Antitubercular activities of the novel synthesized 1,2,4-triazole derivatives

Article abstract of DOI:10.1002/bkcs.10009

1,2,4-Triazoles exert antimycobacterial activity by inhibiting the cell wall biosynthesis. In an attempt to developing lead compounds exhibiting antitubercular activities, a series of 1,2,4-triazole derivatives were synthesized by introducing various substitutes into a scaffold and the antitubercular activity was evaluated. The most potent compounds 3e and 8d showed their minimum inhibitory concentrations against Mycobacterium tuberculosis as 12.5 ??M. The results indicate that those compounds can be considered as leads for further development of new 1,2,4-triazole type candidates with high antitubercular activities.

Full text of DOI:10.1002/bkcs.10009

Article
DOI: 10.1002/bkcs.10009
BULLETIN OF THE
T. Oh et al.
KOREAN CHEMICAL SOCIETY
Antitubercular Activities of the Novel Synthesized 1,2,4-Triazole
Derivatives
Taegwon Oh,† Faisal Hayat,‡ Euna Yoo,‡ Sang-Nae Cho,† Yhun Yhung Sheen,‡ Dae-Kee Kim,‡
and Hea-Young Park Choo‡,
*
†DepartmentofMicrobiology andInstituteforImmunologyandImmunologicalDiseases, BrainKorea21Plus
Project for the Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea
‡College of Pharmacy & Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul
120-750, Republic of Korea. *E-mail: hypark@ewha.ac.kr
Received July 2, 2014, Accepted September 3, 2014, Published online January 5, 2015
1,2,4-Triazoles exert antimycobacterial activity by inhibiting the cell wall biosynthesis. In an attempt to devel-
oping lead compounds exhibiting antitubercular activities, a series of 1,2,4-triazole derivatives were synthe-
sized by introducing various substitutes into a scaffold and the antitubercular activity was evaluated. The most
potent compounds 3e and 8d showed their minimum inhibitory concentrations against Mycobacterium tuber-
culosis as 12.5 μM. The results indicate that those compounds can be considered as leads for further develop-
ment of new 1,2,4-triazole type candidates with high antitubercular activities.
Keywords: 1,2,4-Triazole, Antitubercular activities, MIC
Introduction
transmembrane diffusion because of its lipophilic property to
inhibit it target, namely sterol demethylase, a mixed-function
oxidase involved in sterol synthesis.19
Triazole and its derivatives have received considerable attention
in the pastfew decades because of theirchemotherapeuticpoten-
tial.1 The biological profile of triazole derivatives is very exten-
sive.2 1,2,4-Triazole derivatives are reported to show a broad
spectrum of pharmacological activities such as antibacterial,3,4
antifungal,5,6 antimicrobial,7 antimycobacterial,8 antipyretic,9
anticancer,10,11 anticonvulsant,12 and antiinflammatory.
Tuberculosis is an infectious disease caused by Mycobacte-
rium tuberculosis. It still remains the leading cause of death
among infectious diseases worldwide. The acquired immuno-
deficiency syndrome (AIDS) epidemic as well as the surge of
multidrug-resistant tuberculosis reaffirms tuberculosis as a
major threat to public health.13 There is a strong need to
developnewinhibitorsagainstlatentandresistanttuberculosis
thatactonnewtargets andhavelittle chanceofcrossresistance
with current drugs.14
Triazoles with various substitutions such as 1,2,4-triazole-
3-thione,20 3-pyridyl-1,2,4-triazole-5-thione,21 clubbed 1,2,4-
triazole,22 and 1,2,4-triazole-3-yl-benzene-1,2,3-triol,23 and
1H-1,2,3-triazoles24 were previously reported to have antitu-
bercular activity.
In this article, we report on the synthesis, characterization,
and antitubercular activities of the synthesized 1,2,4-triazole
derivatives.
