11.72 (bs, 1H,
NH), 10.84 (bs, 1H, OH), 8.18–8.13 (m, 2H, H3′, H6′), 8.04
(dd, 1H, J = 8.10 Hz, J = 1.38 Hz, H6), 7.64 (ddd, 1H,
J = 8.52 Hz, J = 2.47 Hz, J = 0.55 Hz, H4′), 7.47–7.39 (m,
1H, H4), 7.03 (dd, 1H, J = 8.10 Hz, J = 1.37 Hz, H3),
7.01–6.94 (m, 1H, H5), 2.25 (s, 3H, CH3).
4.1.1.1. N-(Pyridin-2-yl)-2-hydroxy-benzamide (1a). White
crystals. Yield 65%, m.p. 212–213 °C [8] 210–212°C. IR
(KBr): m (C=O) 1674 cm–1. 1H NMR (300 MHz): d 11.72 (bs,
1H, NH), 10.91 (bs, 1H, OH), 8.34 (ddd, 1H, J = 4.95 Hz,
J = 1.92 Hz, J = 0.97 Hz, H6′), 8.26 (d, 1H, J = 7.97 Hz, H3′),
8.04 (dd, 1H, J = 8.11 Hz, J = 1.37 Hz, H6), 7.87–7.79 (m,
1H, H4′), 7.48–7.40 (m, 1H, H4), 7.14 (ddd, 1H, J = 7.97 Hz,
4.1.1.7.
N-(6-Methyl-pyridin-2yl)-2-hydroxy-benzamide
(1g). White crystals.Yield 66%, m.p. 188–190 °C, IR (KBr):
m (C=O) 1679 cm–1. 1H NMR (300 MHz): d 11.68 (bs, 1H,

K. Waisser et al. / IL FARMACO 59 (2004) 615–625
617
NH), 10.82 (bs, 1H, OH), 8.08–8.01 (m, 3H, Ar), 7.71 (t, 1H,
J = 7.97 Hz, Ar), 7.47–7.40 (m, 1H, Ar), 7.06–6.95 (m, 3H,
Ar), 2.41 (s, 3H, CH3). 13C NMR (75 MHz): d 164.3, 157.0,
156.8, 151.1, 138.9, 134.1, 131.0, 120.0, 119.3, 118.4, 117.3,
111.2, 23.9.
167.4, 159.0, 145.2, 144.9, 142.7, 135.1, 129.2, 128.3, 123.8,
120.4, 117.7, 114.3, 21.3.
4.1.1.13. N-(Pyridin-4-yl)-2-hydroxy-4-methyl-benzamide
(2c). Beige crystals. Yield 61%, m.p. 264–266 °C, IR (KBr):
m (C=O) 1677 cm–1. 1H NMR (300 MHz): d 10.58 (bs, 1H,
OH), 8.49–8.44 (m, 2H, H2′, H6′), 7.83 (d, 1H, J = 7.69 Hz,
H6), 7.74–7.70 (m, 2H, H3′, H5′), 6.83–6.76 (m, 2H, H3,
H5), 2.29 (s, 3H, CH3). 13C NMR (75 MHz): d 167.3, 158.4,
150.5, 145.5, 144.9, 129.7, 120.5, 117.6, 115.1, 114.5, 21.3.
4.1.1.8. N-(3-Hydroxy-pyridin-2-yl)-2-hydroxy-benzamide
(1h). Brown crystals. Yield 71%, m.p. 256–259 °C, IR
(KBr): m (C=O) 1670 cm–1. 1H NMR (300 MHz): d 12.02 (bs,
1H, NH), 8.05–7.98 (m, 2H, H4′, H6′), 7.93 (dd, 1H,
J = 8.24 Hz, J = 1.10 Hz, H6), 7.57–7.50 (m, 1H, H4), 7.46
(dd, 1H, J = 7.96 Hz, J = 6.04 Hz, H5′), 7.21 (dd, 1H,
J = 8.24 Hz, J = 1.10 Hz, H3), 7.04 (dt, 1H, J = 8.24 Hz,
J = 1.10 Hz, H5). 13C NMR (75 MHz): d 165.6, 157.5, 144.9,
139.1, 135.9, 131.1, 128.1, 127.4, 120.8, 120.5, 117.7, 116.4.
4.1.1.14.
N-(5-Chloro-pyridin-2-yl)-2-hydroxy-4-methyl-
benzamide (2d). Beige crystals. Yield 60%, m.p. 158–
160 °C, IR (KBr): m (C=O) 1677 cm–1. 1H NMR (300 MHz):
d 11.71 (bs, 1H, NH), 10.98 (bs, 1H, OH), 8.39–8.37 (m, 1H,
H6′), 8.30–8.26 (m, 1H, H3′), 7.94 (dd overlapped, 1H,
J = 8.79 Hz, J = 2.47 Hz, H4′), 7.91 (d overlapped, 1H,
J = 7.97 Hz, H6), 6.85–6.77 (m, 2H, H3, H5), 2.29 (s, 3H,
CH3).
4.1.1.9. N-(5-Nitro-pyridin-2-yl)-2-hydroxy-benzamide (1i).
White crystals. Yield 89%, m.p. 281–282 °C, IR (KBr): m
1
(C=O) 1667 cm–1. H NMR (300 MHz): d 11.38 (bs, 1H,
NH), 9.14 (dd,1H, J = 2.75 Hz, J = 0.52, H6′), 8.61 (dd, 1H,
J = 9.34 Hz, J = 2.74 Hz, H4′), 8.44 (dd, 1H, J = 9.34 Hz,
J = 0.53 Hz, H3′), 7.98 (dd, 1H, J = 8.10 Hz, J = 1.38 Hz, H6),
7.50–7.42 (m, 1H, H4), 7.04 (dd, J = 8.11 Hz, J = 1.37 Hz,
H3), 7.02–6.95 (m, 1H, H5). 13C NMR (75 MHz): d 164.5,
156.8, 155.8, 145.1, 140.3, 134.8, 134.7, 131.3, 120.2, 118.0,
117.4, 113.2.
4.1.1.15.
N-(4-Methyl-pyridin-2-yl)-2-hydroxy-4-methyl-
benzamide (2e). Beige crystals. Yield 78%, m.p. 206–
207 °C, IR (KBr): m (C=O) 1682 cm–1. 1H NMR (300 MHz):
d 11.64 (bs, 1H, NH), 10.79 (bs, 1H, OH), 8.17 (d, 1H,
J = 5.22 Hz, H6′), 8.10 (s, 1H, H3′), 7.92 (d, 1H, J = 7.97 Hz,
H6), 6.99–6.95 (m, 1H, H5′), 6.84–6.77 (m, 2H, H3, H5). 13
C
NMR (75 MHz): d 164.4, 156.9, 151.9, 149.3, 148.0, 144.6,
130.8, 121.0, 120.9, 117.5, 115.6, 114.7, 21.3, 21.2.
4.1.1.10. N-(5-Bromo-pyridin-2-yl)-2-hydroxy-benzamide
(1j). Beige crystals. Yield 59%, m.p. 211–213 °C, IR (KBr):
m (C=O) 1658 cm–1. 1H NMR (300 MHz): d 11.75 (bs, 1H,
NH), 11.01 (bs, 1H, OH), 8.46 (dd, 1H, J = 2.48 Hz,
J = 0.69 Hz, H6′), 8.25 (dd, 1H, J = 9.07 Hz, J = 0.69 Hz,
H3′), 8.07 (dd, 1H, J = 9.07 Hz, J = 2.48 Hz, H4′), 8.01 (dd,
1H, J = 8.10 Hz, J = 1.38 Hz, H6), 7.49–7.41 (m, 1H, H4),
7.04 (dd, 1H, J = 8.11 Hz, J = 1.37 Hz, H3), 7.02–6.95 (m,
1H, H5). 13C NMR (75 MHz): d 164.3, 156.8, 150.7, 149.0,
141.1, 134.3, 131.0, 120.0, 118.2, 117.3, 115.8, 114.1.
4.1.1.16.
N-(5-Methyl-pyridin-2-yl)-2-hydroxy-4-methyl-
benzamide (2f). Beige crystals.Yield 79%, m.p. 235–237 °C,
IR (KBr): m (C=O) 1675 cm–1. 1H NMR (300 MHz): d 11.67
(bs, 1H, NH), 10.79 (bs, 1H, OH), 8.17–8.15 (m, 1H, H6′),
8.13 (d, 1H, J = 8.52 Hz, H3′), 7.93 (d, 1H, J = 7.96 Hz, H6),
7.67–7.61 (m, 1H, H4′), 6.84–6.76 (m, 2H, H3, H5), 2.28 (s,
3H, CH3), 2.25 (s, 3H, CH3). 13C NMR (75 MHz): d 164.4,
157.0, 149.7, 148.1, 144.5, 138.9, 130.7, 128.9, 121.0, 117.5,
115.5, 113.8, 21.3, 17.5.
