Design, synthesis and activity evaluation of N-(pyridin-4-yl) salicylamides as antimycobacterial agents

Article abstract of DOI:10.14233/ajchem.2014.16594

A series of N-(pyridin-4-yl) salicylamides derivatives were prepared through acylation of the corresponding acetylsalicyloyl chlorides with substituted 4-amino-pyridines. These compounds were evaluated in vitro for antimycobacterial activities against Myc

Full text of DOI:10.14233/ajchem.2014.16594

Asian Journal of Chemistry; Vol. 26, No. 21 (2014), 7269-7275
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16594
Design, Synthesis and Activity Evaluation of N-(pyridin-4-yl)
Salicylamides as Antimycobacterial Agents
1,*
1,2
1
1
3
HE DIAN , DE-BIN ZHOU , JIAN-PING MOU , ZHU-QING YANG , JIA ZHONG ,
1
1
1
1
XIAO-QUAN DING , CHONG LI , XIAO-HONG WANG and JIAN-GANG ZHANG
1Institute of Medicinal Chemistry, School of Pharmacy, Lanzhou University, Lanzhou 73000, P.R. China
2The First Hospital of PLA, Lanzhou 730030, P.R. China
3Department of Pharmacy, Pulmonary Hospital of Lanzhou, Lanzhou 730046, P.R. China
*Corresponding author: Fax: +86 931 8915686; Tel: +86 13008738922; E-mail: hed@lzu.edu.cn
Received: 28 October 2013;
Accepted: 30 December 2013;
Published online: 30 September 2014;
AJC-16117
A series of N-(pyridin-4-yl) salicylamides derivatives were prepared through acylation of the corresponding acetylsalicyloyl chlorides
with substituted 4-amino-pyridines. These compounds were evaluated in vitro for antimycobacterial activities against Mycobacterium
tuberculosis (TB) and Mycobacterium avium (A) by the minimum inhibitory concentrations (MIC) values. Eight of the compounds
exhibited lower MIC against A than the one of isoniazide. Meanwhile, four of the compounds exhibited good anti-TB activity compared
to isoniazide. Antimycobacterial activities of N-(pyridin-4-yl) salicylamides were influenced by the balance between hydrophobicity and
electron withdrawing substituent effects on the phenyl and pyridine ring. These studies show that the compounds might serve as prospective
wide-spectrum antimycobacterial substances.
Keywords: Mycobacterium tuberculosis, N-(pyridin-4-yl) salicylamides, Activity evaluation, Synthesis.
R6
R6
INTRODUCTION
O
O
a
Searching for new antimycobacterial compounds is one
of the most challenging tasks in current medicinal chemistry.
Particularly, antimycobacterial properties of salicylanilides1,2
R5
R5
OH
Cl
R4
O
R4
O
O
inhibiting two-component regulatory systems in mycobacteria,
as a known strategic opportunity for design of selective anti-
mycobacterial agents1-8, is of great interest. Isosteres of salicy-
lanilides were systematically documented, i.e. 3-hydroxy-
picolinanilides9, 2-sulfanylbenzanilides9, N-benzylsali-
cylamides10 and N-pyridin-2-ylsalicylamides11. However, N-
pyridin-4-ylsalicylamides as antimycobacterial agents have
rarely been studied systematically in literatures. We thus
prepared a series of new N-pyridin-4-yl salicylamide analogues
(Fig. 1) to study their antimycobacterial activities by varying
the substituents on the heterocyclic and salicylic moieties.
The synthetic route to N-(pyridin-4-yl) salicylamides was
shown in Fig. 1. N-(pyridin-4-yl) salicylamides 1a-6h were
prepared by treatment of the corresponding substituted
acetylsalicyloyl chlorides with substituted 4-amino-pyridines
in chloroform in the presence of triethylamine. After addition
of 10 % hydrochloric acid and saturated sodium bicarbonate
the products was isolated in more than 85 % yield according
to the theoretical value. The structure was fully identified by
1H NMR, 13C NMR and IR spectra.
O
R3
H2
N
N
R1
R2
HO
R4
R2
R1
N
NH
b
R5
R3
O
R6
1a-6h
R1= H, Cl, CH3; R2 = H, Cl, CF3; R3= R4 =H, Cl; R5= OCH3; R6 H, Cl, Br, CF
=
3
Reagents and conditions: (a) Pyridine, SOCl2, 75-100 °C, reflux, 3-5h;
(b) CHCl3, NEt3, r. t., 24-48 h.
Fig. 1. Synthesis of Compounds 1a-6h N-(pyridin-4-yl) salicylamides
EXPERIMENTAL
Chemistry. melting points (m.p.) were determined on an
YRT-3 digital melting point apparatus and were uncorrected.

7270 Dian et al.
Asian J. Chem.
Infrared (IR) spectra were measured in KBr pellets on an EQU
1
142.3, 133.8, 128.8, 123.8, 119.2, 118.6, 117.5, 116.8 (J =
267 Hz), 114.1.
NOX-55 instrument. H NMR and 13C NMR spectra were
recorded in DMSO-d6 solution on a Brucker DRX-300M
spectrometer operating at 300 MHz. Chemical shifts were
reported in δ (ppm) units relative to the internal standard tetra-
methylsilane (TMS) via the solvent signal (2.49 for 1H or 39.78
for 13C). EI and FAB mass spectra were obtained on a HP-
5988 and a HS-ZAB mass spectrometer. Elemental analyses
were performed on a CARLOERBA 1106 instrument and the
results of elemental analyses for C, H and N were within 0.4 %
of the theoretical values.All chemicals and solvents used were
of reagent grade purified and dried by standard methods before
use. TLC monitoring all the reaction was performed on pre-
coated silica gel G plates at 254/365 nm under a UV lamp, with
petrol ether/acetone/triethylamine as the mobile phase.
General procedure for the synthesis of compounds of
substitued acetylsalicyloyl chlorides: Thionyl chloride (0.1
mol) was added dropwise to the mixture of 0.1 mol substituted
acetylsalicylic acid and dried pyridine in minute quantities
under stirring in the ice bath. The solution was stirred for 0.5
h at the same temperature, warmed to room temperature and
then stirred under 75-90 °C for further 2.5-5 h. The formed
faint yellow liquid was used in the next step without further
purification.