Experimental
Materials and Methods. Allmeltingpointsofthesynthesized
compounds were measured in Pyrex capillaries using an elec-
trothermal digital melting point apparatus (Buchi Labortechnik
1
AG, Flawil, Switzerland) and were not corrected. H NMR
Targeting enzymes of various metabolic pathways of
M. tuberculosis is a pivotal strategy for the development of
novel antitubercular agents. Two enzymes of the shikimate
pathway, dehydrogenase and shikimate kinase, are relatively
new targets for antitubercular research.15 By mimicking the
key interaction involved in shikimate kinase–substrate com-
plex formation, triazole molecules could demonstrate their
potential as antimycobacterial agents.16
Furthermore, 1,2,4-triazoles exhibit antimycobacterial
activity by inhibiting cell wall biosynthesis.17 The cell envel-
ope of M. tuberculosis is comprised of four classes of poly-
mers (peptidoglycan, arabinogalactan, mycolic acids, and
lipoarabinomanan). This complex lipidoglycan on the cell sur-
face provides a strong physical barrier to drugs that act intra-
cellularly.18 Triazolederivatives cancrossthecellenvelopeby
spectra were recorded on a 400-MHz Varian Fourier transform
NMRspectrometerusingtetramethylsilaneasinternalstandard.
Chemical shiftsareexpressedinppm (d), andpeaksarelisted as
singlet (s), doublet (d), triplet (t), quintet (q), or multiplet (m),
with coupling constants (J) expressed in hertz (Hz). Mass spec-
traldatawereobtainedonanAgilent6220Accurate-Masstime-
of-flight liquid chromatography/mass spectrometry (TOF LC/
MS) using Jeol JMS 700 (JEOL.Ltd , Tokyo, Japan). Most of
the reagents were purchased from Sigma-Aldrich Chemical
Co. (st.Louis, MO, USA) and Merck Co. Thin-layer chroma-
tography (TLC) was run on silica gel-coated plastic sheets
(Silica Gel 60, 230–400 mesh, Merck, Darmstadt, Germany)
and visualized in UV light (254 or 365 nm).
General Procedure for the Preparation of 5-Phenyl-1,2,4-
triazole Compounds 1a–1o and 2a–2d. To a solution of
Bull. Korean Chem. Soc. 2015, Vol. 36, 43–51
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43

BULLETIN OF THE
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Antitubercular Activities of the Novel 1,2,4-Triazole Derivatives
KOREAN CHEMICAL SOCIETY
variously substituted aniline or benzylamine (2 mmol), diiso-
propylethylamine (2 mmol) and benzoyl isothiocyanate
(2 mmol) in acetonitrile were added, and the mixture was
stirred for 8 h. The resulting precipitate was collected by filtra-
tion and washed with acetonitrile. The dried precipitate
(0.5 mmol) was dissolved in dimethylformamide (DMF) and
2-hydrazinopyridine (0.55 mmol), and 1-Ethyl-3-(3-dimethy-
laminopropyl)carbodiimide (EDCI) (1 mmol) was added. The
mixturewasstirredfor18hatroomtemperature.Aftercomplet-
ing the reaction, the mixture was extracted by ethyl acetate,
and the organic layer was washed with 10% HCl and saturated
sodium bicarbonate solution twice, respectively, and washed
finally with brine. The organic layer was dried over sodium
sulfate and concentrated. The compounds were purified by
column chromatography using hexane and ethyl acetate as
eluents (2:1).
N-5-Diphenyl-1-(pyridin-2-yl)-1H-1,2,4-triazol-3-amine
(1a): White solid (23%), mp 139–140 ꢀC: 1H NMR (400 MHz,
CDCl3) δ 8.381 (d, J = 3.6 Hz, 1H), 7.856 (t, J = 9.6 Hz, 1H),
7.677(d, J=8.0 Hz, 1H),7.567–7.537(m, 4H),7.434(t, J=7.6
Hz, 1H), 7.383 (d, J = 7.2 Hz, 2H), 7.326 (d, J = 8.4 Hz, 2H),
7.295–7.274 (m, 1H), 6.956 (t, J = 7.2 Hz, 1H), 6.797 (s,
1H), HR-FABMS calcd for C19H16N5 (M+ + H): 314.1400,
found: 314.1401.
N-(3-Methoxyphenyl)-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (1f ): Brown solid (27%), mp 110–113 ꢀC: 1H
NMR (400 MHz, CDCl3) δ 8.360 (d, J = 4.8 Hz, 1H),
7.874–7.826, 7.686 (d, J = 8.0 Hz, 1H), 7.560–7.536 (m,
2H), 7.426 (t, J = 7.2 Hz, 1H), 7.372 (d, J = 8.0 Hz, 1H),
7.345 (t, J = 1.6 Hz, 1H), 7.296–7.258 (m, 2H), 7.198 (t, J
= 8.0 Hz, 1H), 7.029 (d, J = 8.0 Hz, 1H), 6.925 (s, 1H),
6.510 (d, J = 8.8 Hz, 1H), 3.816 (s, 3H), HR-FABMS calcd
for C20H18N5O (M+ + H): 344.1506, found: 344.1505.
