On the relationship between the structure and antimycobacterial activity of substituted N-benzylsalicylamides

Article abstract of DOI:10.1135/cccc20031275

Sixty-six N-benzylsalicylamides substituted in the acyl moiety in positions 3, 4 or 5 and in position 4 on the benzylic aromatic ring were synthesized. The compounds were tested for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium. To evaluate structure-antimycobacterial activity relationships (QSARs), approaches based on the Free-Wilson as well as a combination of the Free-Wilson and Hansch methods were employed (substituent constants were used to describe the influence of the benzyl substituents, indicator parameters were used for the substituents on the acyl moiety). The use of the Hammett constants for benzyl substituents was not important for QSAR equations. The quadratic representation of lipophilicity parameters (π²) was significant only in QSAR equations of antimycobacterial activity against M. avium.

Full text of DOI:10.1135/cccc20031275

Substituted N-Benzylsalicylamides
1275
ON THE RELATIONSHIP BETWEEN THE STRUCTURE AND
ANTIMYCOBACTERIAL ACTIVITY OF SUBSTITUTED
N-BENZYLSALICYLAMIDES
a3
b
Karel WAISSERa1,*, Milan PEŘINAa2, Věra KLIMEŠOVÁ and Jarmila KAUSTOVÁ
a
Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Heyrovského 1203,
CZ-500 05 Hradec Králové, Czech Republic; e-mail: waisser@faf.cuni.cz, perina@faf.cuni.cz,
1
2
3
klimesova@faf.cuni.cz
b
National Reference Laboratory for Mycobacterium kansasii, Institute of Hygiene,
Partyzánské nám. 7, CZ-728 92 Ostrava, Czech Republic; e-mail: jarmila.kaustova@khsova.cz
Received Decem ber 2, 2002
Accepted April 17, 2003
This paper is dedicated to Professor Václav Horák on the occasion of his 80th birthday.
Sixty-six N-ben zylsalicylam ides substituted in th e acyl m oiety in position s 3, 4 or 5 an d in
position 4 on th e ben zylic arom atic rin g were syn th esized. Th e com poun ds were tested for
in vitro an tim ycobacterial activity again st Mycobacterium tuberculosis, Mycobacterium kansasii
an d Mycobacterium avium. To evaluate structure–an tim ycobacterial activity relation sh ips
(QSARs), approach es based on th e Free–Wilson as well as a com bin ation of th e Free–Wilson
an d Han sch m eth ods were em ployed (substituen t con stan ts were used to describe th e in flu-
en ce of th e ben zyl substituen ts, in dicator param eters were used for th e substituen ts on th e
acyl m oiety). Th e use of th e Ham m ett con stan ts for ben zyl substituen ts was n ot im portan t
for QSAR equation s. Th e quadratic represen tation of lipoph ilicity param eters (π2) was sign ifi-
can t on ly in QSAR equation s of an tim ycobacterial activity again st M. avium.
Keyw ord s: Tuberculostatic; An tituberculotics; Salicylam ides; QSAR; Substituen t effects;
Structure–activity relation sh ips; An tim icrobial activity; Free–Wilson m eth od.
Search for n ew an tim ycobacterial com poun ds is on e of th e m ost ch allen g-
in g tasks of curren t m edicin al ch em istry. In particular, th e study of an ti-
m ycobacterial properties of salicylan ilides1,2 is of great in terest, as salicyl-
an ilides are in h ibitors of bacterial two-com pon en t system s3,4, wh ich can be
also im portan t in m ycobacteria. Th e goal of th is paper was to study th e
an tim ycobacterial activity of N-ben zylsalicylam ides. Given th e sim ilarity in
structure, we assum ed th at N-ben zylsalicylam ides could be a n ew group of
poten tial an tituberculotics actin g by in h ibition of two-com pon en t system s
Collect. Czech. Chem. Commun. (Vol. 68) (2003)
doi:10.1135/cccc20031275

1276
Waisser, Peřina, Klimešová, Kaustová:
in Mycobacteria as well. Th e an tim ycobacterial activity of oth er com -
poun ds isosteric to salicylan ilides h as been described recen tly5.
N-Ben zylsalicylam ides were prepared by treatm en t of substituted salicylic
acids with ben zylam in es (Sch em e 1). Th e com poun ds were ch aracterized by
NMR an d IR spectroscopy. In th e IR spectra, th e carbon yl vibration ν(C=O)
was observed in th e region 1626–1651 cm –1
.
O
NH2
COOH
N
H
OH
PCl3
R2
R1
R1
+
R2
chlorobenzene
OH
R2
1–6
a
R1
1–6
R1
1
H
H
g
h
i
4-OCH3
5-NO2
4-Cl
2
3
4
5
6
4-Cl
b
5-Br
4-CH3
4-F
c
5-Cl
d
3,5-Cl2
5-CH3
3,5-Br2
j
3-OCH3
5-OCH3
3,4-Cl2
4-OCH3
e
k
f
SCHEME 1
Th e an tim ycobacterial activity of th e syn th esized N-ben zylsalicylam ides
is given in Table I. Un like ison iazid, th e m ost active com poun ds exh ibited
con sisten t activity again st all m ycobacterial strain s of th e testin g pan el.
Th eir broad spectrum of activity can be con sidered as an advan tage. Th us,
we h ave iden tified a n ew group of poten tial an tituberculotics – N-ben zyl-
salicylam ides.
EXPERIMENTAL
Syn th esis
Th e m eltin g poin ts were determ in ed on a Kofler apparatus. Th e sam ples for an alysis an d
an tim ycobacterial tests were dried over P2O5 at 61 °C an d 66 Pa for 24 h . Elem en tal an alyses
(C, H, N) were perform ed on a CHNS-O CE elem en tal an alyzer (Fision s EA 1110, Milan ) an d
were with in ±0.4% of th e th eoretical values. Th e IR spectra were m easured in KBr pellets on
a Nicolet Im pact 400 apparatus; th e waven um bers are given in cm –1. TLC was perform ed on
silica gel plates precoated with a fluorescen t in dicator Silufol UV 254 + 366 (Kavalier Votice,
Czech Republic), cycloh exan e–aceton e (3:1) was used as th e m obile ph ase. Th e 1H NMR an d
13C NMR spectra of n ew com poun ds were recorded in CDCl3 or DMSO-d6 solution s at am bi-
en t tem perature on a Varian Mercury-Vx BB 300 spectrom eter operatin g at 300 MHz for
1H NMR an d 75 MHz for 13C NMR. Ch em ical sh ifts were recorded as δ values in ppm an d
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

Substituted N-Benzylsalicylamides
1277
TABLE I
Min im um in h ibitory con cen tration s of N-ben zylsalicylam ides substituted in position s 3, 4
an d 5
MIC, µm ol/l
in cubation 14 d/21 d
Com -
poun ds
M. tuberculosis M. avium
M. kansasii M. kansasii
R1
R2
My 331/88
My 330/88 My 235/80 6509/96
1a
1b
1c
1d
1e
1f
H
H
a/a
125/125
a/a
a/a
a/a
5-Br
H
a/a
a/a
a/a
5-Cl
H
62/a
a/a
a/a
a/a
3,5-Cl2
5-CH3
3,5-Br2
4-CH3O
5-NO2
4-Cl
H
32/62
a/a
125/125
a/a
125/125
a/a
125/125
a/a
H
H
32/32
125/a
125/125
62/62
a/a
125/125
125/a
a/a
125/125
a/a
125/125
a/a
1g
1h
1i
H
H
250/250
125/125
a/a
250/500
125/a
a/a
H
62/62
a/a
1j
3-CH3O
5-CH3O
H
H
1k
2a
2b
2c
2d
2e
2f
H
250/250
32/62
32/32
32/32
32/62
32/32
32/32
32/32
32/32
32/32
62/125
a/a
125/250
16/32
16/16
16/16
62/62
16/32
62/62
32/32
125/250
32/32
62/125
32/a
32/62
62/a
125/250
62/a
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-F
5-Br
32/32
32/32
62/62
62/a
32/32
32/32
62/62
62/62
62/62
62/62
125/250
32/32
62/125
a/a
5-Cl
3,5-Cl2
5-CH3
3,5-Br2
4-CH3O
5-NO2
4-Cl
62/62
62/a
2g
2h
2i
125/125
32/32
125/500
62/a
2j
3-CH3O
5-CH3O
H
2k
3a
3b
3c
3d
3e
3f
125/125
a/a
32/62
32/32
32/32
62/62
32/62
62/62
62/62
500/500
a/a
125/a
62/62
62/62
62/62
62/a
125/a
62/a
5-Br
5-Cl
32/62
62/62
62/a
62/62
125/125
62/a
3,5-Cl2
5-CH3
3,5-Br2
4-CH3O
5-NO2
4-Cl
62/62
125/a
32/32
a/a
62/62
a/a
62/62
a/a
3g
3h
3i
250/250
a/a
125/250
a/a
3j
3-CH3O
5-CH3O
H
125/125
125/a
250/250
125/250
62/a
125/250
62/125
125/250
250/250
125/125
125/125
3k
4a
125/125
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

1278
Waisser, Peřina, Klimešová, Kaustová:
TABLE I
(Continued)
MIC, µm ol/l
in cubation 14 d/21 d
Com -
poun ds
M. tuberculosis M. avium
M. kansasii M. kansasii
R1
R2
My 331/88
My 330/88 My 235/80 6509/96
4b
4c
4d
4e
4f
5-Br
4-F
32/62
62/62
32/62
a/a
62/62
32/62
125/125
a/a
a/a
62/62
62/62
125/125
a/a
5-Cl
4-F
62/a
125/125
a/a
3,5-Cl2
5-CH3
3,5-Br2
4-CH3O
5-NO2
4-Cl
4-F
4-F
4-F
32/32
a/a
62/62
a/a
62/62
a/a
62/62
a/a
4g
4h
4i
4-F
4-F
62/62
32/62
250/250
250/a
32/62
16/32
16/32
32/62
32/a
1000/1000 250/500
250/250
62/62
250/250
125/125
32/62
32/32
32/32
62/62
62/a
4-F
62/62
62/62
250/250
125/125
62/125
32/32
32/62
62/62
a/a
4j
3-CH3O
5-CH3O
H
4-F
250/a
4k
5a
5b
5c
5d
5e
5f
4-F
62/125
32/62
3,4-Cl2
3,4-Cl2
3,4-Cl2
3,4-Cl2
3,4-Cl2
3,4-Cl2
3,4-Cl2
3,4-Cl2
3,4-Cl2
3,4-Cl2
3-Cl
5-Br
16/32
5-Cl
16/32
3,5-Cl2
5-CH3
3,5-Br2
4-CH3O
5-NO2
4-Cl
62/62
32/a
32/32
32/32
16/16
16/32
a/a
62/62
32/62
62/62
62/62
62/62
a/a
32/62
62/62
62/125
32/32
a/a
5g
5h
5i
62/62
125/125
32/32
5j
3-CH3O
5-CH3O
H
a/a
5k
6a
6b
6c
6d
6e
6f
125/250
125/125
32/62
62/62
62/62
125/a
62/62
62/62
8/16
125/250
125/250
62/62
62/62
125/125
62/62
a/125
125/125
a/a
125/250
125/250
125/125
125/a
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
5-Br
5-Cl
62/62
3,5-Cl2
5-CH3
3,5-Br2
4-CH3O
5-NO2
4-Cl
250/250
125/125
125/125
250/250
125/125
a/a
32/62
125/250
32/62
125/125
125/250
62/125
250/500
62/125
4/4
6g
6h
6i
1000/1000 125/250
32/32
125/250
125/250
0.5/1
62/62
62/125
6j
3-CH3O
5-CH3O
250/500
62/125
250/250
250/500
125/125
250/250
6k
INH
a: MIC values could n ot be determ in ed due to th e low solubility. Th e values of com poun ds
1a, 2a, 3a, 4a, 5a an d 6a were taken from th e ref.6
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