N-(3-Methylpyridin-4-yl)-2-hydroxybenzamide (4a).
m.p. 203-204 °C; m.f. C13H12N2O2; IR (KBr, νmax, cm-1): (C=O)
1683; 1H NMR: δ10.65 (bs, 1H, NH), 9.42 (s, 1H, H2'), 8.88
(d, 1H, J =7.52 Hz, H6'), 7.84 (dd, 1H, J =7.20 Hz, J = 2.00
Hz, H6), 7.78-7.75 (m, 2H, H3, H5), 7.49-7.43 (m, 1H, H4),
7.22 (d, 1H, J = 7.52 Hz, H5'), 2.41 (s, 3H, -CH3); 13C NMR:
δ164.9, 157.3, 150.4, 144.7, 141.9, 133.6, 128.3, 123.3, 119.2,
118.7, 117.4, 113.9, 17.7.
N-(2-Chloropyridin-4-yl)-2-hydroxybenzamide (5a):
m.p. 220-221 °C; m.f. C12H9N2O2Cl; IR (KBr, νmax, cm-1):
(C=O) 16 67; 1H NMR: δ10.66 (bs, 1H, NH), 8.84 (d, 1H, J =
8.90 Hz, H6'), 7.88 (dd, 1H, J = 7.92 Hz, J = 1.73 Hz, H6),
7.74-7.72 (m, 2H, H3, H5), 7.48-7.43 (m, 1H, H4), 7.26-7.23
(dd, 2H, J = 8.90 Hz, J = 2.60 Hz, H3', H5'); 13C NMR: δ169.2,
157.0, 151.1, 144.9, 144.4, 133.8, 129.5, 119.5, 118.7, 117.2,
115.7, 114.3.
N-(3,5-Dichloropyridin-4-yl)-2-hydroxybenzamide
(6a): m.p. 230-231 °C; m.f. C12H8N2O2Cl2; IR (KBr, νmax, cm-1):
(C=O) 1652; 1H NMR: δ10.69 (bs, 1H, NH), 8.78 (s, 2H, H2',
H6'), 7.88 (dd, 1H, J = 7.79 Hz, J = 1.96 Hz, H6), 7.76-7.73
(m, 2H, H3, H5), 7.45-7.40 (m, 1H, H4); 13C NMR: δ 164.4,
155.7, 150.4, 141.8, 133.6, 129.3, 119.9, 119.3, 118.7, 117.2.
3,5-Dichloro-2-hydroxy-N-(pyridin-4-yl)benzamide
(1b): m.p. 334-336 °C; m.f. C12H8N2O2Cl2; IR (KBr, νmax, cm-1):
General procedure for the synthesis of the compounds
of series 1a-6h: To a solution of substituted acetylsalicyloyl
chlorides (0.022 mol) in anhydrous chloroform (100 mL) was
added triethylamine (0.023 mol) at 4 °C. After the mixture
was stirred for 5-15 min and then substituted 4-amino pyridine
was added portion wise in the ice bath. After warmed to room
temperature, the solution was stirred for 24-48 h and then
quenched by 1 mL of 1 M hydrochloric acid. The reaction
mixture was extracted with 10 % hydrochloric acid (50, 30
and 30 mL) and the combined aqueous was basified to pH 7-
9 with cooled saturated sodium bicarbonate solution. The
yellow precipitation was filtered producing the crude products.
After recrystallized in ethanol, the products were isolated as
pure form in more than 85 % yields.
1
(C=O) 1679; H NMR: δ10.87 (bs, 1H, NH), 8.57-8.49 (m,
2H, H2', H6'), 7.77-7.71 (m, 2H, H3', H5'), 7.76 (d, 1H, J
=2.01 Hz, H6), 7.45 (d, 1H, J =2.01 Hz, H4); 13C NMR: δ165.4,
154.2, 151.3, 146.1, 132.3, 127.9, 126.9, 126.2, 121.5, 114.0.
3,5-Dichloro-N-(3-chloropyridin-4-yl)-2-hydroxy-
benzamide (2b): m.p. 287-288 °C; m.f. C12H7N2O2Cl3; IR
(KBr, νmax, cm-1): (C=O) 1661; 1H NMR: δ10.88 (bs, 1H, NH),
8.72 (s, 1H, H2'), 8.54 (d, 1H, J = 8.94 Hz, H6'), 7.90 (d, 1H,
J = 8.94 Hz, H5'), 7.84 (d, 1H, J =2.03, H6), 7.51 (d, 1H, J
=2.03, H4); 13C NMR: δ166.8, 157.5, 150.4, 145.4, 133.8,
129.7, 119.3, 118.7, 117.2, 114.3.
3,5-Dichloro-N-(3-(trifluoromethyl)pyridin-4-yl)-2-
hydroxybenzamide (3b): m.p. 363-265 °C; m.f. C13H7N2O2Cl2F3;
IR (KBr, νmax, cm-1): (C=O) 1672; 1H NMR: δ10.99 (bs, 1H,
NH), 9.02-8.94 (m, H2', H6'), 8.19 (d, 1H, J = 9.02 Hz, H5'),
7.85 (d, 1H, J = 2.65 Hz, H6), 7.45 (d, 1H, J = 2.65 Hz, H4);
13C NMR: δ166.8, 157.5, 150.4, 145.4, 133.8, 129.7, 119.3,
118.7, 117.2 (J = 268 Hz), 114.0.
2-Hydroxy-N-(pyridin-4-yl)benzamide (1a): m.p. 233-
234 °C (234-236°C[1]); m.f. C12H10N2O2; IR (KBr, νmax, cm-1):
1
(C=O) 1676; H NMR: δ10.67 (bs, 1H, NH), 8.53-8.45 (m,
2H, H2', H6'), 7.86 (dd, 1H, J = 8.10 Hz, J = 1.80 Hz, H6),
7.75-7.73 (m, 2H, H3, H5), 7.47-7.41 (m, 1H, H4), 7.02-6.94
(m, 2H, H3', H5'); 13C NMR: δ166.8, 157.5, 150.4, 145.4,
133.8, 129.7, 119.3, 118.7, 117.2, 114.3.
3,5-Dichloro-2-hydroxy-N-(2-methylpyridin-4-
yl)benzamide (4b): m.p. 356-358 °C; m.f. C13H10N2O2Cl2; IR
(KBr, νmax, cm-1): (C=O) 1686; 1H NMR: δ10.79 (bs, 1H, NH),
8.60 (d, 1H, J = 7.50 Hz, H6'), 7.76 (d, 1H, J = 1.99 Hz, H6),
7.63 (d, 1H, J = 2.59 Hz, H3'), 7.52 (dd, 1H, J = 7.50 Hz, J =
2.58 Hz, H5'), 7.45 (d, 1H, J = 2.00 Hz, H4), 2.45 (s, 3H,
-CH3); 13C NMR: δ 166.8, 157.5, 150.4, 145.4, 133.8, 129.7,
119.3, 118.7, 117.2, 114.3.
