Heterocyclic isosters of antimycobacterial salicylanilides

Article abstract of DOI:10.1016/j.farmac.2005.02.002

A series of 64 derivatives of substituted heterocyclic analogues of salicylanilides was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacter

Full text of DOI:10.1016/j.farmac.2005.02.002

Il Farmaco 60 (2005) 399–408
http://france.elsevier.com/direct/FARMAC/
Heterocyclic isosters of antimycobacterial salicylanilides
Josef Matyk a, Karel Waisser a,*, Katerˇina Dražková a, Jirˇí Kuneš a, Veˇra Klimešová a,
Karel Palát Jr. a, Jarmila Kaustová b
a Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Heyrovského 1203, CZ 500 05 Hradec Králové, Czech Republic
b Department for Diagnostics of Mycobacteria, Regional Institute of Public Health, Ostrava, Partyzánské nám. 7, CZ-70200 Ostrava, Czech Republic
Received 26 January 2005; received in revised form 11 February 2005; accepted 19 February 2005
Available online 12 April 2005
This paper is dedicated to Professor Otto Exner on the occasion of his 80th birthday
A series of 64 derivatives of substituted heterocyclic analogues of salicylanilides was synthesized. The compounds were evaluated for in
vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii. For
the QSAR study, the combination of Free–Wilson approach with Hansch approach was used. The molecules were separated on the heterocy-
clic and salicyl moieties and the study of influences of electronic and hydrophobic properties was used as well. The compounds are a new
group of potential antituberculotics.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Tuberculostatic; Antituberculotics; Salicylamides; QSAR; Structure–activity relationships; Heterocycles
1. Introduction
were prepared by the treatment of phenyl-salicylate with het-
eroaromatic compound substituted by amino group. An over-
view of the compounds under study is in Fig. 1. The synthe-
sis of some N-(5-methylisoxazol-3-yl)salicylamides by this
pathway was not often successful because of the thermal
decomposition of the product. In these cases we have suc-
ceeded by use more active 4-trifluromethylphenyl-salicylate.
The use of 4-nitrophenyl-salicylate usually was going to
destruction of product, as well.
The study of antimycobacterial properties of salicylanil-
ides [1,2] is of great interest, as salicylanilides can inhibit
bacterial two-component systems [3,4]. We have published
several papers oriented on the antimycobacterial benzylsali-
cylamides [5,6], the activity of isosters of salicylanilides:
2-sulfanylbenzanilides [7], N-benzylsulfanylbenzamides [7],
3-hydroxypicolinanilides [7], N-benzyl-3-hydroxypico-
linamides [7]. In our previous paper, we published in this jour-
nal, the first part of heterocyclic isosters of amide moiety was
presented, e.g., N-pyridinylsalicylamides [8]. The goal of this
paper was to study the antimycobacterial activity of other isos-
ters of salicylanilides with other heterocyclic rings in amide
moiety of compounds (pyrimidine, pyrazine, thiazole, benz-
thiazole, benzimidazole and isoxazole).
1
The structural assignment is based on H NMR and 13C
NMR spectra and IR spectra. In the IR spectra, the carbonyl
vibration m(C=O) was observed in the region 1620–1697 cm–1.
The antimycobacterial activity of the synthesized
N-benzylsalicylamides is given in Table 1.
3. Result and discussion
Compounds under study are a new group of the potential
antitubercuoltics. For the QSAR analysis, we used the com-
bination of Hansch and Free–Wilson approaches. According
to the Free–Wilson method the molecules were separate on
two moieties. We used the experimental values from physical
measurements as electronic parameters. We suppose d(N-H)
from 1H-NMR spectrum is the describing influence of elec-
tronic properties of the heterocyclic moiety. We used the cal-
2. Chemistry
The synthetic pathway leading to N-heteroary-
lsalicylamides is depicted in Fig. 1. N-heteroarylsalicylamides
* Corresponding author. Fax: +4204955144330.
E-mail addresses: waisser@faf.cuni.cz (K. Waisser),
jarmila.kaustova@zuova.cz (J. Kaustová).
0014-827X/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.farmac.2005.02.002

400
J. Matyk et al. / Il Farmaco 60 (2005) 399–408
Fig. 1. Synthesis of N-heteroaryl-2-hydroxy-benzamides.
culated logarithm of partition coefficients for expression of
the hydrophobic properties of molecules. The result is sum-
marised in Table 2. All equations were statistically signifi-
cant (confidents level more as 95%, significant level less as
0.05).
phosphorus oxychloride was added The mixture was heated
at 75–80 °C for 4 h and then poured into a solution of 12 g
sodium carbonate in 80 ml of water. The product was fil-
trated and recrystallised from ethanol.
4.1.1.1. Synthesis of 4-trifluorophenyl-salicylat. White crys-
tals. Yield 48%, m.p. 89–90 °C, IR: m(C=O) 1681 cm–1. 1H
NMR (300 MHz,) d 10.26 (bs, 1H, OH), 8.02–7.96 (m, 1H,
H6), 7.89–7.82 (m, AA′, BB′, 2H, H3′, H5′), 7.60–7.51 (m,
3H, H4, H2′, H6′), 7.09–6.97 (m, 2H, H3, H5). 13C NMR
(75 MHz,) d 166.2, 160.3, 153.4, 136.3, 131.2, 127.2 (q, J
= 3.7 Hz), 127.0 (q, J = 32.1 Hz), 124.2 (q, J = 272.0 Hz),
123.4, 119.7, 117.9, 113.4.
It seems that substitution in position 4 and 5 on the acyl
moiety increases antimycobacterial activity against all strains
of Mycobacterium. From heterocyclic moieties, benzimida-
zolyl brings to molecules good antimycobacterial activity,
isoxazolyl has the strongest influence on the increase of the
activity against M. uberculosis. Some compounds under study
are more active against potentially pathogenic strains (M. kan-
sasii 250/80 and M. avium 330/88, e.g., 2c, 7i) than iso-
niazid.
4.1.1.2. Synthesis of 4-trifluorophenyl-4-methoxysalicy-
late. White crystals.Yield 37%, m.p. 119–121 °C, IR: m(C=O)
1685 cm–1. 1H NMR (300 MHz,): d 10.39 (bs, 1H, OH), 7.94
(d, 1H, J = 8.8 Hz, H6), 7.89–7.79 (m, AA′, BB′, 2H, H3′,
H5′), 7.59–7.49 (m, AA′, BB′, 2H, H2′, H6′), 6.63–6.59 (m,
2H, H3, H5), 3.83 (s, 3H, OCH3). 13C NMR (75 MHz) d
166.5, 166.0, 163.2, 153.3, 132.6, 127.1 (q, J = 3.7 Hz), 126.9
(q, J = 32.3 Hz), 124.2 (q, J = 272.0 Hz), 123.4, 107.9, 105.2,
101.4, 55.9.
4. Experimental
4.1. Chemistry
The melting points were determined on a Kofler appara-
tus. The samples for analysis and antimycobacterial tests were
dried over P2O5 at 61 °C and 66 Pa for 24 h Elemental analy-
ses (C, H, N) were performed on a CHNS-O CE elemental
analyzer (Fisions EA 1110, Milan) and were within 0.4%
of the theoretical values. The IR spectra were measured in
KBr pellets on a Nicolet Impact 400 apparatus; the wavenum-
bers are given in cm–1. TLC was performed on silica gel plates
precoated with a fluorescent indicator Silufol UV 254 + 366
(KavalierVotice, Czech Republic), cyclohexane-acetone (3:1)
was used as the mobile phase. The 1H NMR and 13C NMR
spectra of new compounds were recorded in DMSO-d6 solu-
tions at ambient temperature on a Varian Mercury-Vx BB
4.1.2. Synthesis of N-heteroaryllsalicylamides. 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 recrystallised from the same solvent (yields 22–89%).
For the preparation of compounds 1i 4-trifluorophenyl-
salicylate was used instead of phenyl-salicylate. Similar for
preparation of compounds 3i, 4-trifluorophenyl-4-
methoxysalicylate was used and the reaction mixture was
melted at 132 °C for 24 h.
1
300 spectrometer operating at 300 MHz for H NMR, and
75 MHz for 13C NMR. Chemical shifts were recorded as d
values in parts per million (ppm) and being indirectly refer-
enced to tetramethylsilane via the solvent signal (2.49 for 1H
or 39.7 for 13C).
4.1.2.1. 2-Hydroxy -N-(4,6-dimethylpyrimidin-2-yl)benza-
mide (1a). Yellow crystals.Yield 52%, m.p. 211–213 °C, IR:
1
4.1.1. Synthesis of 4-trifluoromethylphenyl-salycylates
To the mixture of 0.1 mol salicylic acid (or substituted sali-
cylic acid) and 0.1 mol 4-trifluoromethylphenol 0.04 mol of
m(C=O) 1648 cm–1. H NMR (300 MHz): d 11.74 (bs, 1H,
NH), 10.93 (bs, 1H, OH), 7.99 (dd, 1H, J = 7.69 Hz, J
= 1.65 Hz, H6), 7.47–7.39 (m, 1H, H4), 7.03–6.91 (m, 3H,

J. Matyk et al. / Il Farmaco 60 (2005) 399–408
401
Table 1
In vitro antimycobacterial activity of N-heteroarylsalicylamides
Com.