N-(4-Ethoxyphenyl)-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (1g): White solid (22%), mp 173–174 ꢀC: 1H
NMR (400 MHz, CDCl3) δ 8.372 (d, J = 4.8 Hz, 1H), 7.836 (t,
7.6, 1H), 7.647 (d, J = 8.0 Hz, 1H), 7.541 (d, J = 7.2 Hz, 2H),
7.456 (d, J = 7.2 Hz, 2H), 7.413 (d, J = 4.8 Hz, 1H),
7.386–7.344 (m, 2H), 7.290–7.269 (m, 1H), 6.883 (d, J =
6.8 Hz, 2H), 6.541 (s, 1H), 4.014 (q, J = 6.8 Hz, 2H), 1.402
(t, J = 6.8 Hz, 3H), HR-FABMS calcd for C21H20N5O (M+ +
H): 358.1662, found: 358.1663.
N-(2,6-Dimethylphenyl)-5-phenyl-1-(pyridin-2-yl)-1H-
1,2,4-triazol-3-amine (1h): Pale yellow solid (22%), mp
1
170–171 ꢀC: H NMR (400 MHz, CDCl3) δ 8.336 (d, J =
4.8 Hz, 1H), 7.876 (d, J = 7.6 Hz, 1H), 7.748 (t, J = 8.0 Hz,
1H), 7.622 (t, J = 7.6 Hz, 1H), 7.544–7.470 (m, 2H), 7.400
(t, J = 7.2 Hz, 1H), 7.364–7.318 (m, 1H), 7.237–7.204 (m,
1H), 7.133–7.040 (m, 2H), 2.377 (s, 6H), HR-FABMS calcd
for C21H20N5 (M+ + H): 342.1713, found: 342.1715.
N-(4-Fluorophenyl)-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (1b): Pale yellow solid (24%), mp
1
152–154 ꢀC: H NMR (400 MHz, CDCl3) δ 8.388 (d, J =
N-(2-Ethylphenyl)-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (1i): Pale yellow solid (50%), mp
5.2 Hz, 1H), 7.869–7.825 (m, 1H), 7.633 (d, J = 8.0 Hz, 1H),
7.547–7.510 (m, 3H), 7.500–7.466 (m, 2H), 7.432 (t, J = 7.2
Hz, 1H), 7.374 (d, J = 8.0 Hz, 2H), 7.310–7.276 (m, 1H),
6.999 (t, J = 8.8 Hz, 1H), 6.860 (s, 1H), HR-FABMS calcd
for C19H15FN5 (M+ + H): 332.1306, found: 332.1305.
1
120–121 ꢀC: H NMR (400 MHz, CDCl3) δ 8.379 (d, J =
4.8 Hz, 1H), 8.265 (d, J = 8.0 Hz, 1H), 7.844 (t, J = 8.0 Hz,
1H), 7.664 (d, J = 8.0 Hz, 1H), 7.657 (d, J = 7.6 Hz, 2H),
7.454–7.356 (m, 3H), 7.298–7.259 (m, 2H), 7.188 (d, J =
7.6 Hz, 1H), 6.951 (t, J = 7.2 Hz, 1H), 6.622 (s, 1H), 2.701
(q, J = 7.6 Hz, 2H), 1.313 (t, J = 7.6 Hz, 3H), HR-FABMS
calcd for C21H20N5 (M+ + H): 342.1713, found:342.1714.
N-(3-Ethylphenyl)-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (1j): Pale yellow solid (26%), mp
102–105 ꢀC: 1H NMR (400 MHz, CDCl3) δ 8.369 (d,
J = 4.8 Hz, 1H), 7.855 (t, J = 8.0 Hz, 1H), 7.684 (d, J = 8.0
Hz, 1H), 7.554 (d, J = 7.6 Hz, 2H), 7.448–7.412 (m, 2H),
7.390–7.353 (m, 2H), 7.289–7.264 (m, 2H), 7.231 (d,
J = 8.0, 1H), 6.808 (d, J = 8.0 Hz, 1H), 6.721 (s, 1H),
2.655 (q, J = 7.6 Hz, 2H), 1.259 (t, J = 7.6 Hz, 3H), HR-
FABMS calcd for C21H20N5 (M+ + H): 342.1713, found:
342.1714.