Substituted N-Benzylsalicylamides
1279
bein g in directly referen ced to tetram eth ylsilan e via th e solven t sign al (2.49 for 1H or 39.7
for 13C). Couplin g con stan ts (J) are given in Hz.
Preparation of N-Ben zylsalicylam ides 1–6. Gen eral Procedure
A suspen sion of a substituted salicylic acid (0.02 m ol) an d substituted ben zylam in e (0.02 m ol)
in ch loroben zen e (100 m l) was h eated un der reflux in th e presen ce of PCl3 (0.01 m ol) for 3 h .
Th e reaction m ixture was filtered wh ile h ot, an d th e solven ts were evaporated. Th e product
was crystallized from eth an ol–water (yields in th e ran ge 75–95%). Th e syn th esis an d ph ysi-
cal properties of th e com poun ds 1a, 2a, 3a, 4a, 5a an d 6a were described in our previous
paper6.
5-Bromo-N-benzylsalicylamide (1b ). Wh ite crystals. Yield 65%, m .p. 152–154 °C (ref.7
154–156 °C). IR: ν(C=O) 1640. 1H NMR (DMSO-d6): 12.60 s, 1 H (OH); 9.40 t, 1 H, J = 6.00
(NH); 8.12 d, 1 H, J(4,6) = 2.70 (H6); 7.54 dd, 1 H, J(3,4) = 9.00, J(4,6) = 2.70 (H4); 7.35–
7.20 m , 5 H (H2′, H3′, H4′, H5′, H6′); 6.95 d, 1 H, J(3,4) = 9.00 (H3); 4.51 d, 2 H, J = 6.00
(CH2). 13C NMR (DMSO-d6): 167.7, 159.3, 138.9, 136.3, 130.4, 128.6, 127.6, 127.2, 120.0,
117.5, 110.0, 42.8.
N-Benzyl-5-chlorosalicylamide (1c). W h ite crystals. Yield 63%, m .p. 144–145 °C (ref.7
145–146 °C). IR: ν(C=O) 1643. 1H NMR (DMSO-d6): 12.52 s, 1 H (OH); 9.39 t, 1 H, J = 5.70
(NH); 7.98 d, 1 H, J(4,6) = 2.40 (H6); 7.54 dd, 1 H, J(3,4) = 9.00, J(4,6) = 2.40 (H4); 7.38–
7.22 m , 5 H (H2′, H3′, H4′, H5′, H6′); 6.95 d, 1 H, J(3,4) = 9.00 (H3); 4.50 d, 2 H, J = 5.70
(CH2). 13C NMR (DMSO-d6): 167.7, 158.8, 138.9, 133.5, 128.6, 127.6, 127.5, 127.2, 122.6,
119.5, 117.0, 42.7.
N-Benzyl-3,5-dichlorosalicylamide (1d ). Wh ite crystals. Yield 50%, m .p. 119–120 °C. IR:
ν(C=O) 1642. For C14H11Cl2NO2 (296.2) calculated: 56.78% C, 3.74% H, 4.73% N; foun d:
56.80% C, 3.76% H, 4.70% N. 1H NMR (DMSO-d6): 9.70 t, 1 H, J = 6.00 (NH); 8.05 d, 1 H,
J(4,6) = 2.10 (H6); 7.75 d, 1 H, J(4,6) = 2.10 (H4); 7.38–7.22 m , 5 H (H2′, H3′, H4′, H5′, H6′);
4.50 d, 2 H, J = 6.00 (CH2). 13C NMR (DMSO-d6): 168.4, 156.0, 138.3, 133.3, 128.6, 127.6,
127.3, 125.8, 122.6, 122.2, 116.5, 42.9.
N-Benzyl-5-methylsalicylamide (1e). Wh ite crystals. Yield 91%, m .p. 134–135.5 °C. IR:
ν(C=O) 1645. For C15H15NO2 (241.3) calculated: 74.67% C, 6.27% H, 5.81% N; foun d:
74.54% C, 6.35% H, 5.69% N. 1H NMR (CDCl3): 12.14 s, 1 H (OH); 7.40–7.29 m , 5 H (H2′,
H3′, H4′, H5′, H6′); 7.22–7.17 m , 2 H (H4, H6); 6.89 d, 1 H, J(3,4) = 8.40 (H3); 6.76 bs, 1 H
(NH); 4.61 d, 2 H, J = 5.70 (CH2); 2.25 s, 3 H (CH3). 13C NMR (CDCl3): 169.8, 159.2, 137.4,
135.2, 128.8, 127.8, 127.8, 127.7, 125.4, 118.2, 113.6, 43.5, 20.4.
N-Benzyl-3,5-dibromosalicylamide (1f). Wh ite crystals. Yield 73%, m .p. 126–126 °C. IR:
ν(C=O) 1641. For C14H11Br2NO2 (385.1) calculated: 43.67% C, 2.88% H, 3.64% N; foun d:
43.49% C, 2.91% H, 3.51% N. 1H NMR (DMSO-d6): 9.72 t, 1 H, J = 5.70 (NH); 8.20 d, 1 H,
J(4,6) = 2.10 (H6); 7.96 d, 1 H, J(4,6) = 2.10 (H4); 7.37–7.23 m , 5 H (H2′, H3′, H4′, H5′, H6′);
4.51 d, 2 H, J = 5.70 (CH2). 13C NMR (DMSO-d6): 168.3, 157.4, 138.7, 138.3, 129.2, 128.6,
127.7, 127.3, 116.8, 112.4, 109.8, 42.9.
N-Benzyl-4-methoxysalicylamide (1g). Wh ite crystals. Yield 69%, m .p. 105–110 °C. IR:
ν(C=O) 1641. For C15H15NO3 (257.3) calculated: 70.02% C, 5.88% H, 5.44% N; foun d:
70.13% C, 5.89% H, 5.37% N. 1H NMR (CDCl3): 7.39–7.29 m , 5 H (H2′, H3′, H4′, H5′, H6′);
7.25 d, 1 H, J(4,6) = 9.00 (H6); 6.48 bs overlapped, 1 H (NH); 6.47 d overlapped, 1 H, J(3,5) =
2.40 (H3); 7.54 dd, 1 H, J(5,6) = 9.00, J(3,5) = 2.40 (H5); 4.60 d, 2 H, J = 5.70 (CH2); 3.79 s,
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