Minimum inhibitory concentrations (MICs) mol l–1
R1
R2
M. tuberculosis
M. avium
M. kansas ii
M. kansasii
My 331/88
My 330/88
My 235/80
My 6509/96
14 days
1000
n
14 days
14 days
14 days
1a
1b
1c
1d
1e
1f
H
N-(4,6-dimethylpyrimidin-2-yl)
N-(4-methylpyrimidin-2-yl)
N-(pyrazin-2-yl)
1000
n
1000
n
1000
n
H
H
125
62.5
1000
500
n
125
250
n
500
500
n
500
250
n
H
N-(thiazol-2-yl)
H
N-(1,2,4-triazol-4-yl)
N-(1,2,4-triazol-3-yl)
N-(benzimidazol-2-yl)
N-(benzothiazol-2-yl)
N-(4-methylthiazol-2-yl)
N-(4,6-dimethylpyrimidin-2-yl)
N-(pyrazin-2-yl)
H
n
n
n
1g
1h
1k
2a
2c
2d
2e
2f
H
n
n
n
H
n
n
n
500
H
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-OCH3
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
5-F
62.5
16
1000
62.5
125
1000
n
n
n
32
62.5
125
1000
n
N-(thiazol-2-yl)
16
n
N-(1,2,4-triazol-4-yl)
N-(1,2,4-triazol-3-yl)
N-(benzimidazol-2-yl)
N-(benzothiazol-2-yl)
N-(5-methylisoxazol-3-yl)
N-(4-methylpyrimidin-2-yl)
N-(pyrazin-2-yl)
1000
125
n
1000
500
n
2g
2h
2i
n
n
8
n
n
n
16
62.5
n
125
n
125
n
3b
3c
3d
3e
3f
32
16
250
500
1000
1000
n
250
500
1000
1000
n
250
500
1000
1000
n
N-(thiazol-2-yl)
250
1000
500
n
N-(1,2,4-triazol-4-yl)
N-(1,2,4-triazol-3-yl)
N-(benzimidazol-2-yl)
N-(benzothiazol-2-yl)
N-(5-methylisoxazol-3-yl)
N-(4-methylthiazol-2-yl)
N-(4,6-dimethylpyrimidin-2-yl)
N-(4-methylpyrimidin-2-yl)
N-(pyrazin-2-yl)
3g
3h
3i
n
n
n
n
125
125
n
250
250
n
250
250
n
250
250
n
3k
4a
4b
4c
4d
4e
4f
62.5
16
500
250
250
1000
n
1000
125
250
1000
n
1000
125
250
1000
n
N-(thiazol-2-yl)
16
N-(1,2,4-triazol-4-yl)
N-(1,2,4-triazol-3-yl)
N-(benzimidazol-2-yl)
N-(benzothiazol-2-yl)
N-(5-methylisoxazol-3-yl)
N-(4-methylthiazol-2-yl)
N-(4,6-dimethylpyrimidin-2-yl)
N-(4-methylpyrimidin-2-yl)
N-(pyrazin-2-yl)
1000
n
4g
4h
4i
n
n
n
n
n
n
n
n
8
125
250
n
n
125
125
n
4k
5a
5b
5c
5d
5e
5f
16
125
n
n
5-F
n
n
n
n
5-F
125
250
1000
500
n
125
1000
n
125
62.5
1000
500
n
125
62.5
1000
n
5-F
N-(thiazol-2-yl)
5-F
N-(1,2,4-triazol-4-yl)
N-(1,2,4-triazol-3-yl)
N-(benzimidazol-2-yl)
N-(benzothiazol-2-yl)
N-(5-methylisoxazol-3-yl)
N-(4-methylpyrimidin-2-yl)
N-(pyrazin-2-yl)
5-F
250
n
5g
5h
5i
5-F
n
5-F
n
n
n
n
5-F
250
n
250
n
250
n
62.5
n
6b
6c
6d
6e
6f
5-Br
5-Br
5-Br
5-Br
5-Br
5-Br
5-Br
5-Br
5-Br
125
62.5
1000
500
n
250
125
1000
n
n
125
250
1000
n
N-(thiazol-2-yl)
250
1000
n
N-(1,2,4-triazol-4-yl)
N-(1,2,4-triazol-3-yl)
N-(benzimidazol-2-yl)
N-(benzothiazol-2-yl)
N-(5-methylisoxazol-3-yl)
N-(4-methylthiazol-2-yl)
6g
6h
6i
n
n
n
n
n
n
n
125
125
250
250
500
250
500
125
6k
(continued on next page)

402
J. Matyk et al. / Il Farmaco 60 (2005) 399–408
Table 1
(continued)
Com.
Minimum inhibitory concentrations (MICs) mol l–1
R1
R2
M. tuberculosis
M. avium
M. kansas ii
M. kansasii
My 331/88
My 330/88
My 235/80
My 6509/96
14 days
250
62.5
1000
n
14 days
14 days
125
62.5
1000
n
14 days
62.5
62.5
1000
n
7b
7c
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
N-(4-methylpyrimidin-2-yl)
N-(pyrazin-2-yl)
250
250
1000
n
7e
N-(1,2,4-triazol-4-yl)
N-(1,2,4-triazol-3-yl)
N-(benzimidazol-2-yl)
7f
7g
7h
5-Cl
7i
n
n
n
n
N-(benzothiazoln-2-yl)
n
n
n
5-Cl
5-Cl
5-Cl
N-(5-methylisoxazol-3-yl)
125
n
62.5
n
62.5
n
32
n
7j
N-(pyrimidin-2-yl)
N-(4-methylthiazol-2-yl)
(i.g. isoniazide)
7k
INH
62.5
2
250
250
62.5
250
32
4
n—MIC values could not be determined due to the low solubility.
H3, H5, H5′), 2.37 (s, 6H, CH3).13C NMR (75 MHz): d 168.0,
164.5, 157.6, 157.2, 134.2, 130.6, 119.7, 118.2, 117.4, 116.2,
23.6.
4.1.2.3. 2-Hydroxy N-(pyrazin-2-yl)benzamide (1c). Brown
crystals. Yield 74%, m.p. 213–216 °C, Ref. [9] 216–218 °C.
1
IR: m(C=O) 1671 cm–1. H NMR (300 MHz): d 11.78 (bs,
1H, NH), 11.02 (bs, 1H, OH), 9.50 (d, 1H, J = 1.38 Hz, H3′),
8.43–8.39 (m, 2H, H5′, H6′), 8.02 (dd, 1H, J = 7.97 Hz, J
= 1.79 Hz, H6), 7.49–7.42 (m, 1H, H4), 7.08–6.95 (m, 2H,
H3, H5). 13C NMR (75 MHz): d 164.5, 157.0, 148.6, 143.0,
140.4, 136.8, 134.5, 131.0, 120.1, 117.9, 117.4.