4.1.1.11. N-(Pyridin-2-yl)-2-hydroxy-4-methyl-benzamide
(2a). Beige crystals.Yield 65%, m.p. 175–177 °C, IR (KBr):
m (C=O) 1673 cm–1. 1H NMR (300 MHz): d 11.66 (bs, 1H,
NH), 10.86 (bs, 1H, OH), 8.33 (ddd, 1H, J = 4.81 Hz,
J = 1.93 Hz, J = 0.96 Hz, H6′), 8.27–8.22 (m, 1H, H3′), 7.93
(d, 1H, J = 7.97 Hz, H6), 7.86–7.79 (m, 1H, H4′), 7.14 (ddd,
1H, J = 7.41 Hz, J = 4.81 Hz, J = 0.96 Hz, H5′), 6.85–6.78
(m, 2H, H3, H5), 2.29 (s, 3H, CH3). 13C NMR (75 MHz,
DMSO): d 164.4, 156.9, 151.9, 148.4, 144.7, 138.6, 130.9,
121.1, 120.0, 117.5, 115.6, 114.2, 21.3.
4.1.1.17.
N-(6-Methyl-pyridin-2-yl)-2-hydroxy-4-methyl-
benzamide (2g). Beige crystals. Yield 68%, m.p. 205–
207 °C, IR (KBr): m (C=O) 1671 cm–1. 1H NMR (300 MHz):
d 11.63 (bs, 1H, NH), 10.77 (bs, 1H, OH), 8.04 (d, 1H,
J = 7.87 Hz, H3′), 7.93 (d, 1H, J = 7.96 Hz, H6), 7.70 (t, 1H,
J = 7.87 Hz, H4′), 6.99 (d, 1H, J = 7.87 Hz, H5′), 6.84–6.77
(m, 2H, H3, H5), 2.40 (s, 3H, CH3), 2.29 (s, 3H, CH3). 13
C
NMR (75 MHz): d 164.4, 157.0, 156.9, 151.2, 144.6, 138.8,
130.8, 121.0, 119.2, 117.5, 115.6, 111.2, 23.9, 21.3.
4.1.1.18. N-(3-Hydroxy-pyridin-2-yl)-2-hydroxy-4-methyl-
benzamide (2h). Beige crystals. Yield 60%, m.p. 268–
270 °C, IR (KBr): m (C=O) 1642 cm–1. 1H NMR (300 MHz):
d 7.95–7.88 (m, 2H, H6, H6′), 7.32 (dd, 1H, J = 8.11 Hz,
J = 1.65 Hz, H4′), 7.15 (dd, 1H, J = 8.11 Hz, J = 4.67 Hz,
H5′), 6.84–6.76 (m, 2H, H3, H5), 2.29 (s, 3H, CH3). 13C
NMR (75 MHz): d 166.7, 158.6, 146.1, 145.2, 140.4, 138.2,
130.3, 125.1, 122.5, 120.7, 117.6, 114.1, 21.4.
4.1.1.12. N-(Pyridin-3-yl)-2-hydroxy-4-methyl-benzamide
(2b). Beige crystals.Yield 59%, m.p. 194–177 °C, IR (KBr):
m (C=O) 1664 cm–1. 1H NMR (300 MHz): d 11.77 (bs, 1H,
NH), 10.45 (bs, 1H, OH), 8.85 (s, 1H, H2′), 8.38–8.28 (m,
1H, H6′), 8.16–8.11 (m, 1H, H4′), 8.87 (d, 1H, J = 8.52 Hz,
H6), 7.40 (dd, 1H, J = 8.24 Hz, J = 4.67 Hz, H5′), 6.82–6.77
(m, 2H, H3, H5), 2.30 (s, 3H, CH3). 13C NMR (75 MHz): d

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K. Waisser et al. / IL FARMACO 59 (2004) 615–625
4.1.1.19. N-(5-Nitro-pyridin-2-yl)-2-hydroxy-4-methyl-ben-
zamide (2i). Beige crystals. Yield 69%, m.p. 301–304 °C, IR
(KBr): m (C=O) 1669 cm–1. 1H NMR (300 MHz) d 11.32 (bs,
1H, NH), 9.14–9.12 (m, 1H, H6′), 8.60 (dd, 1H, J = 9.34 Hz,
J = 2.74 Hz, H4′), 8.46–8.41 (m, 1H, H3′), 7.88 (d, 1H,
J = 7.97 Hz, H6), 6.84–6.78 (m, 2H, H3, H5), 2.28 (s, 3H,
CH3). 13C NMR (75 MHz): d 164.4, 156.8, 155.9,
145.4, 145.1, 140.2, 134.6, 131.2, 121.3, 117.5, 115.2, 113.1,
21.3.
810 (d, 1H, J = 8.51 Hz, H3′), 8.01 (d, 1H, J = 8.79 Hz, H6),
7.62 (ddd, 1H, J = 8.52 Hz, J = 2.47 Hz, J = 0.54 Hz, H4′),
6.56 (dd, 1H, J = 8.79 Hz, J = 2.33 Hz, H5), 6.52 (d, 1H,
J = 2.33 Hz, H3), 3.78 (s, 3H, OCH3), 2.24 (s, 3H, CH3). 13
C
NMR (75 MHz): d 164.7, 163.8, 159.2, 149.7, 148.1, 138.8,
132.2, 128.8, 114.0, 110.8, 106.8, 101.6, 55.6, 17.5.
4.1.1.25. N-(6-Methyl-pyridin-2-yl)-2-hydroxy-4-methoxy-
benzamide (3g). Beige crystals. Yield 59%, m.p. 145–
148 °C, IR (KBr): m (C=O) 1671 cm–1. 1H NMR (300 MHz):
d 11.92 (bs, 1H, NH), 10.67 (bs, 1H, OH), 8.02 (d, 1H,
J = 7.78 Hz, H3′), 8.00 (d, 1H, J = 8.79 Hz, H6), 7.69 (t, 1H,
J = 7.78 Hz, H4′), 6.99 (d, 1H, J = 7.78 Hz, H5′), 6.57 (dd,
1H, J = 8.79 Hz, J = 2.47 Hz, H5), 6.52 (d, 1H, J = 2.47 Hz,
H3), 3.78 (s, 3H, OCH3), 2.41 (s, 3H, CH3). 13C NMR
(75 MHz): d 164.6, 163.8, 159.1, 156.9, 151.2, 138.8, 132.3,
119.1, 111.3, 110.9, 106.9, 101.5, 55.6, 23.9.
4.1.1.20.
N-(5-Bromo-pyridin-2-yl)-2-hydroxy-4-methyl-
benzamide (2j). Beige crystals.Yield 61%, m.p. 263–265 °C,
IR (KBr): m (C=O) 1671 cm–1. 1H NMR (300 MHz): d 11.69
(bs, 1H, NH), 10.94 (bs, 1H, OH), 8.45–8.43 (m, 1H, H6′),
8.23 (dd, 1H, J = 8.79 Hz, J = 0.82 Hz, H3′), 8.04 (dd, 1H,
J = 8.79 Hz, J = 2.47 Hz, H4′), 7.91 (d, 1H, J = 7.97 Hz, H6),
6.85–6.77 (m, 2H, H3, H5), 2.28 (s, 3H, CH3). 13C NMR
(75 MHz): d 164.4, 156.8, 150.8, 148.9, 144.9, 141.0, 130.9,
121.1, 117.5, 115.8, 115.4, 114.0, 21.3.
4.1.1.26. N-(3-Hydroxy-pyridin-2-yl)-2-hydroxy-4-methoxy-
benzamide (3h). Brown crystals. Yield 74%, m.p. 248–
251 °C, IR (KBr): m (C=O) 1684 cm–1. 1H NMR (300 MHz)
d 10.85 (bs, 1H, NH), 7.98 (d, 1H, J = 8.79 Hz, H6), 7.90 (dd,
1H, J = 4.67 Hz, J = 1.65 Hz, H6′), 7.32 (dd, 1H, J = 7.97 Hz,
J = 1.65 Hz, H4′), 7.16 (dd, 1H, J = 7.97 Hz, J = 4.67 Hz,
H5′), 6.56 (dd, 1H, J = 8.79 Hz, J = 2.48 Hz, H5), 6.51 (d, 1H,
J = 2.47 Hz, H3), 3.79 (s, 3H, OCH3). 13C NMR (75 MHz): d
166.9, 164.3, 160.9, 146.2, 140.4, 138.2, 131.7 125.2, 122.5,
109.3, 106.8, 101.5, 55.6.
4.1.1.21. N-(Pyridin-2-yl)-2-hydroxy-4-methoxy-benzamide
(3a). White crystals.Yield 67%, m.p. 188–190 °C, IR (KBr):
m (C=O) 1681 cm–1. 1H NMR (300 MHz): d 11.94 (bs, 1H,
NH), 10.76 (bs, 1H, OH), 8.36–8.31 (m, 1H, H6′), 8.22 (d,
1H, J = 8.52 Hz, H3′), 8.01 (d, 1H, J = 8.79 Hz, H6),
7.86–7.77 (m, 1H, H4′), 7.17–7.09 (m, 1H, H5′), 6.62–6.52
(m, 2H, H3, H5), 3.78 (s, 3H, OCH3). 13C NMR (75 MHz): d
164.6, 163.9, 159.1, 151.9, 148.4, 138.5, 132.3, 119.9, 114.3,
110.9, 106.9, 101.6, 55.6.