N-(3-Chloropyridin-4-yl)-2-hydroxybenzamide (2a):
m.p. 187-188 °C; m.f. C12H9N2O2Cl; IR (KBr, νmax, cm-1):
1
(C=O) 1658 ; H NMR: δ10.52 (bs, 1H, NH), 8.69 (s, 1H,
H2'), 8.58 (d, 1H, J = 8.93 Hz, H6'), 7.86 (dd, 1H, J =7.92 Hz,
J = 1.90 Hz, H6), 7.75-7.73 (m, 2H, H3, H5), 7.47-7.41 (m,
1H, H4), 7.14 (d, 1H, J = 8.93 Hz, H5'); 13C NMR: δ166.6,
157.4, 150.2, 143.2, 142.9, 133.6, 129.5, 123.0, 119.4, 118.9,
117.0, 115.4.
3,5-Dichloro-N-(2-chloropyridin-4-yl)-2-hydroxy-
benzamide (5b): m.p. 310-311 °C; m.f. C12H7N2O2Cl3; IR
(KBr, νmax, cm-1): (C=O) 1670; 1H NMR: δ10.89 (bs, 1H, NH),
8.72 (d, 1H, J = 9.01, H6'), 7.77 (d, 1H, J = 2.07 Hz, H6), 7.45
(d, 1H, J = 2.08 Hz, H4), 7.06-6.97 (m, 2H, H3', H5'); 13C
NMR: δ166.8, 157.5, 150.4, 145.4, 133.8, 129.7, 119.3, 118.7,
117.2, 114.3.
2-Hydroxy-N-[3-(trifluoromethyl)pyridin-4-yl]benza-
mide (3a): m.p. 174-175 °C; m.f. C13H9F3N2O2; IR (KBr, νmax
,
cm-1): (C=O) 1669; 1H NMR: δ10.98 (bs, 1H, NH), 8.94-8.85
(m, 2H, H2', H6'), 7.88 (dd, 1H, J =7.97 Hz, J = 1.84 Hz, H6),
7.77-7.74 (m, 2H, H3, H5), 7.46-7.42 (m, 1H, H4), 8.27 (d,
1H, J = 8.98 Hz, H5'); 13C NMR: d165.9, 157.1, 150.6, 144.1,

Vol. 26, No. 21 (2014)
Design, Synthesis and Activity Evaluation of N-(pyridin-4-yl) Salicylamides 7271
3,5-Dichloro-N-(3,5-dichloropyridin-4-yl)-2-hydroxy-
benzamide (6b): m.p. 353-354 °C; m.f. C12H6N2O2Cl4; IR (KBr,
3-Chloro-N-(3-chloropyridin-4-yl)-2-hydroxybenza-
mide (2d): m.p. 271-273 °C; m.f. C12H8N2O2Cl2; IR (KBr, νmax
,
1
ν
max, cm-1): (C=O) 1654; 1H NMR: δ10.91 (bs, 1H, NH), 8.81
cm-1): (C=O) 1650; H NMR: δ10.86 (bs, 1H, NH), 8.72 (s,
1H, H2'), 8.58 (d, 1H, J = 9.01 Hz, H6'), 7.91 (d, 1H, J = 9.00
Hz, H5'), 7.67 (dd, 1H, J = 7.58 Hz, J = 2.53 Hz, H6), 7.41
(dd, 1H, J = 7.82 Hz, J = 2.53 Hz, H4), 7.10 (t, 1H, J = 7.81
Hz, J = 7.56 Hz, H5); 13C NMR: δ166.6, 157.5, 150.1, 144.1,
143.8, 133.3, 126.9, 121.1, 120.8, 119.1, 118.4, 114.8.
3-Chloro-N-[3-(trifluoromethyl)pyridin-4-yl]-2-
hydroxybenzamide (3d): m.p. 256-257 °C; m.f. C13H8N2O2ClF3;
IR (KBr, νmax, cm-1): (C=O) 1669; 1H NMR: δ10.90 (bs, 1H,
NH), 8.97-8.92 (m, 2H, H2', H6'), 8.23 (d, 1H, J = 9.09 Hz,
H5'), 7.82 (dd, 1H, J = 7.90 Hz, J = 2.69 Hz, H6), 7.45 (dd,
1H, J = 7.97 Hz, J = 2.69 Hz, H4), 7.11 (t, 1H, J = 7.96 Hz, J
= 7.90 Hz, H5); 13C NMR: δ166.6, 157.6, 150.5, 146.0, 143.2,
133.2, 127.1, 121.5, 120.6, 119.6, 118.9, 117.7 (J = 266 Hz),
113.4.
(s, 2H, H2', H6'), 7.81 (d, 1H, J = 2.06 Hz, H6), 7.46 (d, 1H, J
= 2.07 Hz, H4); 13C NMR: δ166.8, 157.5, 150.4, 145.4, 133.8,
129.7, 119.3, 118.7, 117.2, 114.3.
5-Chloro-2-hydroxy-N-(pyridin-4-yl)benzamide (1c):
m.p. 313-315 °C (314-316 °C[1]); m.f. C12H9N2O2Cl; IR (KBr,
ν
max, cm-1): (C=O) 1677; 1H NMR: δ10.83 (bs, 1H, NH), 8.52-
8.44 (m, 2H, H2', H6'), 7.82 (d, 1H, J = 2.61 Hz, H6), 7.74-
7.68 (m, 2H, H3', H5'), 7.44 (dd, 1H, J = 7.88 Hz, J = 2.60 Hz,
H4), 7.01 (d, 1H, J = 7.88 Hz, H3); 13C NMR: δ166.0, 157.1,
150.4, 145.4, 133.6, 129.1, 122.3, 120.7, 119.2, 114.1.
5-Chloro-N-(3-chloropyridin-4-yl)-2-hydroxybenza-
mide (2c): m.p. 355-357 °C; m.f. C12H8N2O2Cl2; IR (KBr, νmax
,
cm-1): (C=O) 1659; H NMR: δ10.85 (bs, 1H, NH), 8.71 (s,
1H, H2'), 8.53 (d, 1H, J = 9.08 Hz, H6'), 7.93 (d, 1H, J = 9.07
Hz, H5'), 7.82 (d, 1H, J = 1.97 Hz, H6), 7.44 (dd, 1H, J = 7.96
Hz, J = 1.97 Hz, H4), 7.01 (d, 1H, J = 7.96 Hz, H3); 13C NMR:
δ 164.9, 156.9, 150.2, 144.3, 143.6, 133.3, 129.0, 122.4, 121.7,
120.9, 119.4, 115.4.