4.1.2.2. 2-Hydroxy N-(4-methylpyrimidin-2-yl)benzamide
(1b). Brown crystals. Yield 76%, m.p. 261–264 °C. IR:
1
m(C=O) 1686 cm–1. H NMR (300 MHz): d 11.74 (bs, 1H,
NH), 11.01 (bs, 1H, OH), 8.54 (d, 1H, J = 4.94 Hz, H6′), 7.98
(dd, 1H, J = 7.97 Hz, J = 1.65 Hz, H6), 7.48–7.39 (m, 1H,
H4), 7.12 (d, 1H, J = 4.95 Hz, H5′), 7.03–6.93 (m, 2H, H3,
H5), 2.43 (s, 3H, CH3). 13C NMR (75 MHz): d 168.6, 164.4,
158.2, 157.5, 157.4, 134.2, 130.7, 119.8, 118.3, 117.4, 117.0,
23.8,
4.1.2.4. 2-Hydroxy-N-(thiazol-2-yl)benzlamide (1d). Brown
crystals. Yield 56%, m.p. 251–252 °C, Ref. [10] 252 °C. IR:
1
m(C=O) 1671 cm–1. H NMR (300 MHz): d 12.22 (bs, 1H,
NH), d 7.99 (dd, 1H, J = 7.83 Hz, J = 1.37) Hz, H6), 7.54 (d,
Table 2
Activity contribution of the combination of Free–Wilson and Hansch analysis
Fragment
Dlog MIC (µmol/l, incubation 14 days)
M. tuberculosis My 331/88 M. avium My 330/80
M. kansasii My 235/80 My 6509/96
R1: H
0
0
0
0
4-Cl
–0.7144 ( 0.2196)
–0.7159 ( 0.1974)
–0.7570 ( 0.1991)
–0.4518 ( 0.2144)
–0.4324 ( 0.2215)
–0.6772 ( 0.2270)
0
–0.2980 ( 0.2117)
–0.2945 ( 0.2098)
–0.1105 ( 0.2189)
–0.5055 ( 0.2042)
–0.1850 ( 0.2109)
–0.2537 ( 0.2176)
0
–0.8811 ( 0.2871)
–1.0103 ( 0.3358)
–0.4726 ( 0.3199)
–1.0504 ( 0.2892)
–0.9109 ( 0.2998)
–1.0060 ( 0.2889)
0
–1.1168 ( 0.2654)
–0.8459 ( 0.3076)
–0.5030 ( 0.3360)
–0.8196 ( 0.2864)
–1.1828 ( 0.2954)
–1.1547 ( 0.2885)
0
4-CH3
4-OCH3
5-F
5-Br
5-Cl
R2:benzimidazolyl
Pyrimidyl
0.8571 ( 0.2523)
0.4576 ( 0.1671)
0.3834 ( 0.2390)
1.6472 ( 0.2015)
0.0174 ( 0.4377)
–0.0923 ( 0.4370)
–0.5305 ( 0.2051)
0.2198 ( 0.0831)
8.0314
1.2541 ( 0.3590)
0.4797 ( 0.1481)
0.5962 ( 0.2159)
1.2661 ( 0.1762)
0.2803 ( 0.1214)
0.3356 ( 0.1485)
–0.4772 ( 0.1671)
0.1627 ( 0.0672)
7.6572
0.8547 ( 0.4552)
0.5578 ( 0.2189)
1.0135 ( 0.2982)
1.55521 ( 0.2370)
0.1264 ( 0.0573)
0.3267 ( 0.4549)
–0.5760 ( 0.2261)
0.2039 ( 0.0888)
–0.0045
0.7174 ( 0.4323)
0.5720 ( 0.2114)
0.6154 ( 0.2574)
1.6457 ( 0.2271)
0.2344 ( 0.1102)
–0.0459 ( 0.3543)
–0.0001 ( 0.0003)
0.3054 ( 0.0859)
2.3799
Pyrazinyl
Thiazolyl
Triazolyl
Benzothiazolyl
Isoxazolyl
D(NH)
log P2
µ0
R
s
0.853
0.808
0.877
0.839
0.404
0.324
0.428
0.462
F
n
10.55
6.58
9.17
7.96
65
46
46
53

J. Matyk et al. / Il Farmaco 60 (2005) 399–408
403
1H, J = 3.85 Hz, H4′), 7.48–7.40 (m 1H, H4), 7.25 (d, 1H, J
3.85 Hz, H5′), 7.04–6.91 (m, 2H, H3, H5). 13C NMR
(75 MHz): d 160.4, 158.2, 134.4, 130.5, 119.6, 117.4,
4.1.2.11. 2-Hydroxy-4-methyl-N-(4,6-dimethylpyrimidin-2-
yl)benzamide (2a). Yellow crystals. Yield 53%, m.p. 248–
251 °C, IR: m (C=O) 1662 cm–1. 1H NMR (300 MHz): d 11.77
(bs, 1H, NH), d 10.93 (bs, 1H, OH), 7.88 (d, 1H, J = 7.96 Hz,
H6), 7.00 (s, 1H, H5′), 6.82–6.74 (m, 2H, H3, H5), 2.37 (s,
6H, CH3), 2.28 (s, 3H, CH3). 13C NMR (75 MHz): d 168.0,
164.8, 158.0, 157.2, 144.8, 130.4, 120.7, 117.6, 116.1, 115.3,
23.6, 21.3.
=
113.8.
4.1.2.5. 3-Hydroxy-N-(4H-[1,2,4]triazol-4-yl)benzamide
(1e). White crystals. Yield 62%, m.p. 290–293 °C, IR: m
1
(C=O) 1662 cm–1. H NMR (300 MHz): d 11.53 (bs, 1H,
NH), d 8.75 (s, 2H, H3′, H5′), 7.85 (dd, 1H, J = 7.97 Hz, J
= 1.65 Hz, H6), 7.52–7.43 (m, 1H, H4), 7.06–6.94 (m, 2H,
H3, H5). 13C NMR (DMSO): d 166.4, 158.0, 144.2, 134.7,
130.2, 119.6, 117.3, 115.7.
4.1.2.12. 2-Hydroxy-4-methyl-N-(pyrazin-2-yl)benzamide
(2c). Brown crystals. Yield 65%, m.p. 213–215 °C, IR: m
1
(C=O) 1676 cm–1. H NMR (300 MHz): d 11.74 (bs, 1H,
NH), 10.96 (bs, 1H, OH), 9.49 (d,1H, J = 1.37 Hz, H3′), 8.43–
8.39 (m, 2H, H5′, H6′), 7.93 (d, 1H, J = 7.97 Hz, H6), 6.86–
6.79 (m, 2H, H3, H5), 2.29 (s, 3H, CH3). 13C NMR (75 MHz):
d 164.6, 157.0, 148.6, 145.2, 143.0, 140.3, 136.8, 130.9, 121.2,
117.5, 115.0, 21.3.
4.1.2.6. 2-Hydroxy-N-(4H-[1,2,4]triazol-3-yl)benzamide
(1f). White crystals.Yield 80%, m.p. 276–279 °C, IR: m (C=O)
1667 cm–1. 1H NMR (300 MHz): d 11.41 (bs, 1H, NH), d
8.02–7.96 (m, 2H, H6, H5′), 7.50–7.41 (m, 1H, H4), 7.05–
6.92 (m, 2H, H3, H5). 13C NMR (75 MHz): d 165.9, 158.3,
147.3, 134.6, 130.2, 119.7, 117.5, 116.8.
4.1.2.13. 2-Hydroxy-4-methyl-N-(thiazol-2-yl)benzamide
(2d). Brown crystals. Yield 54%, m.p. 254–257 °C, IR: m
1
4.1.2.7.
N-(Benzimidazol-2-yl)-2-hydroxybenzamide
(C=O) 1666 cm–1. H NMR (300 MHz): d 12.10 (bs, 1H,
(1g). White crystals. Yield 90%, m.p. 355–357 °C, Ref. [11]
250 °C IR: m (C=O) 1667 cm–1. For C14H11N3O2 (253.3) cal-
culated: 66.40% C, 16.59% N, 4.38% H; found: 66.23% C,
16.43% N, 4.31% H. 1H NMR (300 MHz): d 8.02–7.97
(m, 1H, H6), 7.49–7.42 (m, 2H, H4′, H7′), 7.38–7.31
(m, 1H, H4), 7.27–7.20 (m, 2H, H5′, H6′), 6.88–6.82
(m, 2H, H3, H5). 13C NMR (75 MHz): d 172.6, 160.7,
151.3, 133.6, 130.1, 129.5, 123.2, 119.8, 118.2, 117.3,
112.1.
NH), 7.89 (d, 1H, J = 7.97 Hz, H6), 7.53 (d, 1H, J = 3.85 Hz,
H4′), 7.24 (d, 1H, J = 3.84 Hz, H5′), 6.83–6.76 (m, 2H, H3,
H5), 2.29 (s, 3H, CH3). 13C NMR (75 MHz): d 179.3, 166.9,
158.2, 145.2, 130.4, 120.8, 117.6, 114.5, 113.8, 21.4.
4.1.2.14. -2-Hydroxy-4-methyl-N-(4H-[1,2,4]triazol-4-yl)
benzamide (2e). White crystals. Yield 65%, m.p. 304–
306 °C, IR: m (C=O) 1661 cm–1. 1H NMR (300 MHz): d 11.51
(bs, 1H, NH), 8.74 (bs, 2H, H3′, H5′), 7.75 (d, 1H, J = 8.24 Hz,
H6), 6.85–6.77 (m, 2H, H3, H5), 2.29 (s, 3H, CH3). 13C NMR
(75 MHz): d 166.6, 158.3, 145.5, 144.2, 129.9, 120.7, 117.5,
112.6, 21.4.
4.1.2.8.
N-(Benzothiazol-2-yl)-2-hydroxybenzamide
(1h). White crystals. Yield 86%, m.p. 322–324 °C, IR: m
1
(C=O) 1676 cm–1. H NMR (300 MHz): d 12.26 (bs, 1H,
NH), d 8.03–7.97 (m, 2H, H6, H7′), 7.72 (d, 1H, J = 7.97 Hz,
H4′), 7.52–7.42 (m, 2H, H4, H6′), 7.37–7.29 (m, 1H, H5′),
7.07–6.95 (m, 2H, H3, H5). 13C NMR (75 MHz): d 166.7,
158.2, 146.5, 134.9, 130.7, 126.8, 124.0, 122.3, 119.8, 119.2,
117.5, 117.3.
4.1.1.15. 2-Hydroxy-4-methyl-N-(4H-[1,2,4]triazol-3-yl)
beznamide (2f). White crystals. Yield 82%, m.p. 315–
317 °C, IR: m (C=O) 1681 cm–1. 1H NMR (300 MHz): d 11.80
(bs, 1H, NH), 7.91 (d, 1H, J = 7.97 Hz, H6), 7.90 (bs, 1H,
H5′), 6.84–6.76 (m, 2H, H3, H5), 2.29 (s, 3H, CH3).13C NMR
(75 MHz): d 166.0, 158.4, 148.6, 145.4, 130.0, 129.8, 120.8,
117.6, 113.7, 21.4.
4.1.2.9. 2-Hydroxy-N-(5-methylioxyzol-3-yl)benzamide
(1i). White crystals. Yield 22%, m. p. 183–1855 °C. IR: m
(C=O) 1653 cm–1. 1H NMR (300 MHz) d 11.73 (bs, 1H, NH),
11.05 (bs, 1H, OH), 7.97 (dd, 1H, J = 8.0 Hz, J = 1.7 Hz, H6),
7.50–7.41 (m, 1H, H4), 7.05–6.93 (m, 2H, H3, H5), 6.76 (d,
1H, J = 0.8 Hz H4′), 2.40 (d, J = 0.8 Hz, 3H, CH3), 13C NMR
(75 MHz,) d 170.1, 165.4, 158.1, 157.9, 134.5, 130.3, 119.7,
117.4, 117.2, 97.1, 12.4.