4.1.1.27.
N-(5-Nitro-pyridin-2-yl)-2-hydroxy-4-methoxy-
4.1.1.22. N-(5-Chloro-pyridin-2-yl)-2-hydroxy-4-methoxy-
benzamide (3d). Beige crystals. Yield 55%, m.p. 225–
228 °C, IR (KBr): m (C=O) 1647 cm–1. 1H NMR (300 MHz)
d 11.97 (bs, 1H, NH), 10.87 (bs, 1H, OH), 8.38–8.36 (m, 1H,
H6′), 8.28–8.24 (m, 1H, H3′), 7.98 (d, 1H, J = 8.93 Hz, H6),
7.93 (dd, 1H, J = 9.06 Hz, J = 2.75 Hz, H4′), 6.58 (dd, 1H,
J = 8.93 Hz, J = 2.34 Hz, H5), 6.53 (d, 1H, J = 2.34 Hz, H3),
3.78 (s, 3H, OCH3). 13C NMR (75 MHz): d 164.5, 164.0,
159.0, 150.6, 146.7, 138.3, 132.4, 125.5, 115.3, 110.7, 107.0,
101.6, 55.6.
benzamide (3i). Beige crystals.Yield 60%, m.p. 251–252 °C,
IR (KBr): m (C=O) 1656 cm–1. 1H NMR (300 MHz): d 11.97
(bs, 1H, NH), 11.20 (bs, 1H, OH), 9.12–9.10 (m, 1H, H6′),
8.58 (dd, 1H, J = 9.34 Hz, J = 2.75 Hz, H4′), 8.41 (d, 1H,
J = 9.34 Hz, H3′), 7.94 (d, 1H, J = 8.79 Hz, H6), 6.58 (dd, 1H,
J = 8.79 Hz, J = 2.47 Hz, H5), 6.51 (d, 1H, J = 2.47 Hz, H3),
3.78 (s, 3H, OCH3). 13C NMR (75 MHz): d 164.4, 164.3,
158.8, 156.0, 145.0, 140.9, 134.5, 132.8, 113.1, 110.6, 107.3,
101.5, 55.7.
4.1.1.28. N-(5-Bromo-pyridin-2-yl)-2-hydroxy-4-methoxy-
benzamide (3j). Beige crystals.Yield 62%, m.p. 216–218 °C,
IR (KBr): m (C=O) 1654 cm–1. 1H NMR (300 MHz): d 11.93
(bs, 1H, NH), 10.83 (bs, 1H, OH), 8.45–8.43 (m, 1H, H6′),
8.21 (d, 1H, J = 8.93 Hz, H3′), 8.04 (dd, 1H, J = 8.93 Hz,
J = 2.47 Hz, H4′), 7.98 (d, 1H, J = 8.79 Hz, H6), 6.58 (dd, 1H,
J = 8.79 Hz, J = 2.48 Hz, H5), 6.53 (d, 1H, J = 2.47 Hz, H3),
3.78 (s, 3H, OCH3). 13C NMR (75 MHz): d 164.5, 164.0,
159.0, 150.9, 148.9, 141.0, 132.4, 115.8, 113.9, 110.7, 107.0,
101.6, 55.6.
4.1.1.23. N-(4-Methyl-pyridin-2-yl)-2-hydroxy-4-methoxy-
benzamide (3e). White crystals. Yield 64%, m.p. 222–
224 °C, IR (KBr): m (C=O) 1680 cm–1. 1H NMR (300 MHz):
d 11.92 (bs, 1H, NH), 10.69 (bs, 1H, OH), 8.17 (d, 1H,
J = 5.22 Hz, H6′), 8.07 (bs, 1H, H3′), 8.00 (d, 1H,
J = 8.79 Hz, H6), 6.98–6.94 (m, 1H, H5′), 6.57 (dd, 1H,
J = 8.79 Hz, J = 2.48 Hz, H5), 6.53 (d, 1H, J = 2.47 Hz, H3),
3.78 (s, 3H, OCH3), 2.33 (s, 3H, CH3). 13C NMR (75 MHz):
d 164.6, 163.9, 159.1, 152.00, 149.3, 147.9, 132.3, 120.9,
114.8, 110.9, 106.9, 101.6, 55.6, 21.2.
4.1.1.29. N-(Pyridin-2-yl)-4-chloro-2-hydroxy-benzamide
(4a). White crystals.Yield 67%, m.p. 222–223 °C, IR (KBr):
m (C=O) 1686 cm–1. 1H NMR (300 MHz): d 12.18 (bs, 1H,
OH), 10.79 (bs, 1H, NH), 8.34 (ddd, 1H, J = 4.95 Hz,
J = 1.93 Hz, J = 0.82 Hz, H6′), 8.25–8.21 (m, 1H, H4′), 8.01
4.1.1.24. N-(5-Methyl-pyridin-2-yl)-2-hydroxy-4-methoxy-
benzamide (3f). Beige crystals.Yield 72%, m.p. 203–204 °C,
IR (KBr): m (C=O) 1678 cm–1. 1H NMR (300 MHz): d 11.95
(bs, 1H, NH), 10.67 (bs, 1H, OH), 8.17–8.14 (m, 1H, H6′),

K. Waisser et al. / IL FARMACO 59 (2004) 615–625
619
(d, 1H, J = 8.52 Hz, H6), 7.87–7.79 (m, 1H, H5′), 7.14 (ddd,
1H, J = 7.42 Hz, J = 4.94 Hz, J = 0.83 Hz, H3′), 7.06 (d, 1H,
J = 1.93 Hz, H3), 7.03 (dd, 1H, J = 8.51 Hz, J = 1.93 Hz, H5).
13C NMR (75 MHz): d 163.5, 157.5, 151.6, 148.4, 138.7,
137.9, 132.6, 120.2, 120.1, 117.8, 116.9, 114.3.
4.1.1.35.
N-(6-Methyl-pyridin-2-yl)-4-chloro-2-hydroxy-
benzamide (4g). White crystals. Yield 68%, m.p. 222–
223 °C, IR (KBr): m (C=O) 1679 cm–1. 1H NMR (300 MHz):
d 12.16 (bs, 1H, NH), 10.71 (bs, 1H, OH), 8.03 (d, 1H,
J = 8.10 Hz, H3′), 8.01 (d, 1H, J = 8.24 Hz, H6), 7.71 (t, 1H,
J = 8.10, H4′), 7.07–6.98 (m, 3H, H3, H5, H5′), 2.41 (s, 3H,
CH3). 13C NMR (75 MHz, DMSO): d 163.4, 157.6, 157.0,
150.9, 138.9, 137.8, 132.6, 120.1, 119.5, 117.8, 116.9, 111.2,
23.9.
4.1.1.30. N-(Pyridin-3-yl)-4-chloro-2-hydroxy-benzamide
(4b). Beige crystals.Yield 60%, m.p. 237–238 °C, IR (KBr):
m (C=O) 1665 cm–1. 1H NMR (300 MHz): d 10.50 (bs, 1H,
OH), 8.85 (d, 1H, J = 2.34 Hz, H2′), 8.33 (dd, 1H,
J = 4.62 Hz, J = 1.10 Hz, H6′), 8.14 (ddd, J = 8.24 Hz,
J = 2.34 Hz, J = 1.10 Hz, H4′), 7.94–7.88 (m, 1H, H6), 7.40
(ddd, 1H, J = 8.24 Hz, J = 4.62 Hz, J = 1.10 Hz, H5′),
7.07–7.01 (m, 2H, H3, H5). 13C NMR (75 MHz): d 165.9,
158.9, 145.2, 142.5, 137.7, 135.1, 131.2, 128.0, 123.8, 119.5,
117.5, 117.0.
4.1.1.36. N-(3-Hydroxy-pyridin-2-yl)-4-chloro-2-hydroxy-
benzamide (4h). Yellow crystals. Yield 57%, m.p. 275–
277 °C, IR (KBr): m (C=O) 1637 cm–1. 1H NMR (300 MHz):
d 11.37 (bs, 1H, NH), 8.00 (d, 1H, J = 8.38 Hz, H6), 7.88 (dd,
1H, J = 4.94 Hz, J = 1.38 Hz, H6′), 7.34 (dd, 1H, J = 7.96 Hz,
J = 1.37 Hz, H4′), 7.15 (dd, 1H, J = 7.96 Hz, J = 4.95 Hz,
H5′), 7.02 (d, 1H, J = 1.92 Hz, H3), 6.99 (dd, 1H, J = 8.38 Hz,
J = 1.92 Hz, H5). 13C NMR (75 MHz): d 166.4, 160.0, 146.2,
141.0, 138.2, 136.7, 131.8, 124.7, 121.8, 119.3, 117.2, 116.5.