1
3-Chloro-2-hydroxy-N-(2-methylpyridin-4-yl)benza-
mide (4d ): m.p. 268-270 °C; m.f. C13H11N2O2Cl; IR (KBr,
ν
max, cm-1): (C=O) 1685; 1H NMR: δ10.74 (bs, 1H, NH), 8.60
(d, 1H, J =7.52 Hz, H6'), 7.63-7.52 (m, 2H, H3', H5'), 7.66
(dd, 1H, J = 7.53 Hz, J = 2.52 Hz, H6), 7.39 (dd, 1H, J = 7.86
Hz, J = 2.52 Hz, H4), 7.02 (t, 1H, J = 7.85 Hz, J = 7.53 Hz,
H5), 2.49 (s, 3H, -CH3); 13C NMR: δ165.7, 158.3, 157.8, 150.4,
144.5, 133.0, 127.1, 121.4, 120.7, 119.2, 114.2, 112.3, 23.9.
3-Chloro-N-(2-chloropyridin-4-yl)-2-hydroxybenza-
5-Chloro-N-(3-(trifluoromethyl)pyridin-4-yl)-2-
hydroxybenzamide (3c): m.p. 343-342 °C; m.f. C13H8N2O2ClF3;
IR (KBr, νmax, cm-1): (C=O) 1672; 1H NMR: δ 10.91 (bs, 1H,
NH), 9.00-8.93 (m, 2H, H2', H6'), 8.21 (d, 1H, J = 9.01 Hz,
H5'), 7.83 (d, 1H, J = 2.72 Hz, H6), 7.46 (dd, 1H, J = 7.93 Hz,
J = 2.72 Hz, H4), 7.01 (d, 1H, J = 7.92 Hz, H3); 13C NMR: δ
165.1, 157.0, 150.5, 146.3, 143.3, 133.4, 129.2, 122.3, 120.8,
120.1, 119.3, 117.4 (J = 271 Hz), 113.9.
mide (5d). m.p. 243-246 °C; m.f. C12H8N2O2Cl2; IR (KBr, νmax
,
cm-1): (C=O) 1669; H NMR: δ10.87 (bs, 1H, NH), 8.72 (d,
1H, J = 9.07, H6'), 8.06-7.97 (m, 2H, H3', H5'), 7.68 (dd, 1H,
J = 7.59 Hz, J = 2.53 Hz, H6), 7.42 (dd, 1H, J = 7.86 Hz, J =
2.53 Hz, H4), 7.05 (t, 1H, J = 7.87 Hz, J = 7.59 Hz, H5); 13C
NMR: δ166.6, 158.1, 157.3, 145.5, 144.0, 133.0, 127.2, 121.3,
120.7, 118.8, 115.2, 114.1.
1
5-Chloro-2-hydroxy-N-(2-methylpyridin-4-yl)benza-
mide (4c): m.p. 338-339 °C; m.f. C13H11N2O2Cl; IR (KBr, νmax
,
cm-1): (C=O) 1684; 1H NMR: δ10.76 (bs, 1H, NH), 8.59 (d,
1H, J = 7.58 Hz, H6'), 7.79 (d, 1H, J = 2.31 Hz, H6), 7.61-
7.49 (m, 2H, H3', H5'), 7.42 (dd, 1H, J = 7.96 Hz, J = 2.31 Hz,
H4), 6.99 (d, 1H, J = 7.96 Hz, H3), 2.50 (s, 3H, -CH3); 13C
NMR: δ165.2, 157.3, 157.0, 150.6, 144.8, 133.5, 128.9, 122.1,
121.0, 119.0, 114.5, 112.6, 24.1.
3-Chloro-N-(3,5-dichloropyridin-4-yl)-2-hydroxy-
benzamide (6d): m.p. 287-288 °C; m.f. C12H7N2O2Cl3; IR
(KBr, νmax, cm-1): (C=O) 1654; 1H NMR: δ10.90 (bs, 1H, NH),
8.81 (s, 2H, H2', H6'), 7.70 (dd, 1H, J = 7.71 Hz, J = 2.62 Hz,
H6), 7.42 (dd, 1H, J = 7. 93 Hz, J = 2.62 Hz, H4), 7.05 (t, 1H,
J = 7.93 Hz, J = 7.71 Hz, H5); 13C NMR: δ165.5, 157.5, 149.5,
142.4, 129.7, 126.8, 121.0, 120.6, 119.4, 118.5.
5-Chloro-N-(2-chloropyridin-4-yl)-2-hydroxybenza-
mide (5c): m.p. 354-356 °C; m.f. C12H8N2O2Cl2; IR (KBr, νmax
,
cm-1): (C=O) 1668; 1H NMR: δ10.86 (bs, 1H, NH), 8.70 (d,
1H, J = 9.04, H6'), 8.06-7.97 (m, 2H, H2', H6'), 7.81 (d, 1H, J
= 2.63 Hz, H6), 7.74-7.68 (m, 2H, H3', H5'), 7.43 (dd, 1H, J =
7.72 Hz, J = 2.63 Hz, H4), 7.01 (d, 1H, J = 7.71 Hz, H3); 13C
NMR: δ166.3, 158.5, 157.4, 145.7, 144.6, 133.4, 129.3, 122.2,
120.7, 119.2, 115.5, 114.4.
5-Bromo-2-hydroxy-N-(pyridin-4-yl)benzamide (1e):
m.p. 302-303 °C (304-305 °C[1]); m.f. C12H9N2O2Br; IR (KBr,
ν
max, cm-1): (C=O) 1678; 1H NMR: δ10.84 (bs, 1H, NH), 8.50-
8.44 (m, H2', H6'), 7.93 (d, 1H, J = 2.46 Hz, H6), 7.72-7.68
(m, 2H, H3', H5'), 7.55 (dd, 1H, J = 8.78 Hz, J = 2.47 Hz, H4),
6.97 (d, 1H, J = 8.78 Hz, H3); 13C NMR: δ165.6, 157.1, 150.4,
145.5, 136.3, 131.7, 121.3, 119.7, 114.2, 110.2.
5-Chloro-N-(3,5-dichloropyridin-4-yl)-2-hydroxy-
benzamide (6c): m.p. 391-393 °C; m.f. C12H7N2O2Cl3; IR
(KBr, νmax, cm-1): (C=O) 1653; 1H NMR: δ10.89 (bs, 1H, NH),
8.81 (s, 2H, H2', H6'), 7.82 (d, 1H, J = 2.58 Hz, H6), 7.43 (dd,
1H, J = 8.09 Hz, J = 2.58 Hz, H4), 7.01 (d, 1H, J = 8.08 Hz,
H3); 13C NMR: δ166.7, 157.5, 149.1, 142.6, 133.6, 129.1,
122.3, 120.7, 120.2, 118.9.