4.1.2.16. N-(Benzimidazol-2-yl)-2-hydroxy4-methylbenza-
mide (2g). White crystals. Yield 82%, m.p. 318–320 °C, IR:
m (C=O) 1664 cm–1. 1H NMR (300 MHz): d 7.87 (d, 1H, J
= 7.69 Hz, H6), 7.49–7.41 (m, 2H, H4′, H7′), 7.26–7.18 (m,
2H, H5′, H6′), 6.68 (s, 1H, H3), 6.67–6.64 (m, 1H, H5), 2.27
(s, 3H, CH3). 13C NMR (75 MHz): d 172.7, 160.6, 151.3,
143.9, 130.1, 129.6, 123.1, 119.5, 117.5, 117.3, 112.0, 21.4.
4.1.2.10. 2-Hydroxy-N-(4-methylthiazol-2-yl)benzamide
(1k). Yellow crystals. Yield 85%, m.p. 254–255 °C. IR: m
4.1.2.17. N-(Benzothiazol-2-yl)-2-hydroxy-4-methylbenza-
mide (2h). White crystals. Yield 78%, m.p. 294–296 °C, IR:
m (C=O) 1677 cm–1. 1H NMR (300 MHz): d 12.12 (bs, 1H,
NH), 7.99 (d, 1H, J = 7.96 Hz, H6), 7.92 (d, 1H, J = 7.97 Hz,
H7′), 7.72 (d, 1H, J = 7.96 Hz, H4′), 7.50–7.42 (m, 1H, H5′),
7.36–7.29 (m, 1H, H6′), 6.87–6.78 (m, 2H, H3, H5), 2.30 (s,
1
(C=O) 1672 cm–1. H NMR (300 MHz): d 7.97 (1H, dd, J
= 8.0 Hz, J = 1.9 Hz, H6), 7.47–7.37 (1H, m, H4), 7.02–6.88
(2H, m, H3, H5), 6.78 (1H, s, H5′), 2.77 (3H, s, CH3). 13C
NMR (75 MHz): d 167.7, 158.6, 134.3, 130.4, 119.4, 117.6,
117.4, 107.8, 15.7.

404
J. Matyk et al. / Il Farmaco 60 (2005) 399–408
3H, CH3). 13C NMR (75 MHz): d 158.1, 145.7, 130.6, 126.7,
124.0, 122.3, 121.0, 117.6, 114.4, 114.3, 21.4.
4.2.1.24. N-(Benzimidazol-2-yl)-2-hydroxy-4-methoxybenza-
mide (3g). White crystals. Yield 59%, m.p. 304–306 °C, IR:
m (C=O) 1665 cm–1. 1H NMR (300 MHz): d 7.90 (d, 1H, J
= 8.79 Hz, H6), 7.47–7.40 (m, 2H, H4′, H7′), 7.25–7.18 (m,
2H, H5′, H6′), 6.44 (dd, 1H, J = 8.79 Hz, J = 2.47 Hz, H5),
6.39 (d, 1H, J = 2.47 Hz, H3), 3.77 (3H, OCH3).13C NMR
(75 MHz) d 172.4, 163.8, 162.5, 151.2, 131.5, 129.6, 123.0,
112.9, 111.9, 106.0, 100.9, 55.4.
4.1.2.18.
2-Hydroxy-4-methyl-N-(5-methylisoxazol-3-yl)
benzamide (2i). Brown crystals. Yield 59%, m.p. 245–
247 °C, IR: m (C=O) 1653 cm–1. 1H NMR (300 MHz): d 11.76
(bs, 1H, NH), 11.02 (bs, 1H, OH), 7.90 (d, 1H, H6), 6.82–
6.75 (m, 2H, H3, H5), 6.74 (d, 1H, J = 0.82 Hz, H4′), 2.40 (s,
3H, CH3), 2.28 (s, 3H, CH3). 13C NMR (75 MHz): d 170.0,
165.6, 158.3, 158.1, 145.3, 130.1, 120.8, 117.6, 114.1, 97.2,
21.3, 12.4.
4.1.2.25. N-(Benzothiazol-2-yl)-2-hydroxy-4-methoxybenza-
mide (3h). White crystals. Yield 62%, m.p. 297–299 °C, IR:
m (C=O) 1676 cm–1. 1H NMR (300 MHz): d 12.27 (bs, 1H,
NH), d 8.00 (d overlapped, 1H, J = 8.79 Hz, H6), 7.97 (d
overlapped, 1H, J = 7.96 Hz, H4′), 7.70 (d, 1H, J = 7.96 Hz,
H7′), 7.49–7.42 (m, 1H, H6′), 7.36–7.28 (m, 1H, H5′),
6.59(dd, 1H, J = 7.89 Hz, J = 2.34 Hz, H5), 6.54 (d, 1H, J
= 2.34 Hz, H3), 3.80 (s, 3H, OCH3). 13C NMR (75 MHz): d
164.7, 160.6, 132.1, 126.7, 123.9, 122.3, 119.8, 118.8, 109.7,
107.2, 101.5, 55.7.
4.1.2.19. 3 Hydroxy-4-methoxy-N-(4-methylpyrimidin-2-yl)
benzamide (3b). White crystals. Yield 52%, m.p. 215–
218 °C, IR: m (C=O) 1671 cm–1. 1H NMR (300 MHz): d 12.10
(bs, 1H, NH), 10.79 (bs, 1H, OH), 8.54 (d, 1H, J = 5.22 Hz,
H6′), 7.97 (d, 1H, J = 8.79 Hz, H6), 7.12 (d, 1H, J = 5.22 Hz,
H5′), 6.55 (dd, 1H, J = 8.80 Hz, J = 2.48 Hz, H5), 6.50 (d,
1H, J = 2.48 Hz, H3), 3.79 (s, 3H, OCH3), 2.43 (s, 3H, CH3).
13C NMR (75 MHz): d 168.5, 165.2, 164.1, 160.4, 158.1,
157.5, 131.9, 116.9, 110.3, 106.8, 101.5, 55.6, 23.8.
4.1.2.26. 2-Hydroxy-4-methoxy-N-(5-methylisoxazol-3-yl)
benzamide (3i). Yellow crystals. Yield 26%, m.p. 194–
196 °C, IR: m (C=O) 1649 cm–1. 1H NMR (300 MHz): d 12.12
(bs, 1H, NH), 10.98 (bs, 1H, OH), 7.99 (d, 1H, J = 8.8 Hz,
H6), 6.73 (bs 1H, H4′), 6.59–6.47 (m, 2H, H3, H5), 3.78 (s,
3H, OCH3), 2.40 (s, 3H, CH3). 13C NMR (75 MHz): d 169.9,
166.0, 164.4, 161.0, 158.2, 131.4, 109.0, 106.9, 101.5, 97.3,
55.7, 12.4.
4.1.2.20. 2-Hydroxy-4-methoxy-N-(pyrazin-2-yl)benzamide
(3c). White crystals. Yield 62%, m.p. 220–222 °C, IR: m
1
(C=O) 1628 cm–1. H NMR (300 MHz): d 12.00 (bs, 1H,
NH), 10.87 (bs, 1H, OH), 9.47 (d, 1H, J = 1.38 Hz, H3′),
8.43–8.38 (m, 2H, H5′, H6′), 8.00 (d, 1H, J = 9.06 Hz, H6),
6.59 (dd, 1H, J = 9.06 Hz, J = 2.47 Hz, H5), 6.54 (d, 1H, J
= 2.47 Hz, H3), 3.79 (s, 3H, OCH3). 13C NMR (75 MHz): d
164.7, 164.2 159.2, 148.7, 143.0, 140.2, 136.9, 132.5, 110.3,
107.1, 101.6, 55.7.
4.1.2.27. 2-Hydroxy-4-methoxy N-(5-methylthiazol-2-yl)ben-
zamide (3k). Yellow crystals. Yield 85%, m.p. 245–246 °C,
IR: m (C=O) 1667 cm–1. 1H NMR (300 MHz): d 12.39 (bs,
1H, NH), 7.95 (d, 1H, J = 8.8 Hz, H6), 6.73 (s, 1H, H5′), 6.52
(dd, 1H, J = 8.8 Hz, J = 2.2 Hz, H5), 6.48 (d, 1H, J = 2.2 Hz,
H3), 3.77 (s, 3H, OCH3), 2.26 (s, 3H, CH3).13C NMR
(75 MHz): d 166.9, 164.3, 161.0, 131.7, 110.1, 107.6, 106.9,
101.4, 55.6, 15.8.
4.1.2.21. 2- Hydroxy-4-methoxy-N-(thiazol-2-yl) benzamide
(3d). Yellow crystals. Yield 20%, m.p. 264–265 °C, IR: m
1
(C=O) 1669 cm–1. H NMR (300 MHz): d 12.28 (bs, 1H,
NH), 7.98 (d, 1H, J = 8.8 Hz, H6), 7.53 (d, 1H, J = 3.4 Hz,
H4′), 7.23 (d, 1H, J = 3.4 Hz, H5′), 6.56 (d, 1H, J = 8.8 Hz,
H5), 6.51 (bs, 1H, H3), 3.78 (s, 3H, OCH3). 13C NMR
(75 MHz): d 167.2, 164.3, 160.6, 131.9, 131.8, 128.9, 113.6,
109.7, 107.0, 101.5, 55.6.