4.1.1.31. N-(Pyridin-4-yl)-4-chloro-2-hydroxy-benzamide
(4c). Yellow crystals. Yield 63%, m.p. 268–270 °C, IR
(KBr): m (C=O) 1679 cm–1. 1H NMR (300 MHz): d 10.92 (bs,
1H, OH), 8.50–8.46 (m, 2H, H2′, H6′), 7.83 (d, 1H,
J = 8.51 Hz, H6), 7.75–7.70 (m, 2H, H3′, H5′), 7.04–7.01 (m,
1H, H3), 7.01–6.96 (m, 1H, H5). 13C NMR (75 MHz): d
166.0, 158.9, 150.1, 145.9, 137.7, 131.6, 119.3, 118.5, 117.1,
114.4.
4.1.1.37. N-(5-Nitro-pyridin-2-yl)-4-chloro-2-hydroxy-ben-
zamide (4i). Brown crystals.Yield 63%, m.p. 296–297 °C, IR
(KBr): m (C=O) 1686 cm–1. 1H NMR (300 MHz): d 12.28 (bs,
1H, NH), 11.22 (bs, 1H, OH), 9.14 (d, 1H, J = 2.75 Hz, H6′),
8.63 (dd, 1H, J = 9.34 Hz, J = 2.75 Hz, H4′), 8.41 (d, 1H,
J = 9.34 Hz, H3′), 7.95 (d, 1H, J = 9.07 Hz, H6), 7.07–7.01
(m, 2H, H3, H5). 13C NMR (75 MHz): d 163.7, 157.4, 155.6,
145.1, 140.4, 138.5, 134.7, 132.8, 120.3, 117.5, 116.9, 113.2.
4.1.1.32.
N-(5-Chloro-pyridin-2-yl)-4-chloro-2-hydroxy-
benzamide (4d). Brown crystals. Yield 61%, m.p. 263–
265 °C, IR (KBr): m (C=O) 1683 cm–1. 1H NMR (300 MHz):
d 12.19 (bs, 1H, NH), 10.87 (bs, 1H, OH), 8.37 (d, 1H,
J = 2.47 Hz, H6′), 8.25 (d, 1H, J = 9.06 Hz, H3′), 7.98 (d, 1H,
J = 8.24 Hz, H6), 7.93 (dd, 1H, J = 9.06 Hz, J = 2.47 Hz, H4′),
7.06–7.00 (m, 2H, H3, H5). 13C NMR (75 MHz): d 163.4,
157.5, 150.3, 146.8, 138.3, 138.0, 132.6, 125.8, 120.1, 117.6,
116.9, 115.3.
4.1.1.38.
N-(5-Bromo-pyridin-2-yl)-4-chloro-2-hydroxy-
benzamide (4j). White crystals. Yield 68%, m.p. 266–
268 °C, IR (KBr): m (C=O) 1684 cm–1. 1H NMR (300 MHz):
d 12.18 (bs, 1H, NH), 10.04 (bs, 1H, OH), 8.43 (dd, 1H,
J = 2.47 Hz, J = 0.82 Hz, H6′), 8.20 (dd, 1H, J = 8.93 Hz,
J = 0.83 Hz, H3′), 8.03 (dd, 1H, J = 8.93 Hz, J = 2.47 Hz,
H4′), 7.97 (d, 1H, J = 8.24 Hz, H6), 7.05–6.99 (m, 2H, H3,
H5). 13C NMR (75 MHz): d 163.4, 157.4, 150.5, 149.0,
141.1, 138.0, 132.6, 120.1, 117.6, 116.9, 115.8, 114.2.
4.1.1.33.
N-(4-Methyl-pyridin-2-yl)-4-chloro-2-hydroxy-
benzamide (4e). White crystals. Yield 72%, m.p. 257–
259 °C, IR (KBr): m (C=O) 1682 cm–1. 1H NMR (300 MHz):
d 12.16 (bs, 1H, NH), 10.75 (bs, 1H, OH), 8.18 (d, 1H,
J = 5.22 Hz, H6′), 8.03 (bs, 1H, H3′), 8.01 (d, 1H,
J = 8.24 Hz, H6), 7.07–7.01 (m, 2H, H3, H5′), 7.00–6.96 (m,
1H, H5), 2.33 (s, 3H, CH3). 13C NMR (75 MHz): d 163.4,
157.6, 151.7, 149.5, 147.9, 137.8, 132.6, 121.1, 120.1, 117.8,
116.9, 114.7, 21.2.
4.1.1.39. N-(Pyridin-2-yl)-5-fluoro-2-hydroxy-benzamide
(5a). Green crystals.Yield 70%, m.p. 228–230 °C, IR (KBr):
m (C=O) 1685 cm–1. 1H NMR (300 MHz): d 11.76 (bs, 1H,
NH), 10.95 (bs, 1H, OH), 8.37–8.32 (m, 1H, H6′), 8.24 (d,
1H, J = 7.97 Hz, H3′), 7.88–7.80 (m, 1H, H4′), 7.74 (dd, 1H,
J = 9.35 Hz, J = 3.30 Hz, H6), 7.36–7.27 (m, 1H, H4), 7.16
(ddd, 1H, J = 7.97 Hz, J = 4.95 Hz, J = 0.82 Hz, H5′), 7.05
(dd, 1H, J = 9.35 Hz, J = 4.67 Hz, H3). 13C NMR (75 MHz):
d 163.1, 157.2 and 154.0 (J = 235.6 Hz); 153.1, 151.6, 148.5,
138.7, 121.2 and 120.9 (J = 23.5 Hz); 120.3, 119.4 and 119.3
(J = 6.9 Hz); 118.9 and 118.8 (J = 7.5 Hz); 116.3 and 116.0
(J = 24.6 Hz), 114.2.
4.1.1.34.
N-(5-Methyl-pyridin-2-yl)-4-chloro-2-hydroxy-
benzamide (4f). White crystals. Yield 73%, m.p. 228–
230 °C, IR (KBr): m (C=O) 1683 cm–1. 1H NMR (300 MHz):
d 12.12 (bs, 1H, NH), 10.73 (bs, 1H, OH), 8.18–8.15 (m, 1H,
H6′), 8.12 (d, 1H, J = 8.52 Hz, H3′), 8.01 (d, 1H, J = 8.52 Hz,
H6), 7.64 (dd, 1H, J = 8.52 Hz, J = 2.47 Hz, H4′), 7.06 (d, 1H,
J = 1.92 Hz, H3), 7.03 (dd, 1H, J = 8.52 Hz, J = 1.92 Hz, H5),
2.25 (s, 3H, CH3). 13C NMR (75 MHz): d 163.6, 157.6,
149.5, 148.1, 139.0, 137.8, 132.5, 129.2, 120.1, 117.7, 116.9,
113.9, 17.5.
4.1.1.40. N-(Pyridin-3-yl)-5-fluoro-2-hydroxy-benzamide
(5b). Brown crystals. Yield 73%, m.p. 255–258 °C, IR
(KBr): m (C=O) 1672 cm–1. 1H NMR (300 MHz): d 11.49 (bs,
1H, NH), 10.53 (bs, 1H, OH), 8.85 (d, 1H, J = 2.47 Hz, H2′),

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K. Waisser et al. / IL FARMACO 59 (2004) 615–625
8.35–8.32 (m, 1H, H6′), 8.17–8.12 (m, 1H, H4′), 7.71 (dd,
1H, J = 9.34 Hz, J = 3.30 Hz, H6), 7.43–7.37 (m, 1H, H5′),
7.35–7.27 (m, 1H, H4), 7.01 (dd, 1H, J = 9.34 Hz,
J = 4.67 Hz, H3). 13C NMR (75 MHz): d 165.6 and 165.6
(J = 2.0 Hz); 156.7 and 153.5 (J = 235.4 Hz); 154.4, 145.3,
142.5, 135.1, 128.0, 123.9, 121.0 and 120.7 (J = 23.2 Hz);
118.8 and 118.7 (J = 7.5 Hz); 115.3 and 114.9 (J = 24.6 Hz).
4.1.1.45.N-(6-Methyl-pyridin-2-yl)-5-fluoro-2-hydroxy-ben-
zamide (5g). White crystals.Yield 60%, m.p. 228–229 °C, IR
(KBr): m (C=O) 1679 cm–1. 1H NMR (300 MHz): d 11.72 (bs,
1H, NH), 10.86 (bs, 1H, OH), 8.04 (d, 1H, J = 7.97 Hz, H3′),
7.74 (dd, 1H, J = 7.42 Hz, J = 3.29 Hz, H6), 7.72–7.68 (m,
1H, H4′), 7.35–7.26 (m, 1H, H4), 7.08–6.98 (m, 2H, H3,
H5′), 2.41 (s, 3H, CH3). 13C NMR (75 MHz): d 163.0,
157.2 and 154.0 (J = 235.4 Hz); 157.1, 153.1, 150.9, 138.9,
121.1 and 120.8 (J = 23.5 Hz); 119.5, 119.4 and 119.4
(J = 6.9 Hz); 118.9 and 118.8 (J = 7.5 Hz); 116.3 and 116.0
(J = 24.3 Hz); 111.2, 23.9.