5-Bromo-N-(3-chloropyridin-4-yl)-2-hydroxy-
benzamide (2e): m.p. 343-345 °C; m.f. C12H8N2O2BrCl; IR
(KBr, νmax, cm-1): (C=O) 1659; 1H NMR: δ10.85 (bs, 1H, NH),
8.71 (s, 1H, H2'), 8.54 (d, 1H, J = 8.97 Hz, H6'), 7.94 (d,
overlapped, 1H, J = 2.46 Hz, H6), 7.92 (d, overlapped, 1H, J
= 8.96 Hz, H5'), 7.55 (dd, 1H, J = 8.79 Hz, J = 2.47 Hz, H4),
6.96 (d, 1H, J = 8.79 Hz, H3); 13C NMR: δ165.2, 157.0, 150.2,
144.5, 144.1, 136.2, 131.6, 121.1, 119.6, 118.6, 114.4, 111.5.
5-Bromo-N-(3-[trifluoromethyl)pyridin-4-yl]-2-hydroxy-
benzamide (3e): m.p. 331-333 °C; m.f. C13H8N2O2BrF3; IR
(KBr, νmax, cm-1): (C=O) 1670; 1H NMR: δ10.89 (bs, 1H, NH),
8.89-8.85 (m, H2', H6'), 7.94 (d, 1H, J = 2.48 Hz, H6), 8.22(d,
3-Chloro-2-hydroxy-N-(pyridin-4-yl)benzamide (1d):
m.p. 296-297 °C; m.f. C12H9N2O2Cl; IR (KBr, νmax, cm-1): (C=O)
1
1678; H NMR: δ10.84 (bs, 1H, NH), 8.53-8.45 (m, 2H, H2',
H6'), 7.69 (dd, 1H, J = 7.61 Hz, J = 2.58 Hz, H6), 7.76-7.70 (m,
2H, H3', H5'), 7.43 (dd, 1H, J = 7.89 Hz, J = 2.58 Hz, H4), 7.05
(t, 1H, J = 7.89 Hz, J = 7.61 Hz, H5); 13C NMR: δ166.4, 157.7,
150.3, 145.2, 133.1, 127.0, 121.3, 120.9, 119.0, 113.8.

7272 Dian et al.
Asian J. Chem.
1H, J = 9.02 Hz, H5'), 7.55 (dd, 1H, J = 8.81 Hz, J = 2.48 Hz,
H4), 6.97 (d, 1H, J = 8.80 Hz, H3); 13C NMR: δ165.8, 157.2,
150.6, 146.3, 143.5, 136.2, 131.5, 121.4, 119.9, 119.4, 115.1,
114.9 (J = 266 Hz), 110.
124.8, 121.4 (J = 270 Hz), 120.2, 119.3, 117.8, 110.7, 108.8,
23.8.
N-(2-Chloropyridin-4-yl)-5-(trifluoromethyl)-2-
hydroxybenzamide (5f): m.p. 233-235 °C; m.f. C13H8N2O2ClF3;
IR (KBr, νmax, cm-1): (C=O) 1723; 1H NMR: δ11.56 (bs, 1H,
NH), 8.72 (d, 1H, J = 9.06, H6'), 8.05-8.01 (m, 2H, H3', H5'),
8.29 (d, 1H, J = 2.36 Hz, H6), 7.82 (dd, 1H, J = 8.35 Hz, J =
2.37 Hz, H4), 7.23 (d, 1H, J = 8.35 Hz, H3); 13C NMR: δ166.3,
161.7 154.5, 146.0, 145.6, 130.2, 125.1, 121.5 (J = 270 Hz),
120.2, 119.3, 117.6, 111.7, 110.6.
5-Bromo-2-hydroxy-N-(2-methylpyridin-4-yl)-benza-
mide (4e): m.p. 299-301 °C; m.f. C13H11N2O2Br; IR (KBr, νmax
,
cm-1): (C=O) 1684; H NMR: δ10.71 (bs, 1H, NH), 8.59 (d,
1H, J = 7.56 Hz, H6'), 7.62-7.54 (m, 2H, H3', H5'), 7.91 (d,
1H, J = 1.96 Hz, H6), 7.53 (dd, 1H, J = 8.93 Hz, J = 1.96 Hz,
H4), 6.94 (d, 1H, J = 8.93 Hz, H3), 2.45 (s, 3H, -CH3); 13C
NMR: δ165.9, 158.6, 157.0, 150.6, 146.9, 136.4, 131.6, 121.0,
119.9, 114.4, 110.6, 108.7, 23.9.
1
N-(3,5-Dichloropyridin-4-yl)-5-(trifluoromethyl)-2-
hydroxybenzamide (6f): m.p. 273-275 °C; m.f. C13H7N2O2Cl2F3;
1
5-Bromo-N-(2-chloropyridin-4-yl)-2-hydroxybenza-
mide (5e): m.p. 274-275 °C; m.f. C12H8N2O2BrCl; IR (KBr,
IR (KBr, νmax, cm-1): (C=O) 1708; H NMR: δ11.61 (bs, 1H,
NH), 8.81-8.76 (m, H2', H6'), 8.29 (d, 1H, J = 2.37 Hz, H6),
7.82 (dd, 1H, J = 8.38 Hz, J = 2.38 Hz, H4), 7.20 (d, 1H, J =
8.38 Hz, H3); 13C NMR: δ165.5, 161.3, 150.8, 142.9, 130.0,
124.7, 121.8 (J = 270 Hz), 120.4, 119.2, 118.7, 117.7.
5-Chloro-2-hydroxy-4-methoxy-N-(pyridin-4-yl)-
benzamide (1g): m.p. 333-334 °C; m.f. C13H11N2O3Cl; IR
(KBr, νmax, cm-1): (C=O) 1678; 1H NMR: δ10.80 (bs, 1H, NH),
8.51-8.45 (m, 2H, H2', H6'), 7.73-7.69 (m, 2H, H3', H5'), 7.71
(s, 1H, H6), 6.52 (s, 1H, H3), 3.76 (s, 3H, -CH3); 13C NMR: δ
166.7, 160.2, 156.6, 150.3, 145.0, 130.9, 114.6, 114.1, 113.7,
103.0, 55.5.
ν
max, cm-1): (C=O) 1666; 1H NMR: δ10.83 (bs, 1H, NH), 8.70
(d, 1H, J = 9.04, H6'), 8.05-7.98 (m, 2H, H3', H5'), 7.94 (d,
1H, J = 2.52 Hz, H6), 7.56 (dd, 1H, J = 8.74 Hz, J = 2.51 Hz,
H4), 6.96 (d, 1H, J = 8.75 Hz, H3); 13C NMR: δ165.6, 156.7,
156.4, 145.8, 144.3, 136.5, 131.4, 121.6, 119.5, 114.1, 111,6,
110.5.