N-(4-Chlorophenyl)-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (1k): White solid (34%), mp 183–185 ꢀC: 1H
NMR (400 MHz, CDCl3) δ 8.398 (d, J = 4.8 Hz, 1H), 7.858 (t,
J = 7.6 Hz, 1H), 7.638 (d, J = 8.0 Hz, 1H), 7.541 (d, J = 6.8 Hz,
2H), 7.480 (d, J = 8.8 Hz, 2H), 7.426 (d, J = 6.0 Hz, 1H),
7.392–7.353 (m, 2H), 7.322–7.288 (m, 1H), 7.254 (d, J =
8.8 Hz, 2H), 6.828 (s, 1H), HR-FABMS calcd for C19H15ClN5
(M+ + H): 348.1010, found: 348.1010.
5-Phenyl-1-(pyridin-2-yl)-N-p-tolyl-1H-1,2,4-triazol-3-
1
amine (1c): White solid (28%), mp 175–177 ꢀC: H NMR
(400 MHz, CDCl3) δ 8.373 (d, J = 4.0 Hz, 1H), 7.847 (t, J =
8.4 Hz, 1H), 7.667 (d, J = 8.4 Hz, 1H), 7.557–7.518 (m,
2H), 7.430 (t, J = 7.2 Hz, 3H), 7.370 (t, J = 7.6 Hz, 2H),
7.296–7.274 (m, 1H), 7.129 (d, J = 8.0 Hz, 2H), 6.578 (s,
1H), 2.311 (s, 3H), HR-FABMS calcd for C20H18N5 (M+ +
H): 328.1557, found: 328.1557.
N-(4-Methoxyphenyl)-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (1d): Yellowsolid(27%), mp182–183 ꢀC:1H
NMR (400 MHz, CDCl3) δ 8.372 (d, J = 4.8 Hz, 1H), 7.837 (t,
J = 8.0 Hz, 1H), 7.647 (d, J = 8.0 Hz, 1H), 7.543 (d, J = 6.8 Hz,
2H), 7.479 (d, J = 6.8 Hz, 2H), 7. 426 (t, J = 7.2 Hz, 2H), 7.366
(t, J = 7.2 Hz, 1H), 7.292–7.267 (m, 1H), 7.392 (d, J = 6.8 Hz,
2H), 3.796 (s, 3H), HR-FABMS calcd for C20H18N5O (M+ +
H): 344.1506, found: 344.1505.
N-(2-Methoxyphenyl)-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (1e): Yellow solid (26%), mp 135-136 ꢀC: 1H
NMR(400 MHz,CDCl3)δ8.372(d,J=4.8 Hz,1H),8.293(d,J
= 8.4 Hz, 1H), 7.854 (t, J = 8.0 Hz, 1H), 7.698 (d, J = 8.0 Hz,
1H), 7.566 (d, J = 8.0 Hz, 2H), 7.449–7.351 (m, 4H),
7.295–7.255 (m, 1H), 7.006 (t, J = 6.8 Hz, 1H), 6.938–6.890
(m, 2H), 2.044 (s, 3H), HR-FABMS calcd for C20H18N5O
(M+ + H): 344.1506, found: 344.1506.
N-(4-Bromophenyl)-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (1l): White solid (19%): 1H NMR (400 MHz,
CDCl3) δ 8.399 (d, J = 4.8 Hz, 1H), 7.860 (t, J = 7.8 Hz, 1H),
Bull. Korean Chem. Soc. 2015, Vol. 36, 43–51
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BULLETIN OF THE
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Antitubercular Activities of the Novel 1,2,4-Triazole Derivatives
KOREAN CHEMICAL SOCIETY
7.633 (d, J = 8.0 Hz, 1H), 7.536 (d, J = 7.2 Hz, 2H),
7.463–7.356 (m, 7H), 7.325–7.291 (m, 1H), 6.726 (s, 1H).
N-(2-Ethoxyphenyl)-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (1m): Yellow solid (28%), mp 122–125 ꢀC:
1H NMR (400 MHz, CDCl3) δ 8.370 (d, J = 4.8, Hz 1H),
7.884–7.826 (m, 2H), 7.695 (d, J = 8.0 Hz, 1H), 7.616 (t, J =
7.2 Hz, 1H), 7.565 (d, J = 6.8 Hz, 2H), 7.511 (t, J = 8.0 Hz,
2H), 7.440–7.411 (m, 1H), 7.400–7.355 (m, 2H),
7.291–7.258 (m, 1H), 6.869 (s, 1H), 4.130 (q, J = 7.2 Hz,
2H), 1.477 (t, J = 7.2 Hz, 3H), HR-FABMS calcd for
C21H20N5O (M+ + H): 358.1662, found: 358.1663.