4.1.1.41. N-(Pyridin-4-yl)-5-fluoro-2-hydroxy-benzamide
(5c). Yellow crystals. Yield 82%, m.p. 321–322 °C, IR
(KBr): m (C=O) 1683 cm–1. 1H NMR (300 MHz): d 10.72 (bs,
1H, OH), 8.52–8.44 (m, 2H, H2′, H6′), 7.73–7.68 (m, 2H,
H3′, H5′), 7.63 (dd, 1H, J = 9.35 Hz, J = 3.30 Hz, H6),
7.34–7.26 (m, 1H, H4), 7.01 (dd, 1H, J = 9.35 Hz,
J = 4.67 Hz, H3). 13C NMR (75 MHz): d 165.6 and 165.6
(J = 2.3 Hz); 156.7 and 153.6 (J = 235.3 Hz); 153.9 and 153.9
(J = 1.4 Hz); 150.5, 145.4, 120.9 and 120.6 (J = 23.2 Hz);
119.8 and 119.7 (J = 6.9 Hz); 118.8 and 118.7 (J = 7.5 Hz);
115.6 and 115.2 (J = 24.3 Hz); 114.4.
4.1.1.46. N-(3-Hydroxy-pyridin-2-yl)-5-fluoro-2-hydroxy-ben-
zamide (5h). Yellow crystals. Yield 57%, m.p. 285–286 °C,
IR (KBr): m (C=O) 1670 cm–1. 1H NMR (300 MHz): d 7.89
(dd, 1H, J = 4.95 Hz, J = 1.37 Hz, H6′), 7.76 (dd, 1H,
J = 9.35 Hz, J = 3.29 Hz, H6), 7.38–7.29 (m, 2H, H4, H4′),
7.15 (dd, 7.96 Hz, J = 4.95 Hz, H5′), 7.01 (dd, 1H,
J = 9.35 Hz, J = 4.67 Hz, H3). 13C NMR (75 MHz): d 165.5,
156.7 and 153.6 (J = 235.1 Hz); 155.0, 146.2, 140.6, 137.7,
124.6, 122.2, 121.5 and 121.2 (J = 23.5 Hz); 119.0 and 118.9
(J = 7.5 Hz); 118.0 and 117.9 (J = 6.9 Hz); 115.6 and 115.3
(J = 24.6 Hz).
4.1.1.42.N-(5-Chloro-pyridin-2-yl)-5-fluoro-2-hydroxy-ben-
zamide (5d). White crystals.Yield 69%, m.p. 240–242 °C, IR
(KBr): m (C=O) 1666 cm–1. 1H NMR (300 MHz): d 11.77 (bs,
1H, NH), 11.02 (bs, 1H, OH), 8.38 (d, 1H, J = 2.75 Hz, H6′),
8.26 (d, 1H, J = 9.07 Hz, H3′), 7.95 (dd, 1H, J = 9.06 Hz,
J = 2.74 Hz, H4′), 7.70 (dd, 1H, J = 9.48 Hz, J = 3.29 Hz, H6),
7.36–7.27 (m, 1H, H4), 7.05 (dd, 1H, J = 9.48 Hz,
J = 4.67 Hz, H3). 13C NMR (75 MHz): d 163.1 and 163.0
(J = 2.3 Hz); 157.2 and 154.0 (J = 235.7 Hz); 153.1 and 153.0
(J = 1.7 Hz); 150.2, 146.8, 138.4, 125.9, 121.3 and 121.0
(J = 23.2 Hz); 119.2 and 119.1 (J = 6.9 Hz); 118.9 and 118.8
(J = 7.5 Hz); 116.3 and 116.0 (J = 24.6 Hz); 115.2.
4.1.1.47. N-(5-Nitro-pyridin-2-yl)-5-fluoro-2-hydroxy-ben-
zamide (5i). Brown crystals.Yield 56%, m.p. 264–267 °C, IR
(KBr): m (C=O) 1668 cm–1. 1H NMR (300 MHz): d 11.38 (bs,
1H, NH), 9.12 (dd, 1H, J = 2.75 Hz, J = 0.55 Hz, H6′), 8.60
(dd, 1H, J = 9.34 Hz, J = 2.75 Hz, H4′), 8.40 (dd, 1H,
J = 9.34 Hz, J = 0.55 Hz, H3′), 7.64 (dd, 1H, J = 9.34 Hz,
J = 3.30 Hz, H6), 7.36–7.27 (m, 1H, H4), 7.03 (dd, 1H,
J = 9.34 Hz, J = 4.40 Hz, H3). 13C NMR (75 MHz): d
163.4 and 163.3 (J = 2.3 Hz); 157.2 and 154.1 (J = 235.9 Hz);
155.6, 153.2, 145.1, 140.5, 134.8, 121.9 and 121.6
(J = 23.5 Hz); 119.1 and 119.0 (J = 7.7 Hz); 119.0 and 118.9
(J = 6.9 Hz); 116.4 and 116.1 (J = 24.6 Hz); 113.3.
4.1.1.43. N-(4-Methyl-pyridin-2-yl)-5-fluoro-2-hydroxy-ben
-
zamide (5e). White crystals.Yield 62%, m.p. 225–226 °C, IR
(KBr): m (C=O) 1680 cm–1. 1H NMR (300 MHz): d 11.72 (bs,
1H, NH), 10.86 (bs, 1H, OH), 8.04 (d, 1H, J = 7.97 Hz, H3′),
7.74 (dd, 1H, J = 7.42 Hz, J = 3.29 Hz, H6), 7.72–7.68 (m,
1H, H4′), 7.35–7.26 (m, 1H, H4), 7.08–6.98 (m, 2H, H3,
H5′), 2.41 (s, 3H, CH3). 13C NMR (75 MHz): d 163.0,
157.2 and 154.0 (J = 235.4 Hz); 157.1, 153.1, 150.9, 138.9,
121.1 and 120.8 (J = 23.5 Hz); 119.5, 119.4 and 119.4
(J = 6.9 Hz); 118.9 and 118.8 (J = 7.5 Hz); 116.3 and 116.0
(J = 24.3 Hz); 111.2, 23.9.
4.1.1.48. N-(5-Bromo-pyridin-2-yl)-5-fluoro-2-hydroxy-ben-
zamide (5j). White crystals.Yield 65%, m.p. 252–254 °C, IR
(KBr): m (C=O) 1664 cm–1. 1H NMR (300 MHz): d 11.78 (bs,
1H, NH), 11.02 (bs, 1H, OH), 8.46 (dd, 1H, J = 2.48 Hz,
J = 0.69 Hz, H6′), 8.22 (dd, 1H, J = 8.93 Hz, J = 0.69 Hz,
H3′), 8.07 (dd, 1H, J = 8.93 Hz, J = 2.47 Hz, H4′), 7.70 (dd,
1H, J = 9.34 Hz, J = 3.29 Hz, H6), 7.37–7.28 (m, 1H, H4),
7.05 (dd, 1H, J = 9.34 Hz, J = 4.67 Hz, H3). 13C NMR
(75 MHz): d 163.1 and 163.1 (J = 2.0 Hz); 157.2 and 154.0
(J = 235.7 Hz); 153.1 and 153.0 (J = 1.7 Hz); 150.5, 149.0,
141.2, 121.4 and 121.0 (J = 23.8 Hz); 119.3 and 119.2
(J = 6.9 Hz); 119.0 and 118.9 (J = 7.5 Hz); 116.3 and 116.0
(J = 24.6 Hz); 115.8, 114.3.
4.1.1.44.N-(5-Methyl-pyridin-2-yl)-5-fluoro-2-hydroxy-ben-
zamide (5f). White crystals.Yield 71%, m.p. 265–269 °C, IR
(KBr): m (C=O) 1679 cm–1. 1H NMR (300 MHz): d 11.71 (bs,
1H, NH), 10.87 (bs, 1H, OH), 8.18–8.15 (m, 1H, H6′), 8.13
(d, 1H, J = 8.24 Hz, H4′), 7.74 (dd, 1H, J = 9.48 Hz,
J = 3.30 Hz, H6), 7.67–7.60 (m, 1H, H3′), 7.34–7.25 (m, 1H,
H4), 7.04 (dd, 1H, J = 9.48 Hz, J = 4.67 Hz, H3), 2.24 (s, 3H,
CH3). 13C NMR (75 MHz): d 163.0, 157.2 and 154.0
(J = 235.4 Hz); 153.2, 149.4, 148.2, 139.0, 129.2, 121.0 and
120.7 (J = 23.5 Hz); 119.4 and 119.3 (J = 6.6 Hz); 118.9 and
118.8 (J = 7.4 Hz); 116.2 and 115.9 (J = 24.4 Hz); 113.8,
17.5.