5-Bromo-N-(3, 5-dichloropyridin-4-yl)-2-hydroxy-
benzamide (6e): m.p. 317-319 °C; m.f. C12H7N2O2BrCl2; IR
(KBr, νmax, cm-1): (C=O) 1653; 1H NMR: δ10.88 (bs, 1H, NH),
8.80-8.74 (m, H2', H6'), 7.94 (d, 1H, J = 2.52 Hz, H6), 7.56
(dd, 1H, J = 8.84 Hz, J = 2.52 Hz, H4), 6.96 (d, 1H, J = 8.84
Hz, H3); 13C NMR: δ166.8, 157.5, 150.4, 145.4, 133.8, 129.7,
119.3, 118.7, 117.2, 114.3.
5-Chloro-N-(3-chloropyridin-4-yl)-2-hydroxy-4-
methoxybenzamide (2g): m.p. 365-367 °C; m.f. C13H10N2O3Cl2;
1
IR (KBr, νmax, cm-1): (C=O) 1660; H NMR: δ10.81 (bs, 1H,
5-(Trifluoromethyl)-2-hydroxy-N-(pyridin-4-yl)benza-
NH), 8.69 (s, 1H, H2'), 8.63 (d, 1H, J = 9.55 Hz, H6'), 7.94 (d,
1H, J = 9.56 Hz, H5'), 7.75 (s, 1H, H6), 6.54 (s, 1H, H3), 3.74
(s, 3H, -CH3); 13C NMR: δ166.7, 160.1, 156.7, 150.2, 144.0,
143.6, 130.6, 122.5, 114.6, 114.3, 114.0, 103.0, 55.6.
5-Chloro-N-(3-(trifluoromethyl)pyridin-4-yl)-2-
hydroxy-4-methoxybenzamide (3g): m.p. 349-352 °C; m.f.
C14H10N2O3ClF3; IR (KBr, νmax, cm-1): (C=O) 1671; 1H NMR:
δ10.87 (bs, 1H, NH), 9.02-8.96 (m, 2H, H2', H6'), 8.19 (d,
1H, J = 9.07 Hz, H5'), 7.73 (s, 1H, H6), 6.55 (s, 1H, H3), 3.73
(s, 3H, -CH3); 13C NMR: δ166.3, 159.7, 156.7, 150.5, 144.9.
143.1, 130.9, 122.0, 115.7, 114.9 (J = 263 Hz), 113.8, 113.5,
103.1, 55.6.
mide (1f ): m.p. 261-263 °C; m.f. C13H9N2O2F3; IR (KBr, νmax
,
cm-1): (C=O) 1732; 1H NMR: δ11.57 (bs, 1H, NH), 8.55-8.48
(m, 2H, H2', H6'), 8.28 (d, 1H, J = 2.30 Hz, H6), 7.81 (dd, 1H,
J = 8.31 Hz, J = 2.30 Hz, H4), 7.21 (d, 1H, J = 8.30 Hz, H3),
7.04-6.97 (m, 2H, H3', H5'); 13C NMR: δ 165.3, 161.4, 151.2,
145.7, 130.1, 124.9, 121.6(J = 270 Hz), 120.2, 119.4, 117.8,
110.3.
N-(3-Chloropyridin-4-yl)-5-(trifluoromethyl)-2-
hydroxybenzamide (2f): m.p. 232-234 °C; m.f. C13H8N2O2ClF3;
IR (KBr, νmax, cm-1): (C=O) 1714; 1H NMR: δ11.56 (bs, 1H,
NH), 8.72 (s, 1H, H2'), 8.61 (d, 1H, J = 9.07 Hz, H6'), 8.29 (d,
1H, J = 2.32 Hz, H6), 7.91 (d, 1H, J = 9.06 Hz, H5'), 7.81 (dd,
1H, J = 8.33 Hz, J = 2.33 Hz, H4), 7.22 (d, 1H, J = 8.32 Hz,
H3); 13C NMR: δ165.5, 161.3, 151.4, 144.5, 143.6, 130.0,
124.8, 121.5(J =270 Hz), 120.3, 119.5, 119.1, 117.7, 111.6.
5-(Trifluoromethyl)-N-(3-(trifluoromethyl)pyridin-4-
yl)-2-hydroxybenzamide (3f): m.p. 219-221 °C; m.f.
5-Chloro-2-hydroxy-4-methoxy-N-(2-methylpyridin-
4-yl)benzamide (4g): m.p. 346-348 °C; m.f. C14H13N2O3Cl;
1
IR (KBr, νmax, cm-1): (C=O) 1685; H NMR: δ10.73 (bs, 1H,
NH), 8.59 (d, 1H, J = 7.63 Hz, H6'), 7.63-7.52 (m, 2H, H3',
H5'), 7.68 (s, 1H, H6), 6.47 (s, 1H, H3), 3.76 (s, 3H, -CH3),
2.46 (s, 3H, -CH3); 13C NMR: δ165.8, 159.4, 157.9, 156.3, 150.4,
144.3, 130.8, 114.7, 114.3, 113.9, 112.2, 103.2, 55.3, 24.7.
5-Chloro-N-(2-chloropyridin-4-yl)-2-hydroxy-4-
methoxybenzamide (5g): m.p. 365-367 °C; m.f. C13H10N2O3Cl2;
1
C14H8N2O2F6; IR (KBr, νmax, cm-1): (C=O) 1725; H NMR:
δ11.62 (bs, 1H, NH), 8.91-8.87 (m, 2H, H2', H6'), 8.29 (d,
1H, J = 2.32 Hz, H6), 8.22(d, 1H, J = 9.05 Hz, H5'), 7.81 (dd,
1H, J = 8.28 Hz, J = 2.33 Hz, H4), 7.21 (d, 1H, J = 8.28 Hz,
H3); 13C NMR: δ166.1, 161.6, 151.4, 146.5, 143.5, 130.2,
124.8, 121.5 (J = 270 Hz), 120.3, 119.2, 118.7, 117.8, 117.3
(J = 266 Hz), 110.1.
1
IR (KBr, νmax, cm-1): (C=O) 1670; H NMR: δ10.81 (bs, 1H,
NH), 8.72 (d, 1H, J = 9.38, H6'), 8.06-8.03 (m, 2H, H3', H5'),
7.72 (s, 1H, H6), 6.54 (s, 1H, H3), 3.78 (s, 3H, -CH3); 13C
NMR: δ165.8, 159.1, 156.3, 156.0, 145.3, 143.8, 131.2, 115.0,
114.3, 113.7, 113.2, 103.0, 55.1.