7.466 (d, J = 8.0 Hz, 1H), 7.392 (d, J = 7.2 Hz, 1H), 7.351
(d, J = 8.4 Hz, 1H), 7.330–7.310 (m, 2H), 7.251–7.230 (m,
1H), 7.160 (d, J = 7.6 Hz, 2H), 4.552 (s, 2H), 2.346 (s, 3H).
General Procedure for the Synthesis of Biphenyl Ben-
zoylthiourea Derivative of Anilines. A solution of biphenyl
benzoyl chloride (1 mmol) in dry acetone was stirred for
30 min at room temperature; then Potassium thiocyanate
KSCN/SiO2 (1mmol) was added and stirred at room temper-
ature for 3–4 h. After stirring for 4 h, various anilines (1mmol)
were added in the reaction mixture and further stirred for 10 h.
The resulting mixture was poured in water and extracted with
ethyl acetate. The organic layer was washed with 5% HCl and
dried over anhydrous sodium sulfate. The compound was pur-
ified by recrystallization in ethanol.
N-(3-Ethoxyphenyl)-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (1n): Light brown solid (24%), mp
1
142–144 ꢀC: H NMR (400 MHz, CDCl3) δ 8.369 (d, J =
4.8 Hz, 1H), 7.887–7.835 (m, 1H), 7.685 (d, J = 8.0 Hz, 1H),
7.548 (d, J = 7.2 Hz, 2H), 7.432 (t, J = 7.6 Hz, 1H),
7.391–7.349 (m, 2H), 7.304–7.273 (m, 1H), 7.230–7.190 (m,
2H), 7.081 (d, J = 8.0 Hz, 1H), 6.666 (s, 1H), 6.512 (dd, J =
8.0 Hz, 1H), 4.069 (q, J = 6.8 Hz, 2H), 1.425 (t, J = 6.8 Hz,
3H), HR-FABMS calcd for C21H20N5O (M+ + H): 358.1662,
found: 358.1663.
N1,N1-Dimethyl-N4-(5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-yl)benzene-1,4-diamine (1o):Brownsolid(13%):1H
NMR (400 MHz, CDCl3) δ 8.354 (d, J = 4.8 Hz, 1H), 7.830 (t,
J = 8.0 Hz, 1H), 7.662 (d, J = 8.0 Hz, 1H), 7.537 (d, J = 6.8 Hz,
2H), 7.459 (d, J = 9.2 Hz, 2H), 7.414 (d, J = 7.2 Hz, 1H),
7.382–7.342 (m, 3H), 7.278–7.245 (m, 1H), 6.819 (d, J = 8.4
Hz, 2H), 6.679 (s, 1H), 2.901 (s, 6H), HR-FABMS calcd for
C21H21N6 (M+ + H): 357.1822, found: 357.1826.
General Procedure for the Synthesis of 5-Biphenyl-1,2,4-
triazole Compounds (3a–3g). To a solution of biphenyl ben-
zoylthiourea derivatives (1 mmol), 2-hydrazinopyridine
(1 mmol) and EDCI (2 mmol) in dry DMF were added, and
the mixture was stirred overnight and poured into ice water.
The resulting precipitate was collected by filtration and
washed with water. The compounds were purified by column
chromatographyusing hexaneand ethylacetate aseluent (8:2).
N-(4-Phenyl)-5-biphenyl-1-(pyridine-2-yl)-1H-1,2,4-tria-
1
zol-3-amine (3a): Brown solid (15%), mp 206–207 ꢀC; H
NMR (400 MHz, CDCl3) δ 8.41–8.40 (d, J = 0.8 Hz, 1H),
7.90–7.85 (m, 1H), 7.73–7.70 (m, 1H), 7.65–7.59 (m, 6H),
7.57–7.55 (m, 2H), 7.48–7.43 (m, 2H), 7.39–7.29 (m, 4H),
6.95 (t, J = 7.6 Hz, 1H), 6.88 (s, 1H), HR-FABMS calcd for
C25H20N5 (M+ + H): 390.1713, found: 390.1717.