4.1.2.28. 4-Chloro-2-hydroxy-N-(4,6-dimethylpyrimidin-2-yl)
benzamide (4a). Yellow crystals. Yield 45%, m.p. 264–
1
266 °C. IR: m (C=O) 1662 cm–1. H NMR (300 MHz): d
4.1.2.22. 2-Hydroxy-4-methoxy-N-(4H- [1,2,4]triazol-4-yl)
benzamide (3e). Brown crystals. Yield 53%, m.p. 264–
265 °C, IR: m (C=O) 1643 cm–1. 1H NMR (300 MHz): d 11.65
(bs, 1H, NH), 8.74 (s, 2H, H3′, H5′), 7.81 (d, 1H, J = 9.06 Hz,
H6), 6.58 (dd, 1H, J = 9.07 Hz, J = 2.47 Hz, H5), 6.53 (d, 1H,
J = 2.47 Hz, H3), 3.79 (s, 3H, OCH3). 13C NMR (75 MHz) d
166.9, 164.5, 160.8, 144.2, 131.1, 107.6, 107.0, 101.4, 55.7.
12.09 (bs, 1H, NH), 10.86 (bs, 1H, OH), 7.96 (d, 1H, J
= 8.8 Hz, H6), 7.04–6.96 (m, 3H, H3, H5, H5′), 2.36 (s, 6H,
CH3). 13C NMR (75 MHz): d 169.0, 163.8, 158.3, 157.1,
137.9, 132.3, 119.9, 117.8, 116.9, 116.2, 23.6.
4.1.2.29. 4-Chloro-2-hydroxy-N-(4-methylpyrimidin-2-yl)
benzamide (4b). Yellow crystals. Yield 52%, 276 °C, IR: m
(C=O) 1683 cm–1.
4.1.2.23. 2-Hydroxy-4-methoxy-N-(4H-[1,2,4]triazol-3-yl)
benzamide (3f). Brown crystals. Yield 88%, m.p. 309–
312 °C, IR: m (C=O) 1648 cm–1. 1H NMR (300 MHz): d 12.27
(bs, 1H, NH), d 8.00 (d, 1H, J = 8.79 Hz, H6), 7.84 (bs, 1H,
H5′), 6.56 (dd, 1H, J = 8.79 Hz, J = 2.47 Hz, H5), 6.51 (d,
1H, J = 2.47 Hz, H3). 13C NMR (75 MHz): d 166.2, 164.5,
160.8, 148.5, 148.4, 131.5, 108.8, 107.0, 101.5, 55.7.
1H NMR (300 MHz): d 12.07 (bs, 1H, NH), 10.94 (bs, 1H,
OH), 8.53 (d, 1H, J = 4.9 Hz, H6′), 7.95 (d, 1H, J = 8.3 Hz,
H6), 7.11 (d, 1H, J = 4.9 Hz, H5′), 7.05–6.98 (m, 2H,
H3, H5), 2.41 (s, 3H, CH3). 13C NMR (75 MHz): d 168.7,
163.6, 158.1, 157.3, 137.9, 132.4, 119.9, 117.9, 117.0, 116.9,
23.8.

J. Matyk et al. / Il Farmaco 60 (2005) 399–408
405
4.1.2.30. 4-Chloro-2-hydroxy-N-(pyrazin-2-yl)benzamide
(4c). Brown crystals. Yield 72%, m.p. 239–240 °C, IR: m
(C=O) 1676 cm–1. 1H NMR (300 MHz) d 12.13 (bs, 1H, NH),
d 10.89 (bs, 1H, OH), 9.46 (d, 1H, J = 1.37 Hz, H3′), 8.43–
8.40 (m, 2H, H5′, H6′), 7.98 (d, 1H, J = 8.24 Hz, H6), 7.07–
7.01 (m, 2H, H3, H5). 13C NMR (75 MHz): d 163.6, 157.7,
148.4, 143.0, 140.5, 138.2, 136.8, 132.6, 120.1, 117.3, 116.9.
H6), 7.41 (dd, 1H, J = 8.79 Hz, J = 2.61 Hz, H4), 7.02 (d, 1H,
J = 8.79 Hz, H3), 6.74 (d, 1H, J = 0.82 Hz, H4′), 2.40 (d, 3H,
J = 0.83 Hz, CH3). 13C NMR (75 MHz): d 170.2, 164.0, 157.9,
156.4, 133.9, 129.4, 123.3, 119.3, 119.2, 97.1, 12.4.
4.1.2.37. 4-Chloro-2-hydroxy-N-(4-methylthiazol-2-yl)ben-
zamide (4k). Yellow crystals. Yield 73%, m.p. 294–296 °C,
IR: m (C=O) 1664 cm–1. 1H NMR (300 MHz): d 12.65 (bs,
1H, NH), d 7.93 (d, 1H, J = 8.24 Hz, H6), 6.99 (d, 1H, J
= 1.93 Hz, H3), 6.96 (dd, 1H, J = 8.24 Hz, J = 1.92 Hz, H5),
6.77 (d, 1H, J = 1.09 Hz, H5′), 2.26 (d, 3H, J = 1.10 Hz,
CH3). 13C NMR (75 MHz): d 167.6, 160.0, 137.9, 131.8,
119.3, 117.4, 117.0, 107.5, 14.9.
4.1.2.31. 4-Chloro-2-hydroxy-N-(thiazol-2-yl) benzamide
(4d). Brown crystals. Yield 54%, m.p. 283–285 °C, IR: m
1
(C=O) 1672 cm–1. H NMR (300 MHz): d 12.24 (bs, 1H,
NH), d 7.94 (d, 1H, J = 8.51 Hz, H6), 7.55 (d, 1H, J = 3.85 Hz,
H4′), 7.23 (d, 1H, J = 3.84 Hz, H5′), 7.01 (d, 1H, J = 1.92 Hz,
H3), 6.98 (dd, 1H, J = 8.51 Hz, H5). 13C NMR (75 MHz): d
166.6, 162.3, 159.5, 138.1, 132.4, 132.0, 119.5, 117.2, 117.0,
113.4.
4.1.2.38. 5-Fluoro-2-hydroxy-N-(4,6-dimethylpyrimidin-2-
yl)benzamide (5a). Yellow crystals. Yield 46%, m.p. 275–
276 °C, IR: m (C=O) 1668 cm–1. 1H NMR (300 MHz) d 11.65
(bs, 1H, NH), 10.91 (bs, 1H, OH), 7.70 (dd, 1H, J = 9.5 Hz, J
= 3.3 Hz H6), 7.36–7.24 (m, 1H, H4), 7.00 (dd overlapped,
1H, J = 9,5 Hz, J = 4.7 Hz, H3) 6.98 (s 1H, H5′), 2.35 (s, 6H,
CH3). 13C NMR (75 MHz) d 168.0, 163.0, 155.4 (d, J
= 237.4 Hz), 153.6, 121.0 (d, J = 23.2 Hz), 119.4 (d, J
= 6.6 Hz), 118.9 (d, J = 7.4 Hz), 116.3, 115.9 (J = 24.7 Hz),
23.6.
4.1.2.32. 4-Chloro-2-hydroxy-N-(4H-[1,2,4]triazol-4-yl)
benzamide (4e). White crystals. Yield 53%, m.p. 278–
280 °C, IR: m (C=O) 1655 cm–1. 1H NMR (300 MHz): d 11.72
(bs, 1H, NH), d 8.76 (s, 2H, H2′, H5′), 7.85 (d, 1H, J
= 8.24 Hz, H6), 7.07–7.01 (m, 2H, H3, H5). 13C NMR
(75 MHz) d 165.3, 158.5, 143.9, 138.3, 132.1, 119.7, 116.8,
115.7.
4.1.2.39. 5-Fluoro-2-hydroxy-N-(4-methylpyrimidin-2-yl)
benzamide (5b). Yellow crystals. Yield 40%, m.p. 286–
287 °C, IR: m (C=O) 1682 cm-1 1H NMR (300 MHz) d 11.66
(bs, 1H, NH), 11.01 (bs, 1H, OH), 8.65 (d, 1H, J = 5.1 Hz,
H6′), 7.70 (dd, 1H, J = 9.5 Hz, J = 3.3 Hz, H6), 7.36–7.25 (m,
1H, H4), 7.12 (d, 1H, J = 5.1 Hz, H5′), 7.02 (dd, 1H, J
= 9.5 Hz, J = 4.7 Hz, H3), 2.42 (s, 3H, CH3). 13C NMR
(75 MHz) d 168.7, 163.0, 158.2, 157.2, 155.4 (d, J
= 235.4 Hz), 153.5, 121.1 (d, J = 23.5 Hz), 119.5 (d, J
= 6.6 Hz), 118.9 (d, J = 7.4 Hz), 117.1, 116.0 (d, J = 24.6 Hz),
23.8.
4.1.2.33. 4-Chloro-2-hydroxy-
N-(4H-[1,2,4]triazol-3-yl)benzamide (4f). White crystals.
Yield 80%, m.p. 310–312 °C, IR: m (C=O) 1667 cm–1. H
1
NMR (300 MHz): d 11.54 (bs, 1H, NH), d 8.03 (bs, 1H, H5′),
7.95 (d, 1H, J = 8.24 Hz, H6), 7.05–6.98 (m, 2H, H3, H5),13C
NMR: (75 MHz): d 165.5, 159.2, 150.1, 146.3, 138.2, 131.8,
119.6, 117.0, 116.7.