5-(Trifluoromethyl)-2-hydroxy-N-(2-methylpyridin-4-
yl)benzamide (4f): m.p. 255-256 °C; m.f. C14H11N2O2F3; IR
(KBr, νmax, cm-1): (C=O) 1739; 1H NMR: δ11.44 (bs, 1H, NH),
8.60 (d, 1H, J = 7.58 Hz, H6'), 8.25 (d, 1H, J = 1.83 Hz, H6),
7.62-7.53 (m, 2H, H3', H5'), 7.77 (dd, 1H, J = 8.16 Hz, J =
1.83 Hz, H4), 7.14 (d, 1H, J = 8.16 Hz, H3), 2.47 (s, 3H,
-CH3); 13C NMR: δ165.5, 161.3, 154.6, 151.4, 145.0, 130.2,
5-Chloro-N-(3, 5-dichloropyridin-4-yl)-2-hydroxy-4-
methoxybenzamide (6g): m.p. 386-388 °C; m.f. C13H9N2O3Cl3;
1
IR (KBr, νmax, cm-1): (C=O) 1654; H NMR: δ10.84 (bs, 1H,
NH), 8.79-8.74 (m, H2', H6'), 7.70 (s, 1H, H6), 6.51 (s, 1H,
H3), 3.74 (s, 3H, -CH3); 13C NMR: δ166.6, 169.4, 156.4, 149.9,
142.3, 130.5, 115.5, 114.9, 114.4, 103.6, 55.3.

Vol. 26, No. 21 (2014)
Design, Synthesis and Activity Evaluation of N-(pyridin-4-yl) Salicylamides 7273
2-Hydroxy-4-methoxy-N-(pyridin-4-yl)benzamide
(1h): m.p. 279-281 °C; m.f. C13H12N2O3; IR (KBr, νmax, cm-1):
occurred, were determined after incubation at 37 °C for 4
weeks (Table-1).
1
(C=O) 1683; H NMR: δ10.89 (bs, 1H, NH), 8.55-8.48 (m,
RESULTS AND DISCUSSION
2H, H2', H6'), 7.83 (d, 1H, J = 8.65 Hz, H6), 7.05-6.98 (m,
2H, H3', H5'), 6.60-6.57 (m, 2H, H3, H5), 3.80 (s, 3H, -OCH3);
13C NMR: δ167.5, 164.1, 160.6, 150.5, 145.5, 131.1, 116.3,
114.5, 111.9, 100.2, 55.6.
The salicylanilides could inhibit the TCS nonspecifically
by a mechanism involving in uncoupling oxidative phospho-
rylation6. With respect to the activities against M. tuberculosis
(TB), there are two additional major aspects considered: innate
resistance, the unique structure and composition of the highly
hydrophobic cell wall that must be traversed. It is well known
that increasing the lipophilicity improve cell wall perme-
ability12-14, which implied that the differences in antimicro-
bacterial activities of N-pyridin-4-yl salicylamide analogues
arises from the differences in lipophilicity. Furthermore, we
studied the influence of the substituent effect on the heterocycle
and salicylic moieties. The minimum inhibitory concentrations
(MICs) against M. avium (A) of the eight substrates (2c, 4c,
5c, 4e, 5e, 2d, 4f) are equal to 75 µmol L-1, which are remark-
ably lower than 300 µmol L-1 of the MIC againstA of isoniazide.
Among them, compounds 4c, 5c, 4e and 5e exhibit good anti-
TB activity compared to isoniazide (Table-1). These results
suggest that such compounds might serve as prospective wide-
spectrum antimycobacterial substances.
N-(3-Chloropyridin-4-yl)-2-hydroxy-4-methoxy-
benzamide (2h): m.p. 304-306 °C; m.f. C13H11N2O3Cl; IR
(KBr, νmax, cm-1): (C=O) 1666; 1H NMR: δ10.90 (bs, 1H, NH),
8.72 (s, 1H, H2'), 8.61 (d, 1H, J = 9.60 Hz, H6'), 7.93 (d, 1H,
J = 9.61 Hz, H5'), 8.55-8.48 (m, 2H, H2', H6'), 7.83 (d, 1H, J
= 8.65 Hz, H6), 6.59 -6.55 (m, 2H, H3, H5), 3.82 (s, 3H,
-OCH3);13C NMR: δ167.3, 164.0, 160.4, 150.3, 144.4, 144.0,
131.0, 116.4, 123.4, 115.8, 112.1, 100.3, 55.5.
N-(3-(Trifluoromethyl)pyridin-4-yl)-2-hydroxy-4-
methoxybenzamide (3h): m.p. 290-292 °C; m.f. C14H11N2O3F3;
1
IR (KBr, νmax, cm-1): (C=O) 1667; H NMR: δ10.96 (bs, 1H,
NH), 8.97-8.92 (m, 2H, H2', H6'), 8.24 (d, 1H, J = 9.65 Hz,
H5'), 7.85 (d, 1H, J = 9.27 Hz, H6), 7.05-6.98 (m, 2H, H3',
H5'), 6.59 -6.55 (m, 2H, H3, H5), 3.79 (s, 3H, -OCH3); 13C
NMR: δ167.7, 164.2, 160.7, 150.7, 146.3, 143.5, 131.2, 124.2,
121.5(J = 266 Hz), 116.1, 114.3, 111.8, 100.1, 55.7.
2-Hydroxy-4-methoxy-N-(2-methylpyridin-4-yl)benza-
Table-1 showed that when position 2 of the heterocycle,
or position 3 or 5 of the salicylic moiety was substituted by
chlorine, methyl or bromine, the antimycobacterial activity
will be increased. This antimycobacterial value is particularly
high against the typical mycobacterial strainsA, For example,
the compounds 4c, 5c, 4e and 5e in anti-TB activity are almost
the same as INH. However, they exhibit higher anti-A activity
than INH. Therefore, it is likely that N-(pyridin-4-yl) salicyl-
amides may constitute a new group of promising compounds
bearing potential antimycobacterial activity.
mide (4h): m.p. 285-287°C; m.f. C14H14N2O3; IR (KBr, νmax
,
cm-1): (C=O) 1691; 1H NMR: δ10.82 (bs, 1H, NH), 8.59 (d, 1H,
J = 8.23 Hz, H6'), 7.05-6.97 (m, 2H, H3', H5'), 7.80 (d, 1H, J =
8.68 Hz, J = 1.77 Hz, H6), 6.65-6.52 (m, 1H, H4), 3.80 (s, 3H,
-OCH3); 13C NMR: δ167.6, 164.2, 160.6, 154.2, 150.6, 144.8,
131.1, 116.1, 114.9, 113.0, 111.8, 100.2, 55.8, 24.2.