N-Benzyl-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-triazol-3-
amine (2a): Pale yellow solid (11%): H NMR (400 MHz,
N-(4-Nitrophenyl)-5-biphenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (3b): Yellowsolid(35%), mp238–239 ꢀC;1H
NMR (400 MHz, CDCl3) δ 8.46 (d, J = 2.4 Hz, 1H), 8.24–8.25
(dd,J=2.0,3.2 Hz,2H),7.94–7.90(m,1H),7.70–7.67(m,1H),
7.66–7.59(m, 8H),7.48–7.44 (m, 2H), 7.40–7.36(m, 2H),7.33
(s, 1H), HR-FABMS calcd for C25H19N6O2 (M+ + H):
435.1564, found:435.1563.
N-(2,4-Dimethoxyphenyl)-5-biphenyl-1-(pyridin-2-yl)-
1H-1,2,4-triazol-3-amine (3c): Light yellow solid (40%), mp
140–142 ꢀC; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 2.0
Hz, 1H), 8.18 (d, J = 6.8 Hz, 1H), 7.86 (t, J = 0.8 Hz, 1H),
7.72 (d, J = 6.0 Hz, 1H), 7.65–7.59 (m, 7H), 7.52 (s, 1H),
7.47–7.43 (m, 2H), 7.39–7.35 (m, 1H), 7.30–7.26 (m, 1H),
7.19 (s, 1H), 3.89 (s, 3H), 3.80 (s, 3H), HR-FABMS calcd
for C27H24N5O2 (M+ + H): 450.1925, found: 450.1928.
N-(2,6-Dimethylphenyl)-5-biphenyl-1-(pyridin-2-yl)-1H-
1,2,4-triazol-3-amine (3d): White solid (10%); 1H NMR (400
MHz, CDCl3)δ 8.36(d, J=2.4 Hz, 1H),7.77(t,J=1.2 Hz, 1H),
7.59–7.56 (m, 5H), 7.54–7.52 (m, 2H), 7.46–7.42 (m, 2H),
7.38–7.34 (m, 1H), 7.25–7.22 (m, 1H), 7.12–7.04 (m, 1H),
6.99 (s, 1H), 2.38 (s, 6H), HR-FABMS calcd for C27H24N5
(M+ + H): 418.2026, found: 418.2027.
1
CDCl3) δ 8.396 (d, J = 4.8 Hz, 1H), 7.774 (t, J = 8.0 Hz,
1H), 7.497 (d, J = 6.8 Hz, 2H), 7.468 (d, J = 8.0 Hz, 1H),
7.437 (d, J = 8.0 Hz, 2H), 7.397 (d, J = 7.2 Hz, 1H),
7.374–7.324 (m, 4H), 7.287 (d, J = 7.2 Hz, 1H),
7.257–7.236 (m, 2H), 4.614 (s, 2H), HR-FABMS calcd for
C20H18N5 (M+ + H): 328.1557, found: 328.1555.
N-(4-Fluorobenzyl)-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (2b): Pale yellow solid (12%): 1H NMR (400
MHz, CDCl3) δ 8.407 (d, J = 4.8 Hz, 1H), 7.775 (t, J = 8.0 Hz,
1H), 7.493 (d, J = 6.8 Hz, 2H), 7.449 (d, J = 8.4 Hz, 1H),
7.426–7.380 (m, 3H), 7.369–7.323 (m, 2H), 7.274–7.241 (m,
1H), 7.031 (t, J = 8.8 Hz, 2H), 4.567 (s, 2H), HR-FABMS calcd
for C20H17FN5 (M+ + H): 346.1463, found: 346.1464.
N-(4-Methoxybenzyl)-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (2c): Pale yellow solid (11%): 1H NMR (400
MHz, CDCl3) δ 8.405 (d, J = 4.8 Hz, 1H), 7.775 (t, J =
8.0 Hz, 1H), 7.510–7.456 (m, 4H), 7.405 (t, J = 7.6 Hz, 1H),
7.367–7.322 (m, 4H), 7.268–7.235 (m, 1H), 6.888 (d, J = 8.8
Hz, 2H), 4.534 (s, 2H), 3.809 (s, 3H), HR-FABMS calcd for
C21H20N5O (M+ + H): 358.1662, found: 358.1662.