4.1.2.34. N-(Benzimidazol-2-yl)-4-chloro-2-hydroxybenza-
mide (4g). White crystals. Yield 82%, m.p. 329–331 °C, IR:
m (C=O) 1664 cm–1. 1H NMR (300 MHz): d 7.97 (d, 1H, J
= 8.24 Hz, H6), 7.51–7.43 (m, 2H, H4′, H7′), 7.28–7.21 (m,
2H, H5′, H6′), 6.93 (d, 1H, J = 2.20 Hz, H3), 6.90 (dd, 1H, J
= 8.24 Hz, J = 2.20 Hz, H5). 13C NMR (75 MHz): d 171.6,
161.6, 151.0, 137.4, 131.6, 129.3, 123.3, 118.9, 118.4, 116.9,
112.1.
4.1.2.40. 5-Fluoro-2-hydroxy-N-(pyrazin-2-yl-)benzamide
(5c). Brown crystals. Yield 55%, m.p. 255–258 °C, IR: m
1
(C=O) 1674 cm–1. H NMR (300 MHz): d 11.76 (bs, 1H,
NH), 11.05 (bs, 1H, OH), 9.48 (d, 1H, J = 0.82 Hz, H3′),
8.45–8.41 (m, 2H, H5′, H6′), 7.72 (dd, 1H, J = 9.34 Hz, J
= 3.29 Hz, H6), 7.38–7.29 (m, 1H, H4), 7.06 (dd, 1H, J
= 9.34 Hz, J = 4.67 Hz, H3). 13C NMR (75 MHz): d 163.3 and
163.3 (J = 2.3 Hz), 157.1 and 154.0 (J = 235.7 Hz), 153.3 and
153.3 (J = 1.4 Hz), 148.3, 143.1, 140.6, 136.8, 121.6 and
121.2 (J = 23.5 Hz), 119.0 and 118.9 (J = 7.8 Hz), 118.9 and
118.8 (J = 7.1 Hz), 116.3 and 116.0 (J = 24.3 Hz).
4.1.2.35. N-(Benzothiazol-2-yl)-4-chloro-2-hydroxybenzla-
mide (4h). White crystals. Yield 79%, m.p. 318–320 °C, IR:
m (C=O) 1679 cm–1. 1H NMR (300 MHz): d 12.12 (bs, 1H,
NH), d 8.01–7.95 (m, 1H, H7′), 7.96 (d overlapped J
= 8.24 Hz, H6), 7.69 (d, 1H, J = 7.97 Hz, H4′), 7.51–7.43 (m,
1H, H5′), 7.37–7.30 (m, 1H, H6′), 7.04 (d, 1H, J = 1.92 Hz,
H3), 7.00 (dd, 1H, J = 8.24 Hz, J = 1.92 Hz, H5). 13C NMR
(75 MHz): d 167.0, 161.6, 159.5, 144.0, 138.6, 132.2, 130.1,
126.9, 124.1, 122.5, 119.7, 118.3, 117.1, 117.0.
4.1.2.41. 5-Fluoro-2-hydroxy-N-(thiazol-2-yl)benzamide
(5d). Brown crystals. Yield 65%, m.p. 273–275 °C, IR: m
1
(C=O) 1671 cm–1. H NMR (300 MHz): d 7.67 (dd, 1H, J
4.1.2.36.
4-Chloro-2-hydroxy-N-(5-methylisoxazol-3-yl)
= 9.34 Hz, J = 3.29 Hz, H6), 7.55 (d, 1H J = 3.84 Hz, H4′),
7.34–7.22 (m, 1H, H4), 7.24 (d overlapped, J = 3.85 Hz, H5′),
6.99 (dd, 1H, J = 9.34 Hz, J = 4.40 Hz, H3). 13C NMR
(75 MHz): d 166.0, 161.8, 156.7 and 153.6 (J = 234.8 Hz),
benzamide (4i). Brown crystals. Yield 59%, m.p. 267–
268 °C, IR: m (C=O) 1620 cm–1. 1H NMR (300 MHz): d 11.85
(bs, 1H, NH), 11.05 (bs, 1H, OH), 7.91 (d, 1H, J = 2.61 Hz,

406
J. Matyk et al. / Il Farmaco 60 (2005) 399–408
155.1, 133.2, 121.4 and 121.1 (J = 23.2 Hz), 119.0 and 118.9
(J = 7.8 Hz), 118.4 and 118.4 (J = 6.9 Hz), 115.6 and 115.3 (J
= 24.0 Hz), 113.6.
4.1.2.47. 5-Bromo-2-hydroxy-N-(4-methylpyrimidin-2-yl)
benzamide (6b). Yellow crystals. Yield 59%, m.p. 292–
294 °C, IR: m (C=O) 1684 cm–1. 1H NMR (300 MHz): d 11.91
(bs, 1H, NH), 10.98 (bs, 1H, OH), 8.54 (d, 1H, J = 4.95 Hz,
H6′), 8.04 (d, 1H, J = 2.41 Hz, H6), 7.58 (dd, 1H, J = 8.79 Hz,
J = 2.41 Hz, H4), 7.13 (d, 1H, J = 4.95 Hz, H5′), 6.97 (d, 1H,
J = 8.79 Hz, H3), 2.42 (s, 3H, CH3). 13C NMR (75 MHz): d
168.7, 169.1, 158.1, 157.2, 156.5, 136.4, 132.7, 120.9, 119.7,
117.1, 110.8, 23.8.
4.1.2.42. 5-Fluoro-2-hydroxy-N-(4H-[1,2,4]triazol-4-yl)ben-
zamide (5e). White crystals. Yield 88%, m.p. 328–330 °C,
IR: m (C=O) 1672 cm–1. 1H NMR (300 MHz): d 11.34 (bs,
1H, NH), d 8.77 (s, 2H, H2′, H5′), 7.58 (dd, 1H, J = 9.21 Hz,
J = 3.29 Hz, H6), 7.39–7.30 (m, 1H, H4), 7.04 (dd, 1H, J
= 9.21 Hz, J = 4.67 Hz, H3). 13C NMR (75 MHz): d 165.1 and
165.1 (J = 2.0 Hz), 156.8 and 153.7 (J = 235.7 Hz), 154.1 and
154.1 (J = 1.4 Hz), 144.1, 121.8 and 121.5 (J = 23.2 Hz),
118.9 and 118.8 (J = 7.7 Hz), 117.0 and 116.9 (J = 7.2 Hz),
115.9 and 115.6 (J = 24.4 Hz).
4.1.2.48.
5-Bromo-2-hydroxy-N-(pyrazin-2-y)benzamide
(6c). Brown crystals. Yield 57%, m.p. 254–256 °C, IR: m
1
(C=O) 1677 cm–1. H NMR (300 MHz): d 12.03 (bs, 1H,
NH), 10.96 (bs, 1H, OH), 9.46 (d, 1H, J = 1.38 Hz, H3′),
8.43–8.41 (m, 2H, H5′, H6′), 8.05 (d, 1H, J = 2.47 Hz, H6),
7.59 (dd, 1H, J = 8.79 Hz, J = 2.47 Hz, H4), 7.00 (d, 1H, J
= 8.79 Hz, H3). 13C NMR (75 MHz): d 163.2, 156.2, 148.3,
143.1, 140.6, 136.8, 136.7, 132.9, 120.1, 119.7, 111.1.
4.1.2.43.
5-Fluoro-2-hydroxy-N-(4H-[1,2,4]triazol-3-yl)
benzamide (5f). White crystals. Yield 89%, m.p. 357–
360 °C, IR: m (C=O) 1673 cm–1. 1H NMR (300 MHz): d 8.03
(bs, 1H, H5′), 7.71 (dd, 1H, J = 9.34 Hz, J = 3.30 Hz, H6),
7.38–7.27 (m, 1H, H4), 7.01 (dd, 1H, J = 9.34 Hz, J = 4.67 Hz,
H3). 13C NMR (75 MHz): d 165.1, 156.7 and 153.6 (J
= 233.0 Hz), 155.0, 146.5, 121.6 and 121.3 (J = 23.5 Hz),
119.1 and 119.0 (J = 7.7 Hz), 118.0 and 117.9 (J = 6.9 Hz),
115.6 and 115.3 (J = 25.7 Hz.)
4.1.2.49. 5-Bromo-2-hydroxy-N-(thiazol-2-yl benzamide
(6d). White crystals. Yield 53%, m.p. 272–273 °C, IR: m
1
(C=O). 1668 cm–1. H NMR (300 MHz): d 12.59 (bs, 1H,
NH), 8.03 (d, 1H, J = 2.8 Hz, H6), 7.59–7.53 (m, 2H, H4,
H4′), 7–25 (d, 1H, J = 3.8 Hz, H5′), 6.94 (d, 1H, J = 8.8 Hz,
H3). 13C NMR (75 MHz): d 165.6, 157.9, 136.5, 132.3, 120.0,
119.8, 113.6, 110.3.