1280
Waisser, Peřina, Klimešová, Kaustová:
3 H (OCH3). 13C NMR (CDCl3): 169.7, 164.4, 163.8, 137.6, 128.8, 127.8, 127.7, 126.6, 107.0,
106.9, 101.5, 55.4, 43.5.
N-Benzyl-5-nitrosalicylamide (1h ). Yellow crystals. Yield 62%, m .p. 152–154 °C (ref.8
161.5–162.5 °C). IR: ν(C=O) 1649. For C14H12N2O4 (272.3) calculated: 61.76% C, 4.44% H,
10.29% N; foun d: 61.78% C, 4.53% H, 10.34% N. 1H NMR (DMSO-d6): 9.66 t, 1 H, J = 6.00
(NH); 8.89 d, 1 H, J(4,6) = 3.00 (H6); 8.25 dd, 1 H, J(3,4) = 9.30, J(4,6) = 3.00 (H4);
7.37–7.23 m , 5 H (H2′, H3′, H4′, H5′, H6′); 7.10 d, 1 H, J(3,4) = 9.30 (H3); 4.53 d, 2 H, J =
6.00 (CH2). 13C NMR (DMSO-d6): 167.0, 165.3, 139.4, 138.7, 129.0, 128.6, 127.7, 127.3,
125.1, 118.6, 116.1, 42.9.
N-Benzyl-4-chlorosalicylamide (1i). W h ite crystals. Yield 64%, m .p. 129–132 °C (ref.9
124–127 °C). IR: ν(C=O) 1636. For C14H12ClNO2 (261.7) calculated: 64.25% C, 4.62% H,
5.35% N; foun d: 64.12% C, 4.69% H, 5.28% N. 1H NMR (CDCl3): 12.53 s, 1 H (OH);
7.40–7.26 m , 6 H (H6, H2′, H3′, H4′, H5′, H6′); 6.99 d, 1 H, J(3,5) = 3.00 (H3); 6.80 dd, 1 H,
J(5,6) = 8.40, J(3,5) = 3.00 (H5); 6.62 bs, 1 H (NH); 4.61 d, 2 H, J = 5.40 (CH2). 13C NMR
(CDCl3): 169.1, 162.3, 139.8, 137.0, 128.9, 127.9, 127.8, 126.3, 119.1, 118.6, 112.6, 43.7.
N-Benzyl-3-methoxysalicylamide (1j). Wh ite crystals. Yield 33%, m .p. 127–129 °C (ref.10
134 °C). IR: ν(C=O) 1641. For C15H15NO3 (257.3) calculated: 70.02% C, 5.88% H, 5.44% N;
foun d: 69.91% C, 5.69% H, 5.32% N. 1H NMR (CDCl3): 11.85 bs, 1 H (OH); 7.34–7.27 m ,
5 H (H2′, H3′, H4′, H5′, H6′); 7.18 bs overlapped, 1 H (NH); 7.12 dd overlapped, 1 H, J(5,6) =
8.05, J(4,6) = 1.20 (H6); 6.95 dd, 1 H, J(4,5) = 8.05, J(4,6) = 1.20 (H4); 6.80 t, 1 H, J = 8.05
(H5); 4.60 d, 2 H, J = 5.70 (CH2); 3.85 s, 3 H (OCH3). 13C NMR (CDCl3): 169.2, 150.7, 148.7,
137.5, 128.7, 127.7, 127.6, 118.3, 117.8, 114.8, 114.6, 56.0, 43.5.
N-Benzyl-5-methoxysalicylamide (1k). Wh ite crystals. Yield 18%, m .p. 94–97 °C. IR: ν(C=O)
1644. For C15H15NO3 (257.3) calculated: 70.02% C, 5.88% H, 5.44% N; foun d: 70.21% C,
5.84% H, 5.41% N. 1H NMR (CDCl3): 11.77 s, 1 H (OH); 7.40–7.28 m , 5 H (H2′, H3′, H4′,
H5′, H6′); 7.02 dd, 1 H, J(3,4) = 9.00, J(4,6) = 3.00 (H4); 6.93 d, 1 H, J(3,4) = 9.00 (H3);
6.83 d, 1 H, J(4,6) = 3.00 (H6); 6.64 bs, 1 H (NH); 4.62 d, 2 H, J = 5.70 (CH2); 3.74 s, 3 H
(OCH3). 13C NMR (CDCl3): 169.5, 155.5, 151.8, 137.4, 128.9, 127.9, 127.8, 121.0, 119.3,
113.9, 109.7, 56.0, 43.7.
5-Bromo-N-(4-chlorobenzyl)salicylamide (2b). Wh ite crystals. Yield 53%, m .p. 152–155 °C
(ref.7 158–159 °C). IR: ν(C=O) 1621. 1H NMR (CDCl3): 12.16 s, 1 H (OH); 7.48–7.44 m , 2 H
(H4, H6); 7.35–7.23 m AA′ BB′, 4 H (H2′, H3′, H5′, H6′); 6.88 d, 1 H, J(3,4) = 9.30 (H3);
6.62 bs, 1 H (NH); 4.57 d, 2 H, J = 5.70 (CH2). 13C NMR (CDCl3): 168.7, 160.5, 137.1, 135.5,
133.8, 129.3, 129.0, 127.9, 120.6, 115.5, 110.3, 43.1.
5-Chloro-N-(4-chlorobenzyl)salicylamide (2c). Wh ite crystals. Yield 58%, m .p. 154–155 °C
(ref.7 156–158 °C). IR: ν(C=O) 1621. 1H NMR (CDCl3): 12.14 s, 1 H (OH); 7.37–7.27 m , 6 H
(H4, H6, H2′, H3′, H5′, H6′); 6.94 d, 1 H, J(3,4) = 8.70 (H3); 6.57 bs, 1 H (NH); 4.59 d, 2 H,
J = 5.70 (CH2). 13C NMR (CDCl3): 168.8, 160.1, 135.6, 134.3, 133.9, 129.3, 129.1, 124.9,
123.4, 120.2, 114.8, 43.1.
3,5-Dichloro-N-(4-chlorobenzyl)salicylamide (2d). Wh ite crystals. Yield 69%, m .p. 124–126 °C.
IR: ν(C=O) 1647. For C14H10Cl3NO2 (330.6) calculated: 50.86% C, 3.05% H, 4.24% N; foun d:
50.67% C, 3.28% H, 4.18% N. 1H NMR (DMSO-d6): 9.70 t, 1 H, J = 5.70 (NH); 8.02 d, 1 H,
J(4,6) = 2.40 (H6); 7.76 d, 1 H, J(4,6) = 2.40 (H4); 7.40–7.32 m , 4 H (H2′, H3′, H5′, H6′);
4.48 d, 2 H, J = 5.70 (CH2). 13C NMR (DMSO-d6): 168.4, 156.0, 137.4, 133.4, 131.9, 129.6,
128.6, 125.9, 122.6, 122.3, 116.5, 42.3.
N-(4-Chlorobenzyl)-5-methylsalicylamide (2e). Wh ite crystals. Yield 37%, m .p. 110–114 °C.
IR: ν(C=O) 1644. For C15H14ClNO2 (275.5) calculated: 65.34% C, 5.12% H, 5.08% N; foun d:
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65.57% C, 5.39% H, 5.08% N. 1H NMR (CDCl3): 12.02 s, 1 H (OH); 7.33–7.15 m , 6 H (H4,
H6, H2′, H3′, H5′, H6′); 6.88 d, 1 H, J(3,4) = 8.10 (H3); 6.72 bs, 1 H (NH); 4.57 d, 2 H, J =
5.70 (CH2); 2.52 s, 3 H (CH3). 13C NMR (CDCl3): 169.9, 159.3, 136.0, 135.4, 133.5, 129.1,
128.9, 127.9, 125.3, 118.3, 113.5, 42.8, 20.4.
3,5-Dibromo-(N-4-chlorobenzyl)salicylamide (2f). Wh ite crystals. Yield 68%, m .p. 138–140 °C
(ref.11 139–142 °C). IR: ν(C=O) 1641. 1H NMR (CDCl3): 7.78 d, 1 H, J(4,6) = 2.40 (H6); 7.47 d,
1 H, J(4,6) = 2.40 (H4); 7.34–7.31 m AA′ BB′, 2 H (H2′, H6′); 7.29–7.24 m AA′ BB′, 2 H (H3′,
H5′); 6.69 bs, 1 H (NH); 4.59 d, 2 H, J = 5.70 (CH2). 13C NMR (CDCl3): 168.0, 157.3, 139.6,
135.2, 134.0, 129.3, 129.1, 127.4, 116.1, 113.5, 110.1, 43.3.
N-(4-Chlorobenzyl)-4-methoxysalicylamide (2g). Wh ite crystals. Yield 58%, m .p. 115–117.5 °C.
IR: ν(C=O) 1641. For C15H14ClNO3 (291.7) calculated: 61.76% C, 4.84% H, 4.80% N; foun d:
61.44% C, 4.82% H, 4.90% N. 1H NMR (CDCl3): 7.33–7.15 m , 5 H (H6, H2′, H3′, H5′, H6′);
6.51 bs overlapped, 1 H (NH); 6.46 d overlapped, 1 H, J(3,5) = 2.40 (H3); 6.37 dd, 1 H, J(5,6) =
9.00, J(3,5) = 2.40 (H5); 4.56 d, 2 H, J = 5.70 (CH2); 3.80 s, 3 H (OCH3). 13C NMR (CDCl3):
169.8, 164.5, 163.8, 136.2, 133.5, 129.1, 128.9, 126.6, 107.1, 106.8, 101.5, 55.4, 42.8.
N-(4-Chlorobenzyl)-5-nitrosalicylamide (2h ). Yellow crystals. Yield 62%, m .p. 212–214 °C.
IR: ν(C=O) 1648. For C14H11ClN2O4 (306.7) calculated: 54.83% C, 3.62% H, 9.13% N; foun d:
54.92% C, 3.72% H, 8.99% N. 1H NMR (DMSO-d6): 9.65 t, 1 H, J = 5.70 (NH); 8.86 d, 1 H,
J(4,6) = 2.70 (H6); 8.24 dd, 1 H, J(3,4) = 9.00, J(4,6) = 2.70 (H4); 7.40–7.37 m , 4 H (H2′, H3′,
H5′, H6′); 7.10 d, 1 H, J(3,4) = 9.00 (H3); 4.52 d, 2 H, J = 5.70 (CH2). 13C NMR (DMSO-d6):
167.0, 165.2, 139.4, 137.8, 131.8, 129.5, 129.0, 128.5, 125.2, 118.6, 116.2, 42.3.
4-Chloro-N-(4-chlorobenzyl)salicylamide (2i). Wh ite crystals. Yield 95%, m .p. 164–166 °C.
IR: ν(C=O) 1632. For C14H11Cl2NO2 (296.2) calculated: 56.78% C, 3.74% H, 4.73% N; foun d:
56.68% C, 4.01% H, 4.58% N. 1H NMR (DMSO-d6): 9.38 t, 1 H, J = 6.00 (NH); 7.90 d, 1 H,
J(5,6) = 8.10 (H6); 7.33–7.15 m , 4 H (H2′, H3′, H5′, H6′); 6.99 dd, 1 H, J(5,6) = 8.10, J(3,5) =
1.80 (H5); 6.95 d, 1 H, J(3,5) = 1.80 (H3); 4.48 d, 2 H, J = 6.00 (CH2). 13C NMR (DMSO-d6):
168.1, 160.8, 138.1, 137.9, 131.7, 129.9, 129.4, 128.5, 119.2, 117.2, 114.8, 42.0.
N-(4-Chlorobenzyl)-3-methoxysalicylamide (2j). Wh ite crystals. Yield 48%, m .p. 127–129 °C.
IR: ν(C=O) 1638. For C15H14ClNO3 (291.7) calculated: 61.76% C, 4.84% H, 4.80% N; foun d:
61.84% C, 4.75% H, 4.95% N. 1H NMR (CDCl3): 11.49 s, 1 H (OH); 7.28–7.19 m , 4 H (H2′,
H3′, H5′, H6′); 7.22 bs overlapped, 1 H (NH); 7.15 d, 1 H, J(5,6) = 7.80 (H6); 6.96 d, 1 H,
J(4,5) = 7.80 (H4); 6.80–6.75 m , 1 H (H5); 4.56 d, 2 H, J = 5.70 (CH2); 3.86 s, 3 H (OCH3).
13C NMR (CDCl3): 169.1, 150.4, 148.6, 136.2, 133.3, 129.0, 128.8, 118.5, 118.0, 114.8,
114.6, 56.0, 42.9.
N-(4-Chlorobenzyl)-5-methoxysalicylamide (2k). Wh ite crystals. Yield 50%, m .p. 157.5–159 °C.
IR: ν(C=O) 1644. For C15H14ClNO3 (291.7) calculated: 61.76% C, 4.84% H, 4.80% N; foun d:
61.63% C, 4.72% H, 4.79% N. 1H NMR (DMSO-d6): 11.96 s, 1 H (OH); 9.35 t, 1 H, J = 6.30
(NH); 7.44 d, 1 H, J = 3.00 (H6); 7.40–7.31 m , 4 H (H2′, H3′, H5′, H6′); 7.25 dd, 1 H, J(4,6) =
9.00, J(4,6) = 3.00 (H4); 6.84 d, 1 H, J(3,4) = 9.00 (H3); 4.51 d, 2 H, J = 6.30 (CH2); 3.72 s,
3 H (OCH3). 13C NMR (DMSO-d6): 168.8, 154.2, 151.8, 138.3, 131.7, 129.4, 128.6, 121.3,
118.5, 115.1, 111.3, 55.9, 42.0.
5-Bromo-N-(4-methylbenzyl)salicylamide (3b). Wh ite crystals. Yield 63%, m .p. 157–160 °C.
IR: ν(C=O) 1622. For C15H14BrNO2 (320.2) calculated: 56.27% C, 4.41% H, 4.37% N; foun d:
55.92% C, 4.33% H, 4.22% N. 1H NMR (DMSO-d6): 12.60 s, 1 H (OH); 9.35 t, 1 H, J = 5.70
(NH); 8.10 d, 1 H, J(4,6) = 2.70 (H6); 7.53 dd, 1 H, J(3,4) = 8.70, J(4,6) = 2.70 (H4); 7.22–
7.10 m AA′ BB′, 4 H (H2′, H3′, H5′, H6′); 6.88 d, 1 H, J(3,4) = 8.70 (H3); 4.45 d, 2 H, J = 5.70
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(CH2); 2.26 s, 3 H (CH3). 13C NMR (DMSO-d6): 167.6, 129.3, 136.3, 136.3, 135.8, 130.4,
129.1, 127.6, 120.0, 117.5, 110.0, 42.5, 20.9.
5-Chloro-N-(4-methylbenzyl)salicylamide (3c). Wh ite crystals. Yield 38%, m .p. 157–159 °C.
IR: ν(C=O) 1622. For C15H14ClNO2 (275.5) calculated: 65.34% C, 5.12% H, 5.08% N; foun d:
65.76% C, 5.13% H, 5.29% N. 1H NMR (DMSO-d6): 12.48 s, 1 H (OH); 9.35 t, 1 H, J = 5.70
(NH); 7.98 d, 1 H, J(4,6) = 2.70 (H6); 7.42 dd, 1 H, J(3,4) = 9.00, J(4,6) = 2.70 (H4); 7.22–
7.11 m AA′ BB′, 4 H (H2′, H3′, H5′, H6′); 6.88 d, 1 H, J(3,4) = 9.00 (H3); 4.45 d, 2 H, J = 5.70
(CH2); 2.26 s, 3 H (CH3). 13C NMR (DMSO-d6): 167.6, 158.8, 136.3, 135.8, 133.5, 129.1,
127.6, 127.6, 122.6, 119.5, 116.9, 42.5, 20.9.
3,5-Dichloro-N-(4-methylbenzyl)salicylamide (3d). Wh ite crystals. Yield 57%, m .p. 110–112 °C.
IR: ν(C=O) 1646. For C15H13Cl2NO2 (310.2) calculated: 58.08% C, 4.22% H, 4.52% N; foun d:
58.46% C, 4.03% H, 4.29% N. 1H NMR (CDCl3): 7.47 d, 1 H, J(4,6) = 2.40 (H6); 7.28 d, 1 H,
J(4,6) = 2.40 (H4); 7.25–7.15 m AA′ BB′, 4 H (H2′, H3′, H5′, H6′); 6.69 bs, 1 H (NH); 4.56 d,
2 H, J = 5.40 (CH2); 2.35 s, 3 H (CH3). 13C NMR (CDCl3): 168.0, 156.0, 137.9, 133.8, 133.5,
129.6, 128.0, 124.0, 123.8, 123.0, 115.8, 43.82, 21.1.
5-Methyl-N-(4-methylbenzyl)salicylamide (3e). Wh ite crystals. Yield 68%, m .p. 103–105 °C.
IR: ν(C=O) 1641. For C16H17NO2 (275.5) calculated: 75.27% C, 6.71% H, 5.49% N; foun d:
74.89% C, 6.73% H, 5.54% N. 1H NMR (CDCl3): 12.15 s, 1 H (OH); 7.27–7.13 m , 6 H (H4,
H6, H2′, H3′, H5′, H6′); 6.89 d, 1 H, J(3,4) = 8.70 (H3); 6.64 bs, 1 H (NH); 4.45 d, 2 H, J =
5.40 (CH2); 2.36 s, 3 H (CH3); 2.25 s, 3 H (CH3). 13C NMR (CDCl3): 169.7, 159.3, 137.6,
135.1, 134.4, 129.5, 127.9, 127.7, 125.3, 118.7, 43.4, 21.0, 20.4.
3,5-Dibromo-N-(4-methylbenzyl)salicylamide (3f). Wh ite crystals. Yield 69%, m .p. 125–127 °C.
IR: ν(C=O) 1641. For C15H13Br2NO2 (399.1) calculated: 45.14% C, 3.28% H, 3.51% N; foun d:
45.01% C, 3.21% H, 3.25% N. 1H NMR (CDCl3): 7.76 d, 1 H, J(4,6) = 2.10 (H6); 7.43 d, 1 H,
J(4,6) = 2.10 (H4); 7.26–7.13 m AA′ BB′, 4 H (H2′, H3′, H5′, H6′); 6.58 bs, 1 H (NH); 4.57 d,
2 H, J = 5.70 (CH2); 2.36 s, 3 H (CH3). 13C NMR (CDCl3): 167.9, 127.4, 139.4, 138.0, 133.5,
129.6, 128.0, 127.3, 116.2, 113.4, 110.0, 43.9, 21.1.
4-Methoxy-N-(4-methylbenzyl)salicylamide (3g). Wh ite crystals. Yield 68%, m .p. 93–95 °C.
IR: ν(C=O) 1645. For C16H17NO3 (271.3) calculated: 70.83% C, 6.32% H, 5.16% N; foun d:
70.81% C, 6.26% H, 5.13% N. 1H NMR (CDCl3): 7.25 d overlapped, 1 H, J(5,6) = 8.70 (H6);
7.24–7.15 m overlapped AA′ BB′, 4 H (H2′, H3′, H5′, H6′); 6.46 bs overlapped, 1 H (NH);
6.46 d overlapped, 1 H, J(3,5) = 2.70 (H3); 6.36 dd, 1 H, J(5,6) = 8.70, J(3,5) = 2.70 (H5);
4.56 d, 2 H, J = 5.40 (CH2); 3.79 s, 3 H (OCH3); 2.35 s, 3 H (CH3). 13C NMR (CDCl3): 169.6,
164.3, 163.8, 137.5, 134.5, 129.4, 127.8, 126.6, 107.0, 106.9, 101.5, 55.3, 43.3, 21.1.
N-(4-Methylbenzyl)-5-nitrosalicylamide (3h ). Yellow crystals. Yield 58%, m .p. 187–189 °C.
IR: ν(C=O) 1641. For C15H14N2O4 (286.3) calculated: 62.93% C, 4.93% H, 9.79% N; foun d:
63.02% C, 4.85% H, 9.43% N. 1H NMR (DMSO-d6): 9.63 t, 1 H, J = 5.70 (NH); 8.88 d, 1 H,
J(4,6) = 2.70 (H6); 8.23 dd, 1 H, J(3,4) = 9.30, J(4,6) = 2.70 (H4); 7.26–7.13 m AA′ BB′, 4 H
(H2′, H3′, H5′, H6′); 7.08 d, 1 H, J(3,4) = 9.30 (H3); 4.47 d, 2 H, J = 5.70 (CH2); 2.25 s, 3 H
(CH3). 13C NMR (DMSO-d6): 167.1, 165.5, 139.4, 136.4, 135.7, 129.2, 129.0, 127.7, 125.1,
118.6, 115.9, 42.7, 20.9.
4-Chloro-N-(4-methylbenzyl)salicylamide (3i). Wh ite crystals. Yield 71%, m .p. 162–165 °C.
IR: ν(C=O) 1632. For C15H14ClNO2 (275.7) calculated: 65.34% C, 5.12% H, 5.08% N; foun d:
65.02% C, 4.89% H, 4.96% N. 1H NMR (DMSO-d6): 9.33 t, 1 H, J = 6.00 (NH); 7.91 d, 1 H,
J(5,6) = 8.40 (H6); 7.22–7.10 m AA′ BB′, 4 H (H2′, H3′, H5′, H6′); 6.99 d overlapped, 1 H,
J(3,5) = 1.80 (H3); 6.96 dd overlapped, 1 H, J(5,6) = 8.40, J(3,5) = 1.80 (H5); 4.45 d, 2 H, J =
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6.00 (CH2); 2.25 s, 3 H (CH3). 13C NMR (DMSO-d6): 168.1, 161.0, 137.9, 136.3, 135.9, 129.8,
129.1, 127.5, 119.1, 117.3, 114.7, 42.4, 20.9.
3-Methoxy-N-(4-methylbenzyl)salicylamide (3j). Wh ite crystals. Yield 56%, m .p. 108–110 °C.
IR: ν(C=O) 1640. For C16H17NO3 (271.3) calculated: 70.83% C, 6.32% H, 5.16% N; foun d:
70.38% C, 5.99% H, 4.95% N. 1H NMR (CDCl3): 11.92 s, 1 H (OH); 7.23–7.11 m AA′ BB′, 4 H
(H2′, H3′, H5′, H6′); 7.08 dd, 1 H, J(5,6) = 7.95, J(4,6) = 1.35 (H6); 6.97 bs overlapped, 1 H
(NH); 6.95 dd overlapped, 1 H, J(4,5) = 7.95, J(4,6) = 1.35 (H4); 6.77 t, 1 H, J(4,5) = 7.95
(H5); 4.57 d, 2 H, J = 6.00 (CH2); 3.87 s, 3 H (OCH3); 2.33 s, 3 H (CH3). 13C NMR (CDCl3):
169.2, 150.9, 148.8, 137.4, 134.4, 129.4, 127.8, 118.2, 117.6, 114.7, 114.6, 56.0, 43.4, 21.0.
5-Methoxy-N-(4-methylbenzyl)salicylamide (3k). Wh ite crystals. Yield 50%, m .p. 109–110 °C.
IR: ν(C=O) 1652. For C16H17NO3 (271.3) calculated: 70.83% C, 6.32% H, 5.16% N; foun d:
70.54% C, 6.21% H, 4.95% N. 1H NMR (CDCl3): 11.84 s, 1 H (OH); 7.24–7.12 m AA′ BB′,
4 H (H2′, H3′, H5′, H6′); 7.00 dd, 1 H, J(3,4) = 9.00, J(4,6) = 3.00 (H4); 6.90 d, 1 H, J(3,4) =
9.00 (H3); 6.88 d, 1 H, J(4,6) = 3.00 (H6); 6.77 bs, 1 H (NH); 4.56 d, 2 H, J = 6.00 (CH2);
3.73 s, 3 H (OCH3); 2.35 s, 3 H (CH3). 13C NMR (CDCl3): 169.4, 155.4, 151.7, 137.5, 134.3,
129.4, 127.8, 121.0, 119.2, 114.0, 109.7, 55.9, 43.4, 21.0.
5-Bromo-N-(4-fluorobenzyl)salicylamide (4b). Wh ite crystals. Yield 60%, m .p. 159–162 °C.
IR: ν(C=O) 1621. For C14H11BrFNO2 (324.2) calculated: 51.87% C, 3.42% H, 4.32% N; foun d:
51.65% C, 3.21% H, 3.81% N. 1H NMR (DMSO-d6): 9.33 t, 1 H, J = 6.00 (NH); 7.91 d, 1 H,
J(4,6) = 2.40 (H6); 7.54 dd, 1 H, J(3,4) = 8.70, J(4,6) = 2.40 (H4); 7.37–7.33 m , 2 H (H2′, H6′);
7.19–7.11 m , 2 H (H3′, H5′); 6.90 d, 1 H, J(3,4) = 8.70 (H3); 4.47 d, 2 H, J = 6.00 (CH2).
13C NMR (DMSO-d6): 167.6, 161.5 (d, J = 241.05); 159.1, 136.4, 135.2 (d, J = 2.85); 130.5,
129.7 (d, J = 7.95); 118.0, 117.6, 115.4 (d, J = 21.30); 110.0, 42.1.
5-Chloro-N-(4-fluorobenzyl)salicylamide (4c). Wh ite crystals. Yield 61%, m .p. 155–157 °C.
IR: ν(C=O) 1621. For C14H11ClFNO2 (279.7) calculated: 60.12% C, 3.96% H, 5.01% N; foun d:
59.89% C, 3.97% H, 4.57% N. 1H NMR (DMSO-d6): 9.39 t, 1 H, J = 6.00 (NH); 7.96 d, 1 H,
J(4,6) = 2.40 (H6); 7.45–7.36 m , 3 H (H4, H2′, H6′); 7.19–7.11 m , 2 H (H3′, H5′); 6.94 d, 1 H,
J(3,4) = 8.70 (H3); 4.48 d, 2 H, J = 6.00 (CH2). 13C NMR (DMSO-d6): 167.6, 161.5 (d, J =
241.28); 158.7, 135.1 (d, J = 2.85); 133.6, 129.7 (d, J = 7.95); 127.6, 122.6, 119.6, 117.0,
115.4 (d, J = 21.08); 42.1.
3,5-Dichloro-N-(4-fluorobenzyl)salicylamide (4d). Wh ite crystals. Yield 73%, m .p. 124–126 °C.
IR: ν(C=O) 1647. For C14H10Cl2FNO2 (314.1) calculated: 53.53% C, 3.21% H, 4.46% N;
foun d: 54.12% C, 3.11% H, 4.43% N. 1H NMR (DMSO-d6): 9.70 t, 1 H, J = 5.70 (NH); 8.03 d,
1 H, J(4,6) = 2.40 (H6); 7.76 d, 1 H, J(4,6) = 2.40 (H4); 7.40–7.35 m , 2 H (H2′, H6′);
7.19–7.12 m , 2 H (H3′, H5′); 4.48 d, 2 H, J = 5.70 (CH2). 13C NMR (DMSO-d6): 168.4, 161.6
(d, J = 241.28); 156.0, 134.6 (d, J = 3.08); 133.4, 129.8 (d, J = 7.95); 125.9, 122.6, 122.3,
116.5, 115.4 (d, J = 21.38); 42.2.
N-(4-Fluorobenzyl)-5-methylsalicylamide (4e). Wh ite crystals. Yield 63%, m .p. 143.5–145 °C.
IR: ν(C=O) 1644. For C15H14FNO2 (259.3) calculated: 69.49% C, 5.44% H, 5.40% N; foun d:
69.52% C, 5.59% H, 5.49% N. 1H NMR (DMSO-d6): 12.28 s, 1 H (OH); 9.31 t, 1 H, J = 5.70
(NH); 7.71 d, 1 H, J(4,6) = 1.50 (H6); 7.39–7.34 m , 2 H (H2′, H6′); 7.19 dd overlapped, 1 H,
J(3,4) = 8.10, J(4,6) = 1.50 (H4); 7.18–7.12 m overlapped, 2 H (H3′, H5′); 6.80 d, 1 H, J(3,4)=
8.10 (H3); 4.48 d, 2 H, J = 5.70 (CH2); 2.23 s, 3 H (CH3). 13C NMR (DMSO-d6): 169.2, 161.5
(d, J = 240.98); 156.2, 135.5 (d, J = 3.15); 134.7, 129.6 (d, J = 7.95); 127.9, 127.5, 117.4,
115.3 (d, J = 21.08); 114.9, 41.9, 20.3.
3,5-Dibromo-N-(4-fluorobenzyl)salicylamide (4f). Wh ite crystals. Yield 69%, m .p. 135–137 °C.
IR: ν(C=O) 1641. For C14H10Br2FNO2 (403.1) calculated: 41.72% C, 2.50% H, 3.48% N;