4.1.1.49. N-(Pyridin-2-yl)-5-bromo-2-hydroxy-benzamide
(6a). White crystals.Yield 66%, m.p. 244–246 °C, IR (KBr):
m (C=O) 1691 cm–1. 1H NMR (300 MHz): d 12.00 (bs, 1H,
NH), 10.88 (bs, 1H OH), 8.34 (ddd, 1H, J = 4.94 Hz,
J = 1.93 Hz, J = 0.83 Hz, H6′), 8.23 (d, 1H, J = 8.52 Hz, H3′),

K. Waisser et al. / IL FARMACO 59 (2004) 615–625
621
8.09 (d, 1H, J = 2.75 Hz, H6), 7.88–7.80 (m, 1H, H4′), 7.58
(dd, 1H, J = 8.79 Hz, J = 2.75 Hz, H4), 7.16 (ddd, 1H,
J = 7.42 Hz, J = 4.94 Hz, J = 1.10 Hz, H5′), 7.01 (d, 1H,
J = 8.79 Hz, H3). 13C NMR (75 MHz): d 162.9, 156.1, 151.5,
148.5, 138.7, 136.4, 132.9, 120.6 120.3, 119.7, 114.3, 111.1.
4.1.1.55.
N-(6-Methyl-pyridin-2-yl)-5-bromo-2-hydroxy-
benzamide (6g). White crystals. Yield 61%, m.p. 223–
224 °C, IR (KBr): m (C=O) 1679 cm–1. 1H NMR (300 MHz):
d 12.00 (bs, 1H, NH), 10.79 (bs, 1H, OH), 8.09 (d, 1H,
J = 2.61 Hz, H6), 8.05–8.01 (m, 1H, H3′), 7.71 (t, 1H,
J = 7.56 Hz, H4′), 7.57 (dd, 1H, J = 8.79 Hz, J = 2.61 Hz, H4),
7.00 (d overlapped, 1H, J = 7.56 Hz, H5′), 6.99 (d over-
lapped, 1H, J = 8.79 Hz, H3), 2.40 (s, 3H, CH3). 13C NMR
(75 MHz): d 162.9, 157.1, 156.1, 150.9, 138.9, 136.3, 132.9,
120.6, 119.7, 119.5, 111.2, 111.1, 23.9.
4.1.1.50. N-(Pyridin-3-yl)-5-bromo-2-hydroxy-benzamide
(6b). Beige crystals.Yield 58%, m.p. 289–291 °C, IR (KBr):
1
m (C=O) 1671 cm–1. H NMR (300 MHz) d 11.73 (bs, 1H,
NH), 10.54 (bs, 1H, OH), 8.85 (d, 1H, J = 2.20 Hz, H2′),
8.37–8.30 (m, 1H, H6′), 8.18–8.10 (m, 1H, H4′), 8.03 (d, 1H,
J = 2.47 Hz, H6), 7.57 (dd, 1H, J = 8.79 Hz, J = 2.47 Hz, H4),
7.40 (dd, 1H, J = 8.24 Hz, J = 4.67 Hz, H5′), 6.96 (d, 1H,
J = 8.79 Hz, H3). 13C NMR (75 MHz): d 165.5, 157.3,
145.3, 142.5, 136.2, 135.1, 131.6, 128.0, 123.9, 120.4, 119.7,
110.4.
4.1.1.56. N-(3-Hydroxy-pyridin-2-yl)-5-bromo-2-hydroxy-
benzamide (6h). Yellow crystals. Yield 73%, m.p. 288–
291 °C, IR (KBr): m (C=O) 1641 cm–1. 1H NMR (300 MHz):
d 8.12 (d, 1H, J = 2.74 Hz, H6), 7.88 (dd, 1H, J = 4.94 Hz,
J = 1.37 Hz, H6′), 7.58 (dd, 1H, J = 8.79 Hz, J = 2.47 Hz, H4),
7.33 (dd, 1H, J = 7.96 Hz, J = 1.65 Hz, H4′), 7.14 (dd, 1H,
J = 7.97 Hz, J = 4.95 Hz, H5′), 6.95 (d, 1H, J = 8.79 Hz, H3).
13C NMR (75 MHz): d 165.7, 158.2, 146.3, 140.8, 136.9,
136.6, 132.2, 124.5, 123.9, 120.0, 119.4, 110.2.
4.1.1.51. N-(Pyridin-4-yl)-5-bromo-2-hydroxy-benzamide
(6c). Yellow crystals. Yield 86%, m.p. 304–305 °C, IR
(KBr): m (C=O) 1677 cm–1. 1H NMR (300 MHz): d 10.84 (bs,
1H, OH), 8.51–8.45 (m, 2H, H2′, H6′), 7.93 (d, 1H,
J = 2.74 Hz, H6), 7.73–7.69 (m, 2H, H3′, H5′), 7.55 (dd, 1H,
J = 8.79 Hz, J = 2.48 Hz, H4), 6.96 (d, 1H, J = 8.79 Hz, H3).
13C NMR (75 MHz): d 165.5, 157.1, 150.4, 145.6, 136.1,
131.9, 121.4, 119.7, 114.4, 110.1.
4.1.1.57. N-(5-Nitro-pyridin-2-yl)-5-bromo-2-hydroxy-ben-
zamide (6i). White crystals.Yield 62%, m.p. 301–303 °C, IR
(KBr): m (C=O) 1663 cm–1. 1H NMR (300 MHz): d 12.11 (bs,
1H, NH), 11.30 (bs, 1H, OH), 9.14–9.12 (m, 1H, H6′), 8.62
(dd, 1H, J = 9.34 Hz, J = 2.75 Hz, H4′), 8.40 (d, 1H,
J = 9.34 Hz, H3′), 7.99 (d, 1H, J = 2.61 Hz, H6), 7.58 (dd, 1H,
J = 8.79 Hz, J = 2.61 Hz, H4), 6.99 (d, 1H, J = 8.79 Hz, H3).
13C NMR (75 MHz): d 163.2, 156.1, 155.5, 145.0, 140.4,
136.9, 134.7, 133.0, 120.2, 119.8, 113.3, 111.2.
4.1.1.52.
N-(5-Chloro-pyridin-2-yl)-5-bromo-2-hydroxy-
benzamide (6d). White crystals. Yield 56%, m.p. 271–
273 °C, IR (KBr): m (C=O) 1658 cm–1. 1H NMR (300 MHz,
DMSO): d 12.01 (bs, 1H, NH), 10.91 (bs, 1H, OH), 8.35 (d,
1H, J = 2.47 Hz, H6′), 8.24 (d, 1H, J = 9.06 Hz, H3′), 8.04 (d,
1H, J = 2.48 Hz, H6), 7.91 (dd, 1H, J = 9.06 Hz, J = 2.47 Hz,
H4′), 7.56 (dd, 1H, J = 8.79 Hz, J = 2.47 Hz, H4), 6.98 (d, 1H,
J = 8.79 Hz, H3). 13C NMR (75 MHz): d 162.9, 156.0,
150.1, 146.8, 138.3, 136.5, 132.9, 125.9, 120.4, 119.7, 115.3,
111.1.
4.1.1.58. N-(5-Bromo-pyridin-2-yl)-5-bromo-2-hydroxy-ben-
zamide (6j). White crystals.Yield 57%, m.p. 279–281 °C, IR
(KBr): m (C=O) 1658 cm–1. 1H NMR (300 MHz): d 12.03 (bs,
1H, NH), 10.92 (bs, 1H, OH), 8.47–8.44 (m, 1H, H6′), 8.21
(dd, 1H, 8.79 Hz, J = 0.55 Hz, H3′), 8.06 (dd overlapped, 1H,
J = 8.79 Hz, J = 2.75 Hz, H4′), 8.05 (d overlapped 1H,
J = 2.75 Hz, H6), 7.58 (dd, 1H, J = 8.79 Hz, J = 2.74 Hz, H4),
7.00 (d, 1H, J = 8.79 Hz, H3). 13C NMR (75 MHz): d 162.9,
156.0, 150.4, 149.0, 141.1, 136.5, 132.9, 120.4, 119.7, 115.8,
114.3, 111.1.
4.1.1.53.
N-(4-Methyl-pyridin-2-yl)-5-bromo-2-hydroxy-
benzamide (6e). White crystals. Yield 60%, m.p. 245–
247 °C, IR (KBr): m (C=O) 1677 cm–1. 1H NMR (300 MHz):
d 10.89 (bs, 1H, NH), 8.18 (d, 1H, J = 4.94 Hz, H6′),
8.09–8.07 (m, 2H, H6, H3′), 7.57 (dd, 1H, J = 8.79 Hz,
J = 2.47 Hz, H4), 7.00 (d overlapped 1H, J = 8.79 Hz, H3),
7.01–6.97 (m, 1H, H5′), 2.34 (s, 3H, CH3). 13C NMR
(75 MHz): d 162.9, 156.2, 151.6, 149.5, 148.0, 136.3, 132.9,
121.2, 120.6, 119.8, 114.7, 110.9, 21.2.