4.1.2.44. N-(Benzimidazol-2-yl)-5-fluoro-2-hydroxybenza-
mide (5g). White crystals. Yield 80%, m.p. 336–338 °C, IR:
m (C=O) 1643 cm–1. 1H NMR (300 MHz): d 7.66 (dd, 1H, J
= 9.34 Hz, J = 3.29 Hz, H6), 7.52–7.42 (m, 2H, H4′, H7′),
7.29–7.16 (m, 3H, H4, H5′, H6´), 6.88 (dd, 1H, J = 9.34 Hz,
J = 4.67 Hz, H3). 13C NMR (75 MHz): d 171.6, 157.0,
156.3 and 153.2 (J = 233.4 Hz), 151.2, 129.3, 123.3, 120.7 and
120.4 (J = 23.5 Hz), 120.4 and 120.3 (J = 6.6 Hz), 118.7 and
118.6 (J = 7.5 Hz), 115.0 and 114.7 (J = 23.5 Hz), 112.1.
4.1.2.50. 5-Bromo-2-hydroxy-N-(4H-[1,2,4]triazol-4-yl)ben-
zamide (6e). White crystals. Yield 88%, m.p. 304–306 °C,
IR: m (C=O) 1670 cm–1. 1H NMR (300 MHz): d 11.68 (bs,
1H, NH), 8.78 (s, 2H, H3′, H5′), 7.93 (d, 1H, J = 2.60 Hz,
H6), 7.61 (dd, 1H, J = 8.79 Hz, J = 2.60 Hz, H4), 6.99 (d, 1H,
J = 8.79 Hz, H3). 13C NMR (75 MHz): d 164.9, 156.9, 143.9,
136.7, 132.3, 119.6, 118.6, 110.4.
4.1.2.45. N-(Benzothiazol-2-yl)-5-fluoro-2-hydroxybenza-
mide (5h). White crystals. Yield 85%, m.p. 349–351 °C, IR:
m (C=O) 1679 cm–1. 1H NMR (300 MHz): d 11.88 (bs, 1H,
NH), d 7.98 (d, 1H, J = 7.69 Hz, H7′), 7.74–7.67 (m, 2H, H6,
H4′), 7.51–7.43 (m, 1H, H5′), 7.39–7.29 (m, 2H, H4, H6′),
7.03 (dd, 1H, J = 9.07 Hz, J = 4.67 Hz, H3). 13C NMR
(75 MHz): d 166.6, 161.1, 156.8 and 153.7 (J = 235.4 Hz),
154.9, 144.6, 130.3, 126.9, 124.2, 122.5, 121.9 and 121.6 (J
= 23.5 Hz), 119.1 and 119.0 (J = 7.5 Hz), 118.6, 118.3 and
118.2 (J = 6.9 Hz), 115.8 and 115.5 (J = 24.3 Hz).
4.1.2.51. 5-Bromo-2-hydroxy-N-(4H-[1,2,4]triazol-4-yl)ben-
zamide (6f). White crystals. Yield 72%, m.p. 335–338 °C,
IR: m (C=O) 1676 cm–1. 1H NMR (300 MHz): d 12.10 (bs,
1H, NH), d 8.07–8.02 (m, 2H, H6, H5′), 7.57 (dd, 1H, J
= 8.79 Hz, J = 2.47 Hz, H4), 6.95 (d, 1H, J = 8.79 Hz, H3).
13C NMR (75 MHz) d 165.0 157.6, 146.0, 136.6, 132.1, 119.8,
119.6, 110.4.
4.1.2.52. N-(Benzimidazol-2-yl)-5-bromo-2-hydroxybenza-
mide (6g). White crystals.Yield 87%, m.p. 319–321 °C, Ref.
[11] 323–324 °C. IR: m (C=O) 1634 cm–1. 1H NMR
(300 MHz): d 8.05 (d, 1H, J = 2.48 Hz, H6), 7.50–7.44 (m,
3H, H4, H4′, H7′), 7.28–7.21 (m, 2H, H5′, H6′), 6.85 (d, 1H,
J = 8.79 Hz, H3). 13C NMR (75 MHz) d 171.2, 160.1, 151.1,
135.8, 131.9, 129.3, 123.4, 121.7, 119.9, 112.1, 109.2.
4.1.2.46. 5-Fluoro-2-hydroxy N-(5-methylisoxazol-3-yl
benzamide (5i). Brown crystals. Yield 53%, m.p. 258–
261 °C, IR: m (C=O) 1660 cm–1. 1H NMR (300 MHz): d 11.67
(bs, 1H, NH), 11.07 (bs, 1H, OH), 7.71 (dd, 1H, J = 9.34 Hz,
J = 3.29 Hz, H6), 7.37–7.27 (m, 1H, H4), 7.02 (dd, 1H, J
= 9.34 Hz, J = 4.67 Hz, H3), 6.74 (d, 1H, J = 0.83, H4′), 2.40
(s, 3H, CH3). 13C NMR (75 MHz): d 170.2, 164.1 and 164.1
(J = 2.3 Hz), 157.9, 156.9 and 153.7 (J = 235.7 Hz), 154.0 and
154.0 (J = 1.4 Hz), 121.6 and 121.3 (J = 23.5 Hz), 119.0 and
118.9 (J = 7.7 Hz), 118.2 and 118.1 (J = 7.2 Hz), 115.8 and
115.5 (J = 24.9 Hz), 97.0, 12.4.
4.1.2.53. N-(Benzothiazol-2-yl)-5-bromo-2-hydroxybenza-
mide (6h). White crystals. Yield 75%, m.p. 317–321 °C, IR:
m (C=O) 1678 cm–1. 1H NMR (300 MHz): d 12.38 (bs, 1H,
NH), 8.04 (d, 1H, J = 2.61 Hz, H6), 8.00–7.96 (m, 1H, H7′),
7.69 (d, 1H, J = 7.97 Hz, H4′), 7.58 (dd, 1H, J = 8.79 Hz, J

J. Matyk et al. / Il Farmaco 60 (2005) 399–408
407
= 2.61 Hz, H4), 7.51–7.43 (m, 1H, H5′), 7.37–7.30 (m, 1H,
H6′), 6.97 (d, 1H, J = 8.79 Hz, H3). 13C NMR (75 MHz): d
161.5, 158.0, 143.9, 143.7, 136.9, 132.5, 130.1, 127.0, 124.2,
122.5, 119.9, 119.8, 118.3, 110.4.
4.1.2.60. N-/Benzimidazol-2-yl)-5-chloro-2-hydroxybenza-
mide (7g). White crystals. Yield 72%, m.p. 328-329 °C, Ref.
1
[12] m.p. 329–330 °C. IR: m (C=O) 1631 cm–1. H NMR
(300 MHz): d 7.92 (d, 1H, J = 2.89 Hz, H6), 7.51–7.44 (m,
2H, H4′, H7′), 7.37 (dd, 1H, J = 8.79 Hz, J = 2.89 Hz, H4),
7.29–7.21 (m, 2H, H5′, H6′), 6.90 (d, 1H, J = 8.79 Hz, H3).
13C NMR (75 MHz): d 171.3, 159.6, 151.1, 133.1, 129.3,
128.9, 123.4, 121.8, 121.2, 119.4, 112.1.
4.1.2.54. 5-Bromo-2-hydroxy-N-(5-methylisoxazol-3-yl)ben-
zamide (6i). White crystals. Yield 54%, m.p. 248–250 °C,
IR: m (C=O) 1655 cm–1. 1H NMR (300 MHz): d 11.86 (bs,
1H, NH), 11.04 (bs, 1H, OH), 8.04 (d, 1H, J = 2.48 Hz, H6),
7.59) dd, 1H, J = 8.79 Hz, J = 2.48 Hz, H4), 6.97 (d, 1H, J
= 8.79 Hz, H3), 6.74 (d, 1H, J = 0.82 Hz, H4′), 2.40 (d, 3H, J
= 0.82 Hz, CH3). 13C NMR (75 MHz): d 170.2, 163.9, 157.9,
156.8, 136.7, 132.3, 119.8, 119.7, 110.7, 97.0, 12.4.
4.1.2.61. N-(Benzothiazol-2-yl)-5-chloro-2-hydroxybenza-
mide (7 h). White crystals. Yield 81%, m.p. 335–336 °C, IR:
m (C=O) 1678 cm–1. 1H NMR (300 MHz): d 11.85 (bs, 1H,
NH), 11.05 (bs, 1H, OH), d 8.00–7.95 (m, 1H, H7′), 7.93–
7.90 (m, 1H, H6), 7.72–7.66 (m, 1H, H4′), 7.51–7.42 (m, 2H,
H4, H5′), 7.38–7.29 (m, 1H, H6′), 7.06–6.98 (m, 1H, H3).
13C NMR (75 MHz): d 166.8, 161.6, 157.7, 144.0, 134.1,
130.2, 129.5, 126.9, 124.1, 123.0, 122.5, 119.5, 119.3, 118.3.
4.1.2.55. 5-Bromo-2-hydroxy-N-(4-methylthiazol-2-yl)ben-
zamide (6k). White crystals. Yield 82%, m.p. 287–289 °C,
IR: m (C=O) 1670 cm–11H NMR (300 MHz): d 8.02 (d, 1H, J
= 2.75 Hz, H6), 7.54 (dd, 1H, J = 8.79 Hz, J = 2.75 Hz, H4),
6.91 (d, 1H, J = 8.79 Hz, H3), 6.79 (d, 1H, J = 0.97 Hz, H5′),
2.27 (d, 3H, J = 0.97 Hz, CH3). 13C NMR (75 MHz): d 159.0,
136.8, 132.6, 120.8, 120.3, 110.6, 108.0.