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foun d: 41.81% C, 2.41% H, 3.29% N. 1H NMR (DMSO-d6): 9.71 t, 1 H, J = 5.70 (NH); 8.18 d,
1 H, J(4,6) = 2.40 (H6); 7.97 d, 1 H, J(4,6) = 2.40 (H4); 7.40–7.35 m , 2 H (H2′, H6′);
7.19–7.12 m , 2 H (H3′, H5′); 4.48 d, 2 H, J = 5.70 (CH2). 13C NMR (DMSO-d6): 168.3, 161.6
(d, J = 241.28); 157.3, 138.8, 134.5 (d, J = 3.08); 129.8 (d, J = 7.95); 129.2, 116.8, 115.4 (d,
J = 21.08); 112.4, 109.8, 42.3.
N-(4-Fluorobenzyl)-4-methoxysalicylamide (4g). Wh ite crystals. Yield 44%, m .p. 139–141 °C.
IR: ν(C=O) 1649. For C15H14FNO3 (275.3) calculated: 65.45% C, 5.13% H, 5.09% N; foun d:
65.02% C, 4.96% H, 4.95% N. 1H NMR (DMSO-d6): 9.21 t, 1 H, J = 6.00 (NH); 7.96 (d, 1 H,
J(5,6) = 9.00 (H6); 7.37–7.32 m , 2 H (H2′, H6′); 7.18–7.12 m , 2 H (H3′, H5′); 6.47 dd, 1 H,
J(5,6) = 9.00, J(3,5) = 2.70 (H5); 6.42 d, 1 H, J(3,5) = 2.70 (H3); 4.46 d, 2 H, J = 6.00 (CH2);
3.76 s, 3 H (OCH3). 13C NMR (DMSO-d6) 169.4, 163.9, 162.9, 161.5 (d, J = 240.75); 135.5 (d,
J = 2.85); 129.5 (d, J = 7.95); 129.0, 115.3 (d, J = 21.08); 107.8, 106.4, 101.4, 55.6, 41.8.
N-(4-Fluorobenzyl)-5-nitrosalicylamide (4h ). Yellow crystals. Yield 58%, m .p. 193–195 °C. IR:
ν(C=O) 1651. For C14H11FN2O4 (290.3) calculated: 62.93% C, 4.93% H, 9.79% N; foun d:
62.45% C, 4.78% H, 9.56% N. 1H NMR (DMSO-d6): 9.68 t, 1 H, J = 6.00 (NH); 8.86 d, 1 H,
J(4,6) = 2.70 (H6); 8.25 dd, 1 H, J(3,4) = 9.00, J(4,6) = 2.70 (H4); 7.41–7.36 m , 2 H (H2′, H6′);
7.19–7.12 m overlapped, 2 H (H3′, H5′); 7.09 d overlapped, 1 H, J(3,4) = 9.00 (H3); 4.51 d,
2 H, J = 6.00 (CH2). 13C NMR (DMSO-d6): 166.9, 165.5, 161.5 (d, J = 240.98); 139.3, 135.0
(d, J = 2.78); 129.7 (d, J = 7.95); 129.0, 125.3, 118.7, 116.2, 115.3 (d, J = 21.38); 42.2.
4-Chloro-N-(4-fluorobenzyl)salicylamide (4i). Wh ite crystals. Yield 52%, m .p. 153–154.5 °C.
IR: ν(C=O) 1632. For C14H11ClFNO2 (279.7) calculated: 60.12% C, 3.96% H, 5.01% N; foun d:
59.98% C, 4.03% H, 5.05% N. 1H NMR (DMSO-d6): 9.36 t, 1 H, J = 6.00 (NH); 7.96 d, 1 H,
J(5,6) = 8.40 (H6); 7.38–7.33 m , 2 H (H2′, H6′); 7.18–7.12 m , 2 H (H3′, H5′); 7.00–6.95 m ,
2 H (H3, H5); 4.48 d, 2 H, J = 6.00 (CH2). 13C NMR (DMSO-d6): 168.1, 161.5 (d, J = 240.05);
160.8, 137.9, 135.2 (d, J = 3.15); 129.9, 129.6 (d, J = 7.95); 119.2, 117.2, 115.4 (d, J = 21.08);
114.8, 42.0.
N-(4-Fluorobenzyl)-3-methoxysalicylamide (4j). Wh ite crystals. Yield 53%, m .p. 104–105 °C.
IR: ν(C=O) 1641. For C15H14FNO3 (275.3) calculated: 65.45% C, 5.13% H, 5.09% N; foun d:
65.64% C, 5.25% H, 5.02% N. 1H NMR (DMSO-d6): 9.37 t, 1 H, J = 6.00 (NH); 7.45 d, 1 H,
J = 8.40 (H6); 7.37–7.32 m , 2 H (H2′, H6′); 7.18–7.09 m , 3 H (H4, H3′, H5′); 6.85–6.78 m ,
1 H (H5); 4.48 d, 2 H, J = 6.00 (CH2); 3.77 s, 3 H (OCH3). 13C NMR (DMSO-d6): 169.6, 161.5
(d, J = 240.98); 151.0, 148.7, 135.3 (d, J = 3.15); 129.6 (d, J = 7.95); 118.8, 118.1, 115.7,
115.3 (d, J = 21.08); 115.0, 56.0, 41.9.
N-(4-Fluorobenzyl)-5-methoxysalicylamide (4k). Wh ite crystals. Yield 43%, m .p. 119–120 °C.
IR: ν(C=O) 1650. For C15H14FNO3 (291.7) calculated: 65.45% C, 5.13% H, 5.09% N; foun d:
65.02% C, 4.98% H, 4.89% N. 1H NMR (DMSO-d6): 11.98 s, 1 H (OH); 9.32 t, 1 H, J = 6.00
(NH); 7.44 d, 1 H, J(4,6) = 3.00 (H6); 7.39–7.34 m , 2 H (H2′, H6′); 7.18–7.12 m , 2 H (H3′,
H5′); 7.02 dd, 1 H, J(3,4) = 9.00, J(4,6) = 3.00 (H4); 6.84 d, 1 H, J(3,4) = 9.00 (H3); 4.49 d,
2 H, J = 6.00 (CH2); 3.72 s, 3 H (OCH3). 13C NMR (DMSO-d6): 168.8, 161.5 (d, J = 240.98);
154.2, 151.8, 135.4 (d, J = 2.85); 129.6 (d, J = 7.95); 121.3, 118.5 (two peaks overlapped);
115.3 (d, J = 21.38); 111.3, 55.9, 41.9.
5-Bromo-N-(3,4-dichlorobenzyl)salicylamide (5b). Wh ite crystals. Yield 51%, m .p. 168–171 °C
(ref.7 160–161 °C). IR: ν(C=O) 1623. 1H NMR (DMSO-d6): 12.32 s, 1 H (OH); 9.37 t, 1 H, J =
5.70 (NH); 8.04 d, 1 H, J(4,6) = 2.40 (H6); 7.60–7.52 m , 3 H (H4, H2′, H5′); 7.32 dd, 1 H,
J(5′,6′) = 8.25, J(2′,6′) = 2.10 (H6′); 6.90 d, 1 H, J(3,4) = 8.55 (H3); 4.48 d, 2 H, J = 5.70 (CH2).
13C NMR (DMSO-d6): 167.5, 158.8, 140.3, 136.4, 131.1, 130.8, 130.7, 129.7, 129.6, 128.0,
119.9, 117.8, 110.0, 41.8.
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5-Chloro-N-(3,4-dichlorobenzyl)salicylamide (5c). Wh ite crystals. Yield 67%, m .p. 158–161 °C
(ref.7 154–156 °C). IR: ν(C=O) 1619. 1H NMR (DMSO-d6): 12.28 s, 1 H (OH); 9.37 t, 1 H, J =
6.00 (NH); 7.93 d, 1 H, J(4,6) = 2.55 (H6); 7.60–7.57 m , 2 H (H2′, H5′); 7.44 dd, 1 H, J(3,4) =
8.85, J(4,6) = 2.55 (H4); 7.32 dd, 1 H, J(5′,6′) = 8.40, J(2′,6′) = 2.10 (H6′); 6.95 d, 1 H, J(3,4) =
8.85 (H3); 4.49 d, 2 H, J = 6.00 (CH2). 13C NMR (DMSO-d6): 167.5, 158.4, 140.3, 133.5,
131.1, 130.8, 129.7, 129.6, 128.0, 127.8, 122.7, 119.5, 117.3, 41.8.
N-(3,4-dichlorobenzyl)-3,5-dichlorosalicylamide (5d ). Wh ite crystals. Yield 56%, m .p. 149–
151 °C (ref.3 m .p. was n ot publish ed). IR: ν(C=O) 1644. For C14H9Cl4NO2 (330.6) calculated:
46.06% C, 2.49% H, 3.84% N; foun d: 46.29% C, 2.31% H, 3.56% N. 1H NMR (DMSO-d6):
9.70 t, 1 H, J = 5.70 (NH); 8.00 d, 1 H, J(4,6) = 2.40 (H6); 7.77 d, 1 H, J(4,6) = 2.40 (H4);
7.61–7.57 m , 2 H (H2′, H5′); 7.32 dd, 1 H, J(5′,6′) = 8.10, J(2′,6′) = 2.10 (H6′); 4.50 d, 2 H, J =
5.70 (CH2). 13C NMR (DMSO-d6): 168.5, 155.9, 139.6, 133.4, 131.2, 130.8, 129.9, 129.8,
128.0, 126.0, 122.6, 122.3, 116.5, 41.9.
N-(3,4-dichlorobenzyl)-5-methylsalicylamide (5e). Wh ite crystals. Yield 71%, m .p. 141–142.5 °C.
IR: ν(C=O) 1647. For C15H13Cl2NO2 (310.2) calculated: 58.08% C, 4.22% H, 4.52% N; foun d:
57.78% C, 3.98% H, 4.32% N. 1H NMR (DMSO-d6): 12.07 s, 1 H (OH); 9.30 t, 1 H, J = 6.00
(NH); 7.68 d, 1 H, J(4,6) = 1.80 (H6); 7.60–7.56 m , 2 H (H2′, H5′); 7.31 dd, 1 H, J(5′,6′) =
8.40, J(2′,6′) = 2.10 (H6′); 7.20 dd, 1 H, J(3,4) = 8.40, J(4,6) = 1.80 (H4); 6.81 d, 1 H, J(3,4) =
8.40 (H3); 4.48 d, 2 H, J = 6.00 (CH2); 2.23 s, 3 H (CH3). 13C NMR (DMSO-d6): 169.1, 127.9,
140.6, 134.7, 131.1, 130.8, 129.6, 129.6, 128.0, 127.9, 127.6, 117.4, 115.0, 41.6, 20.3.
3,5-Dibromo-N-(3,4-dichlorobenzyl)salicylamide (5f). White crystals. Yield 67%, m .p. 155–157 °C
(ref.11 157–160 °C). IR: ν(C=O) 1641. For C14H9Br2Cl2NO2 (453.9) calculated: 37.04% C,
2.00% H, 3.09% N; foun d: 36.89% C, 2.11% H, 3.23% N. 1H NMR (DMSO-d6): 9.71 t, 1 H,
J = 5.70 (NH); 8.16 d, 1 H, J(4,6) = 2.25 (H6); 7.95 d, 1 H, J(4,6) = 2.25 (H4); 7.61–7.56 m ,
2 H (H2′, H5′); 7.32 dd, 1 H, J(5′,6′) = 8.40, J(2′,6′) = 2.10 (H6′); 4.49 d, 2 H, J = 5.70 (CH2).
13C NMR (DMSO-d6): 168.4, 157.2, 139.6, 138.8, 131.2, 130.8, 129.9, 129.8, 129.3, 128.1,
116.7, 112.4, 109.8, 41.9.
N-(3,4-Dichlorobenzyl)-4-methoxysalicylamide (5g). White crystals. Yield 58%, m .p. 119–119.5 °C.
IR: ν(C=O) 1639. For C15H13Cl2NO3 (326.2) calculated: 55.23% C, 4.02% H, 4.29% N; foun d:
54.95% C, 3.97% H, 4.26% N. 1H NMR (DMSO-d6): 9.21 t, 1 H, J = 6.30 (NH); 7.81 d, 1 H,
J(5,6) = 8.85 (H6); 7.59–7.54 m , 2 H (H2′, H5′); 7.30 dd, 1 H, J(5′,6′) = 8.10, J(2′,6′) = 1.80
(H6′); 6.48 dd, 1 H, J(5,6) = 8.85, J(3,5) = 2.55 (H5); 6.43 d, 1 H, J(3,5) = 2.55 (H3); 4.47 d,
2 H, J = 6.30 (CH2); 3.76 s, 3 H (OCH3). 13C NMR (DMSO-d6): 169.5, 163.9, 162.7, 140.7,
131.1, 130.8, 129.6, 129.5, 129.2, 127.9, 107.8, 106.4, 101.4, 55.6, 41.5.
N-(3,4-Dichlorobenzyl)-5-nitrosalicylamide (5h ). Yellow crystals. Yield 60%, m .p. 191.5–193 °C.
IR: ν(C=O) 1648. For C14H10Cl2N2O4 (341.2) calculated: 49.29% C, 2.95% H, 8.21% N;
foun d: 48.95% C, 3.05% H, 8.29% N. 1H NMR (DMSO-d6): 9.58 t, 1 H, J = 6.00 (NH); 8.81 d,
1 H, J(4,6) = 2.70 (H6); 8.24 dd, 1 H, J(3,4) = 9.00, J(4,6) = 2.70 (H4); 7.63–7.53 m , 2 H (H2′,
H5′); 7.34 dd, 1 H, J(5′,6′) = 8.40, J(2′,6′) = 2.10 (H6′); 7.09 d, 1 H, J(3,4) = 9.00 (H3); 4.50 d,
2 H, J = 6.00 (CH2). 13C NMR (DMSO-d6): 166.9, 165.0, 140.1, 139.5, 131.2, 130.7, 129.8,
129.7, 128.9, 128.0, 125.3, 118.5, 116.4, 41.9.
4-Chloro-N-(3,4-dichlorobenzyl)salicylamide (5i). Wh ite crystals. Yield 80%, m .p. 154–155 °C.
IR: ν(C=O) 1629. For C14H10Cl3NO2 (330.6) calculated: 50.86% C, 3.05% H, 4.24% N; foun d:
50.68% C, 3.21% H, 4.36% N. 1H NMR (DMSO-d6): 9.35 t, 1 H, J = 6.00 (NH); 7.87 d, 1 H,
J(5,6) = 8.70 (H6); 7.59–7.55 m , 2 H (H2′, H5′); 7.31 dd, 1 H, J(5′,6′) = 8.40, J(2′,6′) = 2.10
(H6′); 7.00–6.94 m , 2 H (H3, H5); 4.49 d, 2 H, J = 6.00 (CH2). 13C NMR (DMSO-d6): 168.0,
160.5, 140.4, 137.9, 131.1, 130.7, 130.1, 129.7, 129.6, 127.9, 119.2, 117.2, 115.0, 41.7.
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Waisser, Peřina, Klimešová, Kaustová:
N-(3,4-Dichlorobenzyl)-3-methoxysalicylamide (5j). Wh ite crystals. Yield 42%, m .p. 144–146 °C.
IR: ν(C=O) 1635. For C15H13Cl2NO3 (291.7) calculated: 55.23% C, 4.02% H, 4.29% N; foun d:
55.01% C, 4.11% H, 4.21% N. 1H NMR (DMSO-d6): 12.45 s, 1 H (OH); 9.38 t, 1 H, J = 6.00
(NH); 7.60–7.55 m , 2 H (H2′, H5′); 7.44 dd, 1 H, J(5,6) = 7.95, J(4,6) = 1.80 (H6); 7.31 dd,
1 H, J(5′,6′) = 8.40, J(2′,6′) = 2.10 (H6′); 7.11 dd, 1 H, J(4,5) = 7.95, J(4,6) =1.80 (H4); 6.82 t,
1 H, J(4,5) = 7.95 (H5); 4.48 d, 2 H, J = 6.00 (CH2); 3.77 s, 3 H (OCH3). 13C NMR (DMSO-d6):
169.7, 150.8, 148.7, 140.4, 131.1, 130.8, 129.7, 129.5, 127.9, 118.9, 118.2, 115.7, 115.0,
56.0, 41.6.
N-(3-Chlorobenzyl)-5-methoxysalicylamide (5k). Wh ite crystals. Yield 49%, m .p. 113.5–115 °C.
IR: ν(C=O) 1637. For C15H14ClNO3 (291.7) calculated: 61.76% C, 4.84% H, 4.80% N; foun d:
61.77% C, 4.97% H, 4.85% N. 1H NMR (DMSO-d6): 11.93 s, 1 H (OH); 9.36 t, 1 H, J = 6.00
(NH); 7.46 d, 1 H, J(4,6) = 3.00 (H6); 7.39–7.26 m , 4 H (H2′, H4′, H5′, H6′); 7.02 dd, 1 H,
J(3,4) = 9.00, J(4,6) = 3.00 (H4); 6.86 d, 1 H, J(3,4) = 9.00 (H3); 4.52 d, 2 H, J = 6.00 (CH2);
3.73 s, 3 H (OCH3). 13C NMR (DMSO-d6): 168.8, 154.1, 151.8, 141.9, 133.3, 130.5, 127.4,
127.1, 126.2, 121.3, 118.5, 115.2, 111.4, 55.9, 42.1.
5-Bromo-N-(4-methoxybenzyl)salicylamide (6b). Wh ite crystals. Yield 74%, m .p. 122–126 °C.
IR: ν(C=O) 1640. For C15H14BrNO3 (336.2) calculated: 53.59% C, 4.20% H, 4.17% N; foun d:
53.50% C, 4.03% H, 4.19% N. 1H NMR (CDCl3): 12.28 s, 1 H (OH); 7.47–7.40 m , 2 H (H4,
H6); 7.28–7.23 m , 2 H (H2′, H6′); 6.92–6.84 m , 3 H (H3, H3′, H5′); 6.63 bs, 1 H (NH); 4.55 d,
2 H, J = 5.70 (CH2); 3.80 s, 3 H (OCH′3). 13C NMR (CDCl3): 168.5, 160.5, 159.3, 136.9,
129.4, 129.0, 127.0, 120.4, 115.7, 114.2, 110.2, 55.3, 43.3.
5-Chloro-N-(4-methoxybenzyl)salicylamide (6c). Wh ite crystals. Yield 63%, m .p. 134–136 °C.
IR: ν(C=O) 1643. For C15H14ClNO3 (291.7) calculated: 61.76% C, 4.84% H, 4.80% N; foun d:
61.56% C, 4.71% H, 4.85% N. 1H NMR (CDCl3): 12.25 s, 1 H (OH); 7.35–7.29 m , 2 H (H4,
H6); 7.28–7.22 m , 2 H (H2′, H6′); 6.94–6.85 m , 3 H (H3, H3′, H5′); 6.65 bs, 1 H (NH); 4.54 d,
2 H, J = 5.70 (CH2); 3.80 s, 3 H (OCH′3). 13C NMR (CDCl3): 168.6, 160.0, 159.3, 134.1,
129.4, 129.0, 125.0, 123.3, 120.1, 115.0, 114.3, 55.3, 43.3.
3,5-Dichloro-N-(4-methoxybenzyl)salicylamide (6d). Wh ite crystals. Yield 62%, m .p. 121–124 °C.
IR: ν(C=O) 1642. For C15H13Cl2NO3 (326.2) calculated: 55.23% C, 4.02% H, 4.29% N; foun d:
55.02% C, 4.03% H, 4.22% N. 1H NMR (CDCl3): 7.46 d, 1 H, J(4.6) = 2.40 (H6); 7.27 d over-
lapped, 1 H, J(4,6) = 2.40 (H4); 7.27–7.21 m overlapped, 2 H (H2′, H6′); 6.91–6.85 m , 2 H
(H3′, H5′); 6.57 bs, 1 H (NH); 4.54 d, 2 H, J = 5.70 (CH2); 3.79 s, 3 H (OCH′3). 13C NMR
(CDCl3): 168.0, 159.4, 156.0, 133.8, 129.4, 128.6, 124.0, 123.7, 123.0, 115.8, 114.3, 55.3,
43.6.
N-(4-Methoxybenzyl)-5-methylsalicylamide (6e). Wh ite crystals. Yield 62%, m .p. 113–115 °C.
IR: ν(C=O) 1644. For C16H17NO3 (271.3) calculated: 70.83% C, 6.32% H, 5.16% N; foun d:
70.89% C, 6.40% H, 5.20% N. 1H NMR (CDCl3): 12.15 s, 1 H (OH); 7.31–7.24 m , 2 H (H2′,
H6′); 7.19 dd, 1 H, J(3,4) = 8.10, J(4,6) = 2.10 (H4); 7.11 d, 1 H, J(4,6) = 2.10 (H6); 6.93–
6.85 m , 3 H (H3, H3′, H5′); 6.56 bs, 1 H (NH); 4.54 d, 2 H, J = 5.70 (CH2); 3.80 s, 3 H
(OCH′3). 13C NMR (CDCl3): 169.7, 159.4, 159.2, 135.1, 129.5, 129.3, 127.7, 125.3, 118.3,
114.2, 113.7, 55.3, 43.1, 20.4.
3,5-Dibromo-N-(4-methoxybenzyl)salicylamide (6f). Wh ite crystals. Yield 50%, m .p. 121–124 °C.
IR: ν(C=O) 1636. For C15H13Br2NO3 (415.1) calculated: 43.40% C, 3.16% H, 3.37% N; foun d:
43.02% C, 3.05% H, 3.25% N. 1H NMR (CDCl3): 7.75 d, 1 H, J(4.6) = 2.10 (H6); 7.44 d, 1 H,
J(4,6) = 2.10 (H4); 7.28–7.21 m , 2 H (H2′, H6′); 6.91–6.85 m , 2 H (H3′, H5′); 6.62 bs, 1 H
(NH); 4.54 d, 2 H, J = 5.70 (CH2); 3.80 s, 3 H (OCH′3). 13C NMR (CDCl3): 167.9, 159.4,
157.4, 139.3, 129.4, 128.6, 127.3, 116.2, 114.3, 113.4, 110.0, 55.3, 43.6.
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4-Methoxy-N-(4-methoxybenzy)salicylamide (6g). Wh ite crystals. Yield 56%, m .p. 103–106 °C.
IR: ν(C=O) 1646. For C16H17NO4 (287.3) calculated: 66.89% C, 5.96% H, 4.88% N; foun d:
66.70% C, 6.16% H, 4.57% N. 1H NMR (CDCl3): 7.28–7.23 m overlapped, 2 H (H2′, H6′);
7.23 d overlapped, 1 H, J(5,6) = 9.00 (H6); 6.91–6.85 m , 2 H (H3′, H5′); 6.46 d, 1 H, J(3,5) =
2.40 (H3); 6.40–6.33 m , 2 H (H5, NH); 4.54 d, 2 H, J = 5.40 (CH2); 3.80 s, 3 H (OCH′3);
3.79 s, 3 H (OCH3). 13C NMR (CDCl3): 169.6, 164.3, 163.9, 159.2, 129.6, 129.3, 126.5, 114.2,
107.0, 106.9, 101.5, 55.4, 55.3, 43.0.
N-(4-Methoxybenzyl)-5-nitrosalicylamide (6h ). Yellow crystals. Yield 42%, m .p. 137–140 °C.
IR: ν(C=O) 1648. For C15H14N2O5 (302.3) calculated: 59.6% C, 4.67% H, 9.27% N; foun d:
59.23% C, 4.64% H, 9.08% N. 1H NMR (CDCl3): 8.41 d, 1 H, J(4,6) = 2.70 (H6); 8.25 dd,
1 H, J(3,4) = 9.30, J(4,6) = 2.70 (H4); 7.33–7.36 m , 2 H (H2′, H6′); 7.06 d, 1 H, J(3,5) = 9.30
(H3); 6.98 bs, 1 H (NH); 6.92–6.86 m , 2 H (H3′, H5′); 4.59 d, 2 H, J = 5.70 (CH2); 3.80 s, 3 H
(OCH′3). 13C NMR (CDCl3): 168.2, 167.3, 159.5, 139.1, 129.6, 129.3, 128.7, 122.4, 119.4,
114.3, 113.6, 55.3, 43.5.
4-Chloro-N-(4-methoxybenzyl)salicylamide (6i). Wh ite crystals. Yield 38%, m .p. 114–118 °C.
IR: ν(C=O) 1632. For C15H14ClNO3 (291.7) calculated: 61.76% C, 4.84% H, 4.80% N; foun d:
61.56% C, 4.85% H, 4.76% N. 1H NMR (CDCl3): 12.55 s, 1 H (OH); 7.28–7.21 m , 3 H (H6,
H2′, H6′); 7.00 d, 1 H, J(3,5) = 1.80 (H3); 6.91–6.85 m , 2 H (H3′, H5′); 6.78 dd, 1 H, J(5,6) =
8.40, J(3,5) = 2.25 (H5); 6.68 bs, 1 H (NH); 4.54 d, 2 H, J = 5.40 (CH2); 3.80 s, 3 H (OCH′3).
13C NMR (CDCl3): 169.0, 162.4, 159.3, 139.8, 129.4, 129.1, 126.3, 119.1, 118.7, 114.3,
112.6, 55.3, 43.3.
3-Methoxy-N-(4-methoxybenzyl)salicylamide (6j). Wh ite crystals. Yield 56%, m .p. 103–104 °C.
IR: ν(C=O) 1644. For C16H17NO4 (287.3) calculated: 66.89% C, 5.96% H, 4.88% N; foun d:
66.79% C, 5.99% H, 4.75% N. 1H NMR (CDCl3): 11.90 s, 1 H (OH); 7.28–7.21 m , 2 H (H2′,
H6′); 7.06 dd, 1 H, J(5,6) = 8.10, J(4,6) = 1.20 (H6); 6.95 dd overlaped, 1 H, J(4,5) = 8.10,
J(4,6) = 1.20 (H4); 6.92 bs overlapped, 1 H (NH); 6.88–6.83 m , 2 H (H3′, H5′); 6.76 t, 1 H,
J(4,5) = 8.10 (H5); 4.54 d, 2 H, J = 5.70 (CH2); 3.81 s, 3 H (OCH′3); 3.76 s, 3 H (OCH3).
13C NMR (CDCl3): 169.2, 159.1, 150.9, 148.8, 129.5, 129.2, 118.2, 117.6, 114.8, 114.6,
114.1, 56.0, 55.2, 43.1.
5-Methoxy-N-(4-methoxybenzyl)salicylamide (6k). Wh ite crystals. Yield 33%, m .p. 84.5–86 °C.
IR: ν(C=O) 1638. For C16H17NO4 (287.3) calculated: 66.89% C, 5.96% H, 4.88% N; foun d:
66.57% C, 6.21% H, 4.77% N. 1H NMR (CDCl3): 11.79 s, 1 H (OH); 7.31–7.24 m , 2 H (H2′,
H6′); 7.02 dd, 1 H, J(3,4) = 9.00, J(4,6) = 3.00 (H4); 6.93 d overlapped, 1 H, J(3,4) = 9.00
(H3); 6.92–6.87 m overlapped, 2 H (H3′, H5′); 6.79 d, 1 H, J(4,6) = 3.00 (H6); 6.46 bs, 1 H
(NH); 4.54 d, 2 H, J = 5.70 (CH2); 3.81 s, 3 H (OCH′3); 3.75 s, 3 H (OCH3). 13C NMR
(CDCl3): 169.4, 159.3, 155.6, 151.7, 129.4 (two peaks overlapped); 121.0, 119.3, 114.2,
113.9, 109.7, 56.1, 55.3, 43.2.
Microbiological Tests
Th e followin g strain s, obtain ed from th e Czech Nation al Collection of Type Cultures
(CNCTC); Nation al In stitute of Public Health , Prague, were used for th e evaluation of in vitro
an tim ycobacterial activity: M. tuberculosis CNCTC My 331/8, M. kansasii CNCTC My 235/80,
an d M. avium CNCTC My 330/88. Activity again st th e clin ical isolate of Mycobacterium
kansasii 6 509/96 was (in equation s MIC(kans.clin.)) tested, as well. Th e an tim ycobacterial ac-
tivity of th e com poun ds was determ in ed in th e Šula sem isyn th etic m edium (SEVAC,
Prague). Th is m edium (with bovin e serum ) is routin ely used in th e Czech Republic. Each
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