N-(4-Methylbenzyl)-5-phenyl-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-amine (2d): Yellow solid (13%), mp 95–97 ꢀC: 1H
NMR (400 MHz, CDCl3) δ 8.399 (d, J = 4.8 Hz, 1H), 7.876
(d, J = 8.0 Hz, 1H), 7.769 (t, J = 7.6 Hz, 1H), 7.621 (t, J =
7.6 Hz, 1H), 7.526 (d, J = 8.4 Hz, 1H), 7.508–7.484 (m, 2H),
4-(5-Biphenyl-1-(pyridin-2-yl)-1H-1,2,4-triazol-3-ylamino)-
3-nitrophenol (3e): Dark brown oil (10%); H NMR (400
MHz, CDCl3) δ 8.36 (d, J = 2.0 Hz, 1H), 7.77 (t, J = 5.6 Hz,
2H), 7.65–7.54 (m, 3H), 7.54–7.51 (m, 1H), 7.49–7.42
(m, 2H), 7.38–7.34 (m, 1H), 7.24–7.22 (m, 2H), 7.12–7.04
1
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© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Antitubercular Activities of the Novel 1,2,4-Triazole Derivatives
KOREAN CHEMICAL SOCIETY
(m, 2H), 6.99 (s, 1H), 5.87 (s, 1H), HR-FABMS calcd for
C25H19N6O3 (M+ + H): 451.1513, found: 451.1506.
(400 MHz, CDCl3) δ 9.67 (s, 1H), 9.42 (s, 1H), 8.41 (d, J =
3.6 Hz, 1H), 8.04 (t, J = 6.0 Hz, 1H), 7.72 (d, J = 5.2 Hz,
1H), 7.62–7.59 (m, 2H), 7.49–7.41 (m, 3H), 7.05–6.91 (m,
7H),6.07(s, 2H),3.78(s, 3H).MS(ESI) m/z:543.14(M + H)+.
N1-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-yl)benzene-1,4-diaminequinoline sulfon amide
N-(5-Biphenyl-1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl)pyr-
1
idin-2-amine (3f ): Light green solid (15%); H NMR (400
MHz, CDCl3) δ 8.44 (d, J = 4.0 Hz, 1H), 8.29 (m, 1H), 8.15
(d, J = 8.4 Hz, 1H), 7.88 (t, J = 6.0 Hz, 1H), 7.71–7.65 (m,
3H), 7.63–7.59 (m, 6H), 7.47–7.43 (m, 2H), 7.39–7.32 (m,
2H), 6.89 (s, 1H), HR-FABMS calcd for C24H19N6 (M+ + H):
391.1666, found: 391.1664.
1
(5c): Dark brown oil (10%); H NMR (400 MHz, CDCl3) δ
10.4 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.02–7.89 (m, 1H),
7.77–7.72 (m, 1H), 7.67–7.57 (m, 3H), 7.43–7.41 (m, 1H),
7.19–7.12 (m, 3H), 7.05–7.03 (m, 1H), 6.93–6.89 (m, 2H),
6.69–6.67 (m, 2H), 6.58–6.53 (m, 2H), 6.14 (s, 2H), 6.06 (d,
J = 2.0 Hz, 1H). MS (ESI) m/z: 563.15 (M + H)+.
4-Chloro-N-(5-biphenyl-1-(pyridin-2-yl)-1H-1,2,4-tria-
zol-3-yl)pyridin-2-amine (3g): Brown solid (10%), mp
1
170–174 ꢀC; H NMR (400 MHz, CDCl3) δ 8.48–8.44 (m,
1H), 8.22 (d, J = 0.4 Hz, 1H), 8.15 (d, J = 4.8 Hz, 1H), 7.91 (t,
J = 1.6 Hz, 1H), 7.63–7.59 (m, 7H), 7.51 (s, 1H), 7.47–7.44
(m, 2H), 7.39–7.34 (m, 2H), 7.01 (s, 1H), HR-FABMS calcd
for C24H18ClN6 (M+ + H): 425.1276, found: 425.1273.
Synthesis of N1-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-
2-yl)-1H-1,2,4-triazol-3-yl)benzene-1,4-diamine (4). To a
solution of piperonyl benzoylthiourea (1 mmol), 2-
hydrazinopyridine (1 mmol) and EDCI (2 mmol) in dry
DMF were added and the mixture was stirred overnight and
poured in ice water. The resulting precipitate was collected
byfiltration and washed with water. Thecompoundswerepur-
ified by column chromatography using hexane and ethyl ace-
tate as an eluent (8:2).