4.1.1.59. N-(Pyridin-2-yl)-5-chloro-2-hydroxy-benzamide
(7a). White crystals.Yield 72%, m.p. 243–245 °C, IR (KBr):
m (C=O) 1690 cm–1. 1H NMR (300 MHz): d 12.00 (bs, 1H,
NH), 10.87 (bs, 1H OH), 8.34 (ddd, 1H, J = 4.94 Hz,
J = 1.92 Hz, J = 0.82 Hz, H6′), 8.23 (d, 1H, J = 7.83 Hz, H3′),
7.96 (d, 1H, J = 2.89 Hz, H6), 7.87–7.80 (m, 1H, H4′), 7.47
(dd, 1H, J = 8.79 Hz, J = 2.89 Hz, H4), 7.16 (ddd, 1H,
J = 7.83 Hz, J = 4.95 Hz, J = 1.10 Hz, H5′), 7.06 (d, 1H,
J = 8.80 Hz, H3). 13C NMR (75 MHz): d 163.0, 155.6,
151.6, 148.5, 138.7, 133.6, 130.0, 123.7, 120.3, 120.1, 119.2,
114.3.
4.1.1.54. N-(5-Methyl-pyridin-2-yl)-5-bromo-2-hydroxy-ben-
zamide (6f). White crystals.Yield 72%, m.p. 293–294 °C, IR
(KBr): m (C=O) 1678 cm–1. 1H NMR (300 MHz): d 11.99 (bs,
1H, NH), 10.81 (bs, 1H, OH), 8.19–8.15 (m, 1H, H6′), 8.12
(d, 1H, J = 8.38 Hz, H3′), 8.09 (d, 1H, J = 2.75 Hz, H6), 7.64
(dd, 1H, J = 8.38 Hz, J = 2.20 Hz, H4′), 7.57 (dd, 1H,
J = 8.79 Hz, J = 2.74 Hz, H4), 7.00 (d, 1H, J = 8.79 Hz, H3),
2.25 (s, 3H, CH3). 13C NMR (75 MHz): d 162.8, 156.1,
149.4, 148.2, 139.0, 136.3, 132.8, 129.3, 120.5, 119.7, 113.9,
111.0, 17.5.
4.1.1.60. N-(Pyridin-4-yl)-5-chloro-2-hydroxy-benzamide
(7c). Yellow crystals. Yield 79%, m.p. 314–316 °C, IR

622
K. Waisser et al. / IL FARMACO 59 (2004) 615–625
(KBr): m (C=O) 1678 cm–1. 1H NMR (300 MHz): d 10.83 (bs,
1H, OH), 8.52–8.44 (m, 2H, H2′, H6′), 7.82 (d, 1H,
J = 2.61 Hz, H6), 7.74–7.68 (m, 2H, H3′, H5′), 7.44 (dd, 1H,
J = 7.89 Hz, J = 2.61 Hz, H4), 7.01 (d, 1H, J = 7.89 Hz, H3).
13C NMR (75 MHz): d 165.6, 156.7, 150.5, 145.6, 133.3,
129.0, 122.7, 120.9, 119.3, 114.4.
J = 2.74 Hz, H4), 7.33 (dd, 1H, J = 7.97 Hz, J = 1.38 Hz, H4′),
7.15 (dd, 1H, J = 7.97 Hz, J = 4.81 Hz, H5′), 7.01 (d, 1H,
J = 8.79 Hz, H3). 13C NMR (75 MHz): d 165.7, 157.8,
146.2, 140.9, 136.9, 133.8, 129.3, 124.6, 122.9, 121.9, 119.5,
118.9.
4.1.1.66. N-(5-Nitro-pyridin-2-yl)-5-chloro-2-hydroxy-ben-
zamide (7i). Beige crystals. Yield 72%, m.p. 293–295 °C, IR
(KBr): m (C=O) 1664 cm–1. 1H NMR (300 MHz): d 12.10 (bs,
1H, NH), 11.79 (bs, 1H, OH), 9.14–9.11 (m, 1H, H6′),
8.64–8.58 (m, 1H, H4′), 8.39 (d, 1H, J = 9.07 Hz, H3′),
7.88–7.84 (m, 1H, H6), 7.47 (dd, 1H, J = 8.79 Hz,
J = 2.75 Hz, H4), 7.04 (d, 1H, J = 8.80 Hz, H3). 13C NMR
(75 MHz): d 163.3, 155.6, 155.5, 145.0, 140.4, 134.7, 134.1,
130.0, 123.8, 119.7, 119.6, 113.3.
4.1.1.61.
N-(5-Chloro-pyridin-2-yl)-5-chloro-2-hydroxy-
benzamide (7d). White crystals. Yield 59%, m.p. 266–
268 °C, IR (KBr): m (C=O) 1660 cm–1. 1H NMR (300 MHz):
d 12.00 (bs, 1H, NH), 10.93 (bs, 1H, OH), 8.36 (d, 1H,
J = 2.75 Hz, H6′), 8.25 (d, 1H, J = 8.93 Hz, H3′), 7.93 (dd,
overlapped, 1H, J = 8.93 Hz, J = 2.75 Hz, H4′), 7.91 (d
overlapped, 1H, J = 2.75 Hz, H6), 7.46 (dd, 1H, J = 8.79 Hz,
J = 2.75 Hz, H4), 7.04 (d, 1H, J = 8.79 Hz, H3). 13C NMR
(75 MHz): d 163.0, 155.5, 150.2, 146.8, 138.4, 133.7, 130.0,
125.9, 123.7, 119.9, 119.3, 115.3.
4.1.1.67. N-(5-Bromo-pyridin-2-yl)-5-chloro-2-hydroxy-ben-
zamide (7j). Yellow crystals. Yield 59%, m.p. 272–274 °C,
IR (KBr): m (C=O) 1661 cm–1. 1H NMR (300 MHz): d 12.00
(bs, 1H, NH), 10.94 (bs, 1H, OH), 8.46 (dd, 1H, J = 2.47 Hz,
J = 0.55 Hz, H6′), 8.23–8.19 (m, 1H, H3′), 8.06 (dd, 1H,
J = 8.79 Hz, J = 2.47 Hz, H4′), 7.92 (d, 1H, J = 2.83 Hz, H6),
7.48 (dd, 1H, J = 8.79 Hz, J = 2.83 Hz, H4), 7.06 (d, 1H,
J = 8.79 Hz, H3). 13C NMR (75 MHz): d 163.0, 155.5, 150.4,
149.0, 141.1, 133.7, 129.9, 123.7, 120.0, 119.3, 115.8, 114.3.
4.1.1.62.
N-(4-Methyl-pyridin-2-yl)-5-chloro-2-hydroxy-
benzamide (7e). White crystals. Yield 63%, m.p. 255–
257 °C, IR (KBr): m (C=O) 1682 cm–1. 1H NMR (300 MHz):
d 12.00 (bs, 1H, NH), 10.83 (bs, 1H, OH), 8.19 (d, 1H,
J = 5.23 Hz, H6′), 8.08 (bs, 1H, H3′), 7.95 (d, 1H,
J = 2.75 Hz, H6), 7.47 (dd, 1H, J = 8.79 Hz, J = 2.75 Hz, H4),
7.05 (d, 1H, J = 8.79 Hz, H3), 6.99 (ddd, J = 5.22 Hz,
J = 1.37 Hz, J = 0.55 Hz, H5′), 2.34 (s, 3H, CH3). 13C NMR
(75 MHz): d 162.9, 155.6, 151.6, 149.5, 148.0, 133.5, 129.9,
123.6, 121.2, 120.1, 119.3, 114.7, 21.2.
4.2. Microbiology
The following strains, obtained from the Czech National
Collection of Type Cultures (CNCTC), National Institute of
Public Health, Prague, were used for the evaluation of in
vitro antimycobacterial activity: M. kansasii CNCTC My
235/80, M. avium CNCTC My 330/88 and a clinical isolate
of M. kansasii 6509/96. Antimycobacterial activity of the
compounds against these strains was determined in the Šula
semisynthetic medium (SEVAC, Prague). The Šula liquid
medium (with bovine serum) is routinely used in the Czech
Republic. Each strain was simultaneously inoculated into a
Petri dish containing the Löwenstein–Jensen medium for the
control of the sterility of the inoculum and its growth. The
compounds were added to the medium in DMSO solutions.
The final concentrations were 1000, 500, 250, 125, 62.5, 32,
16, 8, 4, 2 and 1 µmol/l. The minimum inhibitory concentra-
tions (MICs) were determined after incubation at 37 °C for
14 days (see Table 1). MIC was the lowest concentration of
an antimycobacterially effective substance (on the above-
stated concentration scale), at which inhibition of the growth
of the mycobacteria occurred.
4.1.1.63.