1288
Waisser, Peřina, Klimešová, Kaustová:
strain was sim ultan eously in oculated in to a Petri dish con tain in g th e Löwen stein –Jen sen
m edium for th e con trol of th e sterility of th e in oculum an d its growth . Th e com poun ds
were added to th e m edium in DMSO solution s. Th e fin al con cen tration s were 1000, 500,
250, 125, 62.5, 31, 16, 8, 4, 2 µm ol/l. Th e MICs were determ in ed after in cubation at 37 °C
for 14 an d 21 days (see Table I). MIC was th e lowest con cen tration of an an tim yco-
bacterially effective substan ce (on th e above con cen tration scale); at wh ich in h ibition of th e
growth of th e Mycobacteria occurred.
Calculation s
All calculation s were carried out usin g th e Multireg H program m e (Klem era) for Microsoft
Excel. Th e values of th e Ham m ett con stan ts (Table II) were taken from ref.12
RESULTS AND DISCUSSION
Th e classical Han sch -type equation , usin g th e squared h ydroph obic param -
eters, was n ot statistically sign ifican t. In studyin g th e relation sh ip between
th e structure an d an tim ycobacterial activity, a com bin ation of th e Han sch
an d Free–Wilson approach es was used. Th e Han sch substituen t con stan ts of
h ydroph obicity π of th e substituen ts on th e ben zyl rin g served as on e pa-
ram eter. Th e in fluen ce of th eir electron ic param eters was n ot statistically
sign ifican t. However, th e in fluen ce of th e substituen ts from th e acyl part of
th e m olecule appeared to be m ore com plex, an d h en ce we expressed th em
with in dicator param eters (In ) for each substituen t. We h ave calculated
several h un dred equation s. In th is paper, we presen t on ly th e m ost statisti-
cally sign ifican t on es. Th e QSAR study of th e an tim ycobacterial activity of
salicylam ides in cludes th e results obtain ed both after 21 days of in cubation
TABLE II
Substituen ts con stan ts
–
–
Substituen t
σm
σp
πm
πm
πp
πp
H
0
0
0
0
0
0
Br
0.39
0.37
0.71
–0.07
0.12
0.34
0.23
0.23
0.96
0.77
–0.05
0.52
0.12
0.22
1.17
1.04
0.54
0.50
0.12
0.47
1.19
0.73
0.02
0.60
–0.03
0.15
1.13
0.93
0.45
0.48
–0.12
0.31
Cl
NO2
CH3
OCH3
F
0.78
–0.17
–0.27
0.06
Th e values of th e substituen t con stan ts were taken from ref.12
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