4.1.2.62. 5-Chloro-2-hydroxy-N-(5-methylisoxazol-3-yl)ben-
zamide (7i). White crystals. Yield 64%, m.p. 259–261 °C,
IR: m (C=O) 1652 cm–1. 1H NMR (300 MHz): d 11.85 (bs,
1H, NH), 11.05 (bs, 1H, OH), 7.91 (d, 1H, J = 2.61 Hz, H6),
7.41 (dd, 1H, J = 8.79 Hz, J = 2.61 Hz, H4), 7.02 (d, 1H, J
= 8.79 Hz, H3), 6.74 (d, 1H, J = 0.82 Hz, H4′), 2.40 (d, 3H, J
= 0.83 Hz, CH3). 13C NMR (75 MHz): d 170.2, 164.0, 157.9,
156.4, 133.9, 129.4, 123.3, 119.3, 119.2, 97.1, 12.4.
4.1.2.56. 5-Chloro-2-hydroxy-N-(4-methylpyrimidin-2-yl)
benzamide (7b). Yellow crystals. Yield 59%, m.p. 295–
297 °C, IR: m (C=O) 1684 cm–1. 1H NMR (300 MHz): d 11.89
(bs, 1H, NH), 10.96 (bs, 1H, OH), 8.55–8.52 (m, 1H, H6′),
7.91 (d, 1H, J = 2.75 Hz, H6), 7.47 (dd, 1H, J = 8.79 Hz,
2.75 Hz, H4), 7.13 (d, 1H, J = 4.94 Hz, H5′), 7.02 (d, 1H, J
= 8.79 Hz, H3), 2.42 (s, 3H, CH3). 13C NMR (75 MHz,): d
168.7, 162.9, 158.1, 157.2, 156.0, 133.5, 129.8, 123.4, 120.4,
119.3, 117.1, 23.8.
4.1.2.63. 5-Chloro-5-hydroxy-N-(pyrimidin-2-yl)benzamide
(7J). Yellow crystals.Yield 65%, m.p. 99–101 °C, IR: m (C=O)
1697 cm–1. 1H NMR (300 MHz) d 8.67 (d, 2H, J = 4.4 Hz,
H4′, H6′), 7.80 (d, 1H, J = 2.1 Hz, H6), 7.23 (dd, 1H, J
= 8.7 Hz, J = 2.1 Hz, H4), 7.17 (t, 1H, J = 4.4 Hz, H5′), 6.81
(d, 1H, J = 8.7 Hz, H3). 13C NMR (75 MHz) d 163.8, 163.5,
158.7, 158.1, 133.2, 129.4, 121.6, 119.6, 118.3, 116.7.
4.1.2.57. 5-Chloro-2-hydroxy-N-(pyrazin-2-yl benzamide
(7c). Brown crystals. Yield 66%, m.p. 244–246 °C, IR: m
1
(C=O) 1675 cm–1. H NMR (300 MHz): d 12.02 (bs, 1H,
NH), 10.95 (bs, 1H, OH), 9.47–9.45 (m, 1H, H3′), 8.44–8.41
(m, 2H, H5′, H6′), 7.93 (d, 1H, J = 3.03 Hz, H6), 7.48 (dd,
1H, J = 8.79 Hz, J = 3.03 Hz, H4), 7.05 (d, 1H, J = 8.79 Hz,
H3). 13C NMR (75 MHz): d 160.2, 155.7, 148.3, 143.1, 140.6,
136.8, 133.9, 129.9, 123.7, 119.6, 119.3.
4.1.2.64. 5-Chloro-2-hydroxy-N-(4-methylthiazol-2-yljben-
zamide (7k). White crystals. Yield 90%, m.p. 306–308 °C,
IR: m (C=O) 1671 cm–1. 1H NMR (300 MHz): d 7.89 (d, 1H,
J = 2.88 Hz, H6), 7.42 (dd, 1H, J = 8.79 Hz, J = 2.88 Hz, H4),
6.96 (d, 1H, J = 8.79 Hz, H3), 6.78 (d, 1H, J = 1.10 Hz, H5′),
2.26 (d, 3H, J = 1.10 Hz, CH3). 13C NMR (75 MHz): d 167.9,
164.1, 158.1, 133.5, 129.2, 122.7, 119.7, 119.4, 107.6, 14.9.
4.1.2.58. 5-Chloro-2-hydroxy-N-(4H-[1,2,4]triazol-4-yl)
benzamide (7e). White crystals. Yield 88%, m.p. 321–
322 °C, IR: m (C=O) 1671 cm–1. 1H NMR (300 MHz): d 11.67
(bs, 1H, NH), 8.78 (s, 2H, H2′, H5′), 7.81 (d, 1H, J = 2.75 Hz,
H6), 7.50 (dd, 1H, J = 8.79 Hz, J = 2.75 Hz, H4), 7.05 (d, 1H,
J = 8.79 Hz, H3). 13C NMR (75 MHz): d 165.0, 156.5, 144.0,
134.0, 129.5, 123.1, 119.2, 118.0.
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. tuberculosis CNCTC My
331/8, M. kansasii CNCTC My 235/80, and M. avium
CNCTC My 330/88. Activity against the clinical isolate of
Mycobacterium kansasii 6 509/96 was tested as well. The
antimycobacterial activity of the compounds was determined
in the Šula semisynthetic medium (SEVAC, Prague). This
medium (with bovine serum) is routinely used in the Czech
Republic. Each strain was simultaneously inoculated into a
4.1.2.59. 5-Chloro-2-hydroxy-N-(4H-[1,2,4]triazol-3-yl)
benzamide (7f). White crystals. Yield 84%, m.p. 326–
327 °C, IR: m (C=O) 1677 cm–1. 1H NMR (300 MHz): d 11.49
(bs, 1H, NH), 8.05(s, 1H, H5′), 7.93 (d, 1H, J = 2.74 Hz, H6),
7.47 (dd, 1H, J = 8.80 Hz, J = 2.75 Hz, H4), 7.01 (d, 1H, J
= 8.79 Hz, H3). 13C NMR (75 MHz): d 165.1, 157.1, 150.4,
146.2, 133.9, 129.2, 123.1, 119.4 119.1.

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J. Matyk et al. / Il Farmaco 60 (2005) 399–408
Table 3
The calculated values of logarithm of partition coefficients (log P)
1a
1b
1c
1d
1e
1f
2.43
1.73
0.19
2.17
0.06
2.27
2.21
3.65
1.68
1k
2a
2c
2d
2e
2f
2.87
2.92
0.98
2.66
0.55
2.75
2.70
4.13
2.16
3b
3c
3d
3e
3f
1.60
0.37
2.17
–0.06
2.14
2.08
3.52
1.55
2.75
4a
4b
4c
4d
4e
4f
2.99
2.29
1.05
2.73
0.62
2.82
2.77
4.20
2.23
4k
5a
5c
5d
5e
5f
3.43
2.59
0.65
2.33
0.22
2.42
2.37
3.80
1.83
6b
6c
6d
6e
6f
2.56
1.32
3.00
0.89
3.10
3.04
4.48
2.50
3.70
7b
7c
7e
7f
2.29
1.05
0.62
2.82
2.77
4.20
2.23
1.58
3.43
7g
7h
7i
3g
3h
3i
6g
6h
6i
1g
1h
1i
2g
2h
2i
4g
4h
4i
5g
5h
5i
7j
3k
6k
7k
[2] K. Waisser, O. Bureš, P. Holý, J. Kuneš, R. Oswald, L. Jirásková, et al.,
Relationships between structure and antimycobacterial activity of
substituted salicylanides, Arch. Pharm. (Weinheim) 336 (2003)
53–71.
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, 31,
16, 8, 4, 2 mol/l. The MICs were determined after incubation
at 37 °C for 14 days (see Table 1). MIC was the lowest con-
centration of an antimycobacterially effective substance (on
the above concentration scale), at which inhibition of the
growth of the Mycobacteria occurred. The results were sum-
marised in Table 1.
[3] D.J. Hlasta, J.P. Demers, B.D. Foleto, S. Fraga-Spano, J. Guan,
J.J. Hilligard, et al., Novel inhibitors of bacterial two-component
systems with gram positive antibacterial activity: pharmacophore
identification based on the screening HIT clobantel, Bioorg. Med.
Chem. Lett. 8 (1998) 1923–1928.
[4] M.J. Macielag, J.P. Demers, S.A. Fraga-Spano, D.J. Hlasta,
S.G. Johnson, I.M. Kanojia, et al., Substituted salicylanilides as
inhibitors of two component regulatory systems in bacteria, J. Med.
Chem. 41 (1998) 2939–2945.
4.3. Calculations
[5] K. Waisser, M. Perˇina, V. Klimešová, J. Kaustová, On the relationship
between the structure and antimycobacterial activity substituted
N-benzylsalicylamides, Collect. Czech, Chem. Commun. 68 (2003)
1275–1294.
All regression calculations were set up using the Multireg
H programme (Klemera) for Microsoft Excel. Results are
summarised in Table 2. Logarithms of the partition coeffi-
cients were calculated using ChemOffice 5 software (Table 3).
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of
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Acknowledgements
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The work is a part of the research project no. MSM
0021650822 of the Ministry of Education of the Czech Repub-
lic and by Grant No. 42/G6/2005 of the Higher Education
Development Fund.
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