N-(5-Methyl-pyridin-2-yl)-5-chloro-2-hydroxy-
benzamide (7f). White crystals. Yield 60%, m.p. 280–
282 °C, IR (KBr): m (C=O) 1680 cm–1. 1H NMR (300 MHz):
d 12.12 (bs, 1H, NH), 10.73 (bs, 1H, OH), 8.18–8.15 (m, 1H,
H6′), 8.12 (d, 1H, J = 8.52 Hz, H3′), 8.01 (d, 1H, J = 8.52 Hz,
H6), 7.64 (dd, 1H, J = 8.52 Hz, J = 2.47 Hz, H4′), 7.06 (d, 1H,
J = 1.92 Hz, H3), 7.03 (dd, 1H, J = 8.52 Hz, J = 1.92 Hz, H5),
2.25 (s, 3H, CH3). 13C NMR (75 MHz): d 163.6, 157.6,
149.5, 148.1, 139.0, 137.8, 132.5, 129.2, 120.1, 117.7, 116.9,
113.9, 17.5.
4.1.1.64.
N-(6-Methyl-pyridin-2-yl)-5-chloro-2-hydroxy-
benzamide (7g). White crystals. Yield 71%, m.p. 231–
232 °C, IR (KBr): m (C=O) 1680 cm–1. 1H NMR (300 MHz):
d 11.96 (bs, 1H, NH), 10.78 (bs, 1H, OH), 8.03 (d, 1H,
J = 7.83 Hz, H3′), 7.96 (d, 1H, J = 2.89 Hz, H6), 7.71 (t, 1H,
J = 7.83 Hz, H4′), 7.47 (dd, 1H, J = 8.79 Hz, J = 2.89 Hz, H4),
7.05 (d, 1H, J = 8.79 Hz, H3), 7.01 (d, 1H, J = 7.83 Hz, H5′),
2.40 (s, 3H, CH3). 13C NMR (75 MHz): d 162.9, 157.1,
155.6, 150.8, 139.0, 133.5, 130.0, 123.7 120.1, 119.6, 119.3,
111.2, 23.9.
4.3. Calculations
4.1.1.65. N-(3-Hydroxy-pyridin-2-yl)-5-chloro-2-hydroxy-
benzamide (7h). Yellow crystals. Yield 82%, m.p. 284–
286 °C, IR (KBr): m (C=O) 1641 cm–1. 1H NMR (300 MHz):
d 11.24 (bs, 1H, NH), 7.99 (d, 1H, J = 2.75 Hz, H6), 7.88 (dd,
1H, J = 4.81 Hz, J = 1.37 Hz, H6′), 7.47 (dd, 1H, J = 8.79 Hz,
The logarithms of the partition coefficients were calcu-
lated using ChemOffice 5 software (Table 2). All regression
calculations were set up using the Multireg H programme
(Klemera) for Microsoft Excel.

K. Waisser et al. / IL FARMACO 59 (2004) 615–625
623
Table 1
In vitro antimycobacterial activity of N-pyridinylsalicylamides
Compounds
MICs (µmol l–1
)
R1
R2
Mycobacterium
tuberculosis
My 331/88
M. avium
My 330/88
14 days
M. kansasii
My 235/80
14 days
M. kansasii
My 6509/96
14 days
14 days
n
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
2-pyridyl
n
n
n
H
3-pyridyl
125
62.5
62.5
125
n
n
n
n
H
4-pyridyl
500
n
1000
n
1000
n
H
5-chloro-2-pyridyl
4-methyl-2-pyridyl
5-methyl-2-pyridyl
6-methyl-2-pyridyl
3-hydroxy-2-pyridyl
5-nitro-2-pyridyl
5-bromo-2-pyridyl
2-pyridyl
H
n
n
n
H
n
n
n
H
n
n
n
n
H
250
32
n
500
n
500
n
500
n
H
1j
H
n
n
n
2a
2b
2c
2d
2e
2f
2g
2h
2i
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
5-F
32
16
16
n
125
125
n
n
125
32
250
n
3-pyridyl
62.5
n
4-pyridyl
5-chloro-2-pyridyl
4-methyl-2-pyridyl
5-methyl-2-pyridyl
6-methyl-2-pyridyl
3-hydroxy-2-pyridyl
5-nitro-2-pyridyl
5-bromo-2-pyridyl
2-pyridyl
n
n
16
16
32
250
n
n
n
n
n
n
n
n
n
n
1000
n
250
n
250
n
2j
n
n
n
n
3a
3d
3e
3f
3g
3h
3i
8
n
n
n
5-chloro-2-pyridyl
4-methyl-2-pyridyl
5-methyl-2-pyridyl
6-methyl-2-pyridyl
3-hydroxy-2-pyridyl
5-nitro-2-pyridyl
5-bromo-2-pyridyl
2-pyridyl
8
32
n
62.5
n
32
n
8
8
125
125
500
32
n
n
n
n
250
250
16
n
250
250
32
n
125
8
3j
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
8
32
125
n
62.5
250
n
62.5
125
n
3-pyridyl
16
32
8
4-pyridyl
5-chloro-2-pyridyl
4-methyl-2-pyridyl
5-methyl-2-pyridyl
6-methyl-2-pyridyl
3-hydroxy-2-pyridyl
5-nitro-2-pyridyl
5-bromo-2-pyridyl
2-pyridyl
32
32
8
16
32
8
16
32
4
8
4
4
62.5
500
32
16
62.5
n
8
8
250
8
500
8
500
16
2
4j
4
2
5a
5b
5c
5d
5e
5f
5g
5h
5i
62.5
250
n
n
62.5
250
n
5-F
3-pyridyl
n
5-F
4-pyridyl
n
n
5-F
5-chloro-2-pyridyl
4-methyl-2-pyridyl
5-methyl-2-pyridyl
6-methyl-2-pyridyl
3-hydroxy-2-pyridyl
5-nitro-2-pyridyl
5-bromo-2-pyridyl
2-pyridyl
4
32
32
n
16
32
n
16
32
n
5-F
32
n
5-F
5-F
n
n
n
n
5-F
250
4
500
32
32
n
250
8
250
16
32
n
5-F
5j
5-F
16
n
32
n
6a
6b
6c
5-Br
5-Br
5-Br
3-pyridyl
n
n
n
n
4-pyridyl
n
n
nn
(continued on next page)

624
K. Waisser et al. / IL FARMACO 59 (2004) 615–625
Table 1
(continued)
Compounds
MICs (µmol l–1
)
R1
R2
Mycobacterium
tuberculosis
My 331/88
M. avium
My 330/88
14 days
M. kansasii
My 235/80
14 days
M. kansasii
My 6509/96
14 days
14 days
6d
6e
6f
6g
6h
6i
5-Br
5-Br
5-Br
5-Br
5-Br
5-Br
5-Br
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-chloro-2-pyridyl
4-methyl-2-pyridyl
5-methyl-2-pyridyl
6-methyl-2-pyridyl
3-hydroxy-2-pyridyl
5-nitro-2-pyridyl
5-bromo-2-pyridyl
2-pyridyl
8
32
8
16
32
n
62.5
n
125
n
62.5
n
62.5
250
8
125
500
32
125
500
8
62.5
500
8
6j
8
62.5
62.5
n
16
62.5
n
16
62.5
n
7a
7c
7d
7e
7f
7g
7h
7i
62.5
n
4-pyridyl
5-chloro-2-pyridyl
4-methyl-2-pyridyl
5-methyl-2-pyridyl
6-methyl-2-pyridyl
3-hydroxy-2-pyridyl
5-nitro-2-pyridyl
5-bromo-2-pyridyl
8
62.5
32
16
8
16
8
8
n
n
n
n
16
125
2
62.5
500
16
32
250
4
n
250
8
7j
INH
4
n
8
16
4
1
250
250
n: MIC values could not be determined due to the low solubility.
Table 2
Lipophilicity (log P) of compounds 1a–7j
Compounds
log P
1.30
1.07
1.07
1.92
1.72
1.72
1.77
0.92
1.12
3.07
1.72
1.49
1.49
2.87
2.13
2.13
3.02
1.93
1.61
3.14
Compounds
log P
Compounds
log P
1.99
1.27
1.27
2.55
2.47
2.47
2.69
1.60
1.28
2.82
2.66
1.94
1.94
3.22
3.14
3.14
3.36
2.27
1.95
3.49
Compounds
log P
1a
1b
1c
1d
1e
1f
1g
1h
1i
3a
1.70
5a
5b
5c
5d
5e
5f
5g
5h
5i
7a
1.92
7c
7d
7e
7f
7g
7h
7i
1.69
2.95
2.87
2.87
3.09
2.00
1.68
3.22
3d
3e
3f
3g
3h
3i
2.26
2.19
2.19
2.41
1.31
1.00
2.53
1.92
1.69
1.69
2.95
2.87
2.87
3.09
2.00
1.68
3.62
1j
3j
5j
7j
INH
2a
2b
2c
2d
2e
2f
2g
2h
2i
4a
4b
4c
4d
4e
4f
4g
4h
4i
6a
6b
6c
6d
6e
6f
6g
6h
6i
2j
4j
6j
Acknowledgements
References
This work is a part of the research project No. MSM
111600001 of the Ministry of Education of the Czech Repub-
lic and was supported by grant 203/02/0082 GrantAgency of
Czech Republic.
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