Substituted N-Benzylsalicylamides
1289
an d 14 days of in cubation (see Eqs (1)–(8)), for values of In (see Table III).
Because th e activities after 21 days in cubation are gen erally lower com pared
to th ose after 14 days in cubation , th e effect of th e com poun ds is tuberculo-
static. Th e an tim ycobacterial activity again st M. tuberculosis an d M. kansasii
in creased with th e in crease in h ydroph obicity (lipoph ilicity) of th e substi-
tuen ts in th e ben zyl m oiety (see Eqs (1)–(6)); but th e structure–activity rela-
tion sh ips for M. avium were parabolic (πopt = 1.10–1.15).
log MIC(M.tuber. 14d) = –0.268(±0.056) π + ΣIn + 2.078(±0.103)
r = 0.819 s = 0.218 n = 56 F = 8.13
(1)
TABLE III
Regression coefficien ts of in dicator param eters In in Eqs (1)–(8)
M. kans. M. kans.
M.
avium.
14 d
M.
avium.
21 d
Equation s M. tuber. M. tuber. M. kans. M. kans.
clin.
clin.
(1)–(8)
14 d
21 d
14 d
21 d
14 d
21 d
I(5-Br)
–0.491
–0.387
–0.302
–0.507
–0.179
–0.360
–0.200
–0.343
(±0.146) (±0.111) (±0.105) (±0.127) (±0.102) (±0.112) (±0.109) (±0.102)
–0.346 –0.357 –0.292 –0.359 –0.179 –0.396 –0.258 –0.343
(±0.132) (±0.105) (±0.105) (±0.127) (±0.102) (±0.112) (±0.109) (±0.102)
–0.345 –0.259 –0.052 –0.261 0.052 –0.112 –0.246 0.049
(±0.132) (±0.100) (±0.095) (±0.117) (±0.098) (±0.104) (±0.103) (±0.097)
–0.165 –0.507 –0.162 –0.055 –0.028 –0.255 –0.082 –0.109
(±0.146) (±0.181) (±0.131) (±0.151) (±0.119) (±0.169) (±0.116) (±0.119)
–0.345 –0.453 0.249 –0.361 –0.196 –0.263 0.146 –0.052
(±0.132) (±0.100) (±0.095) (±0.117) (±0.098) (±0.104) (±0.103) (±0.097)
–0.128 –0.409 –0.048 –0.055 0.016 –0.153 0.191 –0.005
(±0.138) (±0.121) (±0.114) (±0.151) (±0.118) (±0.120) (±0.109) (±0.109)
–0.445 –0.503 0.199 0.091 0.203 0.289 0.878 0.735
(±0.132) (±0.100) (±0.095) (±0.117) (±0.098) (±0.104) (±0.109) (±0.102)
–0.450 –0.437 –0.204 –0.354 –0.211 –0.360 –0.106 –0.301
(±0.138) (±0.104) (±0.099) (±0.121) (±0.102) (±0.112) (±0.109) (±0.102)
0.116 0.170 0.223 0.237 0.268 0.258 0.422 0.490
(±0.146) (±0.111) (±0.105) (±0.127) (±0.108) (±0.112) (±0.116) (±0.119)
0.219 0.300 –0.176 –0.277 0.041 0.061 0.095 0.213
(±0.139) (±0.121) (±0.095) (±0.121) (±0.103) (±0.108) (±0.104) (±0.109)
I(5-Cl)
I(3,5-Cl2)
I(5-CH3)
I(3,5-Br2)
I(4-OCH3)
I(5-NO2)
I(4-Cl)
I(3-OCH3)
I(5-OCH3)
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