N-(2-Chloropyridin-4-yl)-2-hydroxy-4-methoxy-
benzamide (5h): m.p. 181-183 °C; m.f. C13H11N2O3Cl; IR
(KBr, νmax, cm-1): (C=O) 1674; 1H NMR: δ10.90 (bs, 1H, NH),
8.74 (d, 1H, J = 9.45, H6'), 8.08-8.06 (m, 2H, H3', H5'), 7.84
(d, 1H, J = 8.57 Hz, H6), 6.62-6.58 (m, 2H, H3, H5), 3.82 (s,
3H, -OCH3); 13C NMR: δ167.9, 164.3, 160.7, 153.6, 145.8,
144.3, 131.2, 116.2, 115.9, 114.8, 111.7, 100.0, 55.8.
N-(3, 5-Dichloropyridin-4-yl)-2-hydroxy-4-methoxy-
benzamide (6h): m.p. 224-226 °C; m.f. C13H10N2O3Cl2; IR
(KBr, νmax, cm-1): (C=O) 1659; 1H NMR: δ10.93 (bs, 1H, NH),
8.81-8.77 (m, 2H, H2', H6'), 7.82 (d, 1H, J = 8.58 Hz, H6),
6.59 -6.55 (m, 2H, H3, H5), 3.77 (s, 3H, -OCH3); 13C NMR:
δ167.1, 163.8, 159.7, 149.6, 142.7, 129.7, 124.3, 116.6, 112.1,
100.5, 55.8
When higher hydrophobicity compounds substituted on
position 2 of the heterocyclic moiety were used, the antimyco-
bacterial activity decreased dramatically (e.g. 4c, 5c, 4e and
5e). While introduction of methoxyl group on position 4 of
the salicylic moiety, with lower hydrophobicity, led to decreased
activity. In general, introduction of higher hydrophobic
substituents leads to higher activity towards both anti-TB and
anti-A. However, based on our research, the activities were
affected not only by hydrophobicity but also structure and
electronic requirements. For example, 5c and 5e with lg P more
than 2.5 resulted in high potency, but 6b and 6e with lg P more
than 3 gave decreased potency.
BiologicalActivity: The following strains, obtained from
Pulmonary Hospital of Lanzhou, were used for the evaluation
of in vitro antimycobacterial activity: Mycobacterium tuber-
culosis PHL 474/528 and Mycobacterium avium PHL 599/
778.Antimycobacterial activity of the compounds against these
strains was determined in the Sauton semiliquid medium (with
5 % bovine serum). The Sauton semiliquid medium was
routinely used in Pulmonary Hospital of Lanzhou. Each strain
was simultaneously inoculated into a Petri dish containing the
improved Löwenstein-Jensen medium for the control of the
sterility of the inoculums and its growth15,16. The compounds
were added to the medium in sodium phosphate buffer solu-
tions with 7.2 of pH value. The final concentrations were 1200,
600, 300, 150, 75, 37.5, 18.8, 9.4, 4.7, 2.3 and 1.2 µmol L-1.
MICs, at which inhibition of the growth of the mycobacteria
The compounds substituted on position 3 and 5 of the
heterocyclic moiety and on position 3 of the salicylic moiety
exhibited decreased antimycobacterial activity in spite of
higher or lower hydrophobicity. These results might be so due
to the steric reasons for the substituents can prevent the donor
or acceptor of amide and hydroxyl groups from interacting
with the corresponding biomacromolecule by hydrogen bond.
Conclusion
Present studies of structure-activity relationship suggests
that the introduction of substitutes with some balance between
hydrophobicity and electron effects in position 2 of the hetero-
cyclic, or in position 3 or 5 of the salicylic moiety may greatly
affect the antimycobacterial activity, which contribute to the

7274 Dian et al.
Asian J. Chem.
TABLE-1
in vitro ANTIMYCOBACTERIAL ACTIVITY AND lgP OF N-(pyridin-4-yl) SALICYLAMIDES
MICs (µmol L-1)
Compd.
R1
R2
R3
R4
R5
R6
lgP
M. tuberculosis PHL 474/528
(28 days)
M. avium PHL 599/778
(28 days)
300
150
1200
75
H
H
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
Cl
CF3
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1.11
1.67
2.03
1.60
2.01
2.23
2.23
2.79
3.15
2.93
3.13
3.35
1.67
2.23
2.59
2.38
2.57
2.79
1.67
2.23
2.59
2.38
2.57
2.79
1.94
2.50
2.86
2.65
2.84
3.06
2.03
2.59
2.96
2.74
2.93
3.15
1.54
2.10
2.47
2.25
2.45
2.66
0.99
1.54
1.91
1.69
1.89
2.10
-0.6
75
75
1a
2a
3a
4a
5a
6a
1b
2b
3b
4b
5b
6b
1c
2c
3c
4c
5c
6c
1d
2d
3d
4d
5d
6d
1e
2e
3e
4e
5e
6e
1f
H
H
H
300
37.5
18.8
75
CH3
Cl
H
H
H
H
H
H
75
Cl
H
H
H
300
1200
300
600
300
37.5
1200
150
75
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
150
75
H
Cl
CF3
H
H
H
H
150
37.5
18.8
300
18.8
9.4
CH3
Cl
H
H
H
H
Cl
H
H
H
H
H
Cl
CF3
H
H
H
H
37.5
2.3
300
9.4
CH3
Cl
H
H
H
H
1.2
4.7
Cl
H
H
37.5
37.5
9.4
300
150
75
H
H
H
Cl
CF3
H
H
H
H
H
H
75
300
150
300
600
150
75
CH3
Cl
H
H
H
18.8
37.5
75
H
H
H
Cl
H
H
H
H
H
Br
Br
Br
Br
Br
Br
CF3
CF3
CF3
CF3
CF3
CF3
Cl
Cl
Cl
Cl
Cl
Cl
H
18.8
18.8
75
H
Cl
CF3
H
H
H
H
300
18.8
18.8
600
300
150
300
75
CH3
Cl
H
H
4.7
H
H
2.3
Cl
H
H
150
37.5
37.5
75
H
H
H
Cl
CF3
H
H
2f
H
H
3f
CH3
Cl
H
H
9.4
4f
H
H
9.4
37.5
150
300
150
300
300
150
600
1200
600
600
150
75
5f
Cl
H
H
37.5
75
6f
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
1g
2g
3g
4g
5g
6g
1h
2h
3h
4h
5h
6h
INH
H
Cl
CF3
H
75
H
75
CH3
Cl
H
37.5
18.8
150
150
18.8
75
H
Cl
H
H
H
Cl
CF3
H
H
H
H
CH3
Cl
H
H
37.5
18.8
150
1.2
H
H
Cl
H
600
300
discovery of a series of prospective wide-spectrum anti-
mycobacterial substances. The applications of these results
and further investigations based on such methodology are
underway in our laboratory.
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for the financial support of this research.

Vol. 26, No. 21 (2014)
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