1290
Waisser, Peřina, Klimešová, Kaustová:
log MIC(M.tuber. 21d) = –0.180(±0.047) π + ΣIn + 2.143(±0.079)
(2)
(3)
(4)
(5)
(6)
r = 0.889 s = 0.165 n = 48 F = 12.3
log MIC(M.kans. 14d) = –0.224(±0.044) π + ΣIn + 2.105(±0.074)
r = 0.845 s = 0.156 n = 51 F = 8.9
log MIC(M.kans. 21d) = –0.232(±0.046) π + ΣIn + 2.323(±0.099)
r = 0.879 s = 0.165 n = 45 F = 11.6
log MIC(M.kans.clin. 14d) = –0.267(±0.044) π + ΣIn + 2.0765(±0.077)
r = 0.838 s = 0.161 n = 53 F = 8.8
log MIC(M.kans.clin. 21d) = –0.245(±0.042) π + ΣIn + 2.229(±0.088)
r = 0.918 s = 0.147 n = 46 F = 16.5
log MIC(M.avium 14d) = –0.946(±0.139) π + 0.411(±0.094) π2 + ΣIn
+
+ 1.999(±0.078)
(7)
r = 0.921 s = 0.179 n = 57 F = 20.5
Optim um (π) = 1.15
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

Substituted N-Benzylsalicylamides
1291
log MIC(M.avium 21d) = –0.870(±0.137) π + 0.395(±0.093) π2 + ΣIn
+
+ 2.167(±0.074)
(8)
r = 0.932 s = 0.168 n = 52 F = 21.4
Optim um (π) = 1.10
Usin g th e in dicator param eters, th e biological activity can be predicted,
but on ly with in th e fram ework of th e selection of th e em ployed substitu-
en ts in th e acyl m oiety. Th us, we attem pted to fin d correlation s with ph ysi-
cal an d ch em ical param eters as well. In th e n ext step we used th e local
param eters approach 13. Th e application to an tituberculotics h as been pub-
lish ed recen tly14. We calculated approxim ately 10 equation s for structure–
an tim ycobacterial activity relation sh ips for each strain . Herein , we presen t
on ly th e statistically m ost sign ifican t equation s (see Eqs (9)–(16)). Th e in -
fluen ce of th e substituen ts on th e ben zyl rin g was again expressed with th e
π con stan ts. Th e in fluen ce of th e substituen ts on th e acyl m oiety was ex-
pressed usin g h ydroph obic con stan ts π with regard to th e h ydroxy group
(π– )
an d carbon yl group (π1)CO. In structure–an tim ycobacterial activity
1 OH
relation sh ips for M. kansasii an d M. avium (21 day in cubation ), Ham m ett
con stan t values h ad to be used. Th e use of all th e above param eters was
n ecessary, as we attem pted to fin d th e m ost active com poun ds.
log MIC(M.tuber. 14d) = –0.893(±0.135)(π– )
– 0.738(±0.143)(π1)CO
–
–
1 OH
– 0.276(±0.053)(π2) + 2.042(±0.048)
r = 0.797 s = 0.211 n = 56 F = 30.2
(9)
log MIC(M.tuber. 21d) = –1.001(±0.124)(π– )
– 0.867(±0.129)(π1)CO
1 OH
– 0.205(±0.049)(π2) + 2.099(±0.046)
r = 0.833 s = 0.180 n = 48 F = 33.4
(10)
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

1292
Waisser, Peřina, Klimešová, Kaustová:
log MIC(M.kans. 14d) = –0.485(±0.136)(π1)CO + 0.198(±0.074)(π1)2
–
CO
– 0.232(±0.053)(π2) + 2.159(±0.049)
r = 0.681 s = 0.194 n = 51 F = 13.6
(11)
Optim um (π1)CO = 1.22
log MIC(M.kans. 21d) = –0.695(±0.151)(π1)CO + 0.277(±0.082)(π1)2
– 0.237(±0.056)(π2) + 2.340(±0.058)
–
CO
(12)
r = 0.757 s = 0.206 n = 45 F = 18.4
Optim um (π1)CO = 1.25
log MIC(M.kans.clin. 14d) = 0.255(±0.104)(σ1)CO – 0.2135(±0.050)(π1)CO
–
– 0.275(±0.049)(π2) + 2.110(±0.0477)
r = 0.720 s = 0.188 n = 53 F = 17.7
(13)
log MIC(M.kans.clin. 21d) = 0.479(±0.118)(σ1)CO – 0.350(±0.055)(π1)CO
– 0.292(±0.055)(π2) + 2.219(±0.054)
–
(14)
r = 0.797 s = 0.201 n = 46 F = 24.3
log MIC(M.avium 14d) = 0.728(±0.129)(σ1)CO – 1.018(±0.148)(π1)CO
+ 0.374(±0.084)(π1)2
+
– 0.938(±0.174)(π2) +
CO
+ 0.407(±0.117)(π2)2 + 2.225(±0.060)
r = 0.847 s = 0.227 n = 57 F = 25.8
(15)
Optim um (π1)CO = 1.37
Optim um (π2) = 1.15
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

Substituted N-Benzylsalicylamides
1293
log MIC(M.avium 21d) = 0.704(±0.128)(σ1)CO – 1.091(±0.143)(π1)CO
+
+ 0.374(±0.081)(π1)2
– 0.798(±0.172)(π2) +
CO
+ 0.327(±0.117)(π2)2 + 2.343(±0.062)
r = 0.861 s = 0.216 n = 52 F = 26.4
(16)
Optim um (π1)CO = 1.45
Optim um (π2) = 1.22
From Eqs (9)–(16), in th e acyl m oiety th e lipoph ilicity seem s to be m ore
im portan t. Th e in fluen ce of electron ic effects was foun d on ly in structure-
an tim ycobacterial activity relation sh ips again st M. kansasii (clin ically iso-
lated strain s) an d M. avium. In all th e cases electron -acceptin g effect ex-
pressed by th e substituen t con stan ts orien ted with respect to th e carbon yl
group decreases th e activity. Th e advan tage of th is approach is th e possibil-
ity of gen eral prediction of n ew structures (com pared with th e use of in di-
cator variables). Th e results of th is study will be used in th e developm en t of
n ew an tituberculotics.
In con clusion , N-ben zylsalicylam ides con stitute a n ew group of poten tial
an tituberculotics. Th eir structure-activity relation sh ips varied for differen t
strain s.
This work is part of the research projects No. MSM 111600001 of the Ministry of Education, Youth
and Sports of the Czech Republic and was supported by the Grant Agency of Czech Republic (grant
No. 203/02/0082), the Grant Agency of the Charles University (grant No. 234/2000/Ch/FaF) and by
the Higher Education Development Fund (grant No. 2251/2000-G4).
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