N1-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-yl)benzene-1,4-diaminethiophenesulfon
amide
1
(5d): Brown solid (30%), mp 270–273 ꢀC; H NMR (400
MHz, CDCl3) δ 9.94 (s, 1H), 9.47 (s, 1H), 8.41 (d, J = 2.0
Hz, 1H), 8.05 (t, J = 6.0 Hz, 1H), 7.85 (d, J = 4.0 Hz, 1H),
7.74 (d, J = 6.4 Hz, 1H), 7.50–7.47 (m, 3H), 7.46–7.42 (m,
1H), 7.10–7.08 (dd, J = 3.6, 4.0 Hz, 1H), 6.99–6.92 (d, 2H),
6.07 (d, 2H). MS (ESI) m/z: 519.09 (M + H)+.
General Procedure for the Synthesis of Derivatives of
N1-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-yl)benzene-1,4-diamine (6a–6c). A solution of N1-
(5-(benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-1,2,4-tria-
zol-3-yl)benzene-1,4-diamine 4 (1 mmol) and CSCO3 (1.2
mmol, 0.391 g) in 15 mL DMF was stirred. The bromo com-
pound (1 mmol) was added, and the reaction mixture was stir-
red at 25–120 ꢀC for 24 h. After cooling to room temperature,
the mixture was quenched with saturated NaHCO3 and
extracted with ethyl acetate. The organic layer was washed
with water, dried over Na2SO4, and the solvent was removed
in vacuo. The crude product was purified by column chroma-
tography using hexane and ethyl acetate as an eluent.
4-((4-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-
1,2,4-triazol-3-ylamino)phenylamino)methyl) benzoni-
trile (6a): Brown solid (30%), mp 80–85 ꢀC; 1H NMR
(400 MHz, CDCl3) δ 9.06 (s, 1H), 8.38 (d, J = 2.0 Hz, 1H),
7.71–7.37 (m, 8H), 7.22–7.20 (m, 1H), 6.94–6.87 (m, 2H),
6.68–6.60 (m, 1H), 6.04 (s, 2H), 5.13 (s, 1H), 4.75 (s, 2H).
HR-FABMS calcd for C28H22N7O2 (M+ + H): 488.1829,
found: 488.1838.
3-((4-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-
1,2,4-triazol-3-ylamino)phenylamino)methyl) benzoni-
trile (6b): Brown solid (30%), mp 90–93 ꢀC; 1H NMR
(400 MHz, CDCl3) δ 9.04 (s, 1H), 8.38 (d, J = 2.8 Hz, 1H),
8.08–7.96 (m, 1H), 7.80–7.74 (m, 3H), 7.47–7.43 (m, 3H),
7.37–7.33 (m, 1H), 7.21–7.19 (m, 2H), 6.98–6.85 (m, 2H),
6.62–6.54 (m, 2H), 6.04 (s, 2H), 5.16 (s, 1H), 4.78–4.71
(m, 2H). HR-FABMS calcd for C28H22N7O2 (M+ + H):
488.1829, found: 488.1849.
General Procedure for the Synthesis of Sulfonamide Deri-
vatives of 5-Benzo[d][1,3]dioxol-1,2,4-triazols (5a–5d). A
solution of N1-(5-(benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-
1H-1,2,4-triazol-3-yl)benzene-1,4-diamine 4 (1 mmol) and
NaH (1 mmol) in 10 mL DMF was stirred at 60 ꢀC for 30
min. Ar-sulfonylchloride (1.5 mmol) in DMF (5 mL) was
added. The reaction mixture was stirred at 100 ꢀC for 16 h. After
coolingtoroomtemperature,themixturewasquenchedwithsat-
urated NaHCO3 and extracted with ethyl acetate. The organic
layerwaswashedwithwater, driedoverNa2SO4, andthesolvent
was removed in vacuo. The crude product was purified by col-
umn chromatography using hexane and ethyl acetate as eluent.
N1-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-yl)benzene-1,4-diamine (4): Brown solid (25%),
1
mp 204–206 ꢀC; H NMR (400 MHz, CDCl3) δ 8.86 (s,
1H), 8.40 (d, J = 0.8 Hz, 1H), 8.04 (t, J = 1.2 Hz, 1H), 7.69
(d, J = 6.0 Hz, 1H), 7.47–7.44 (m, 1H), 7.28–7.26 (m, 2H),
6.97–6.91 (m, 3H), 6.52–6.50 (dd, J = 2.4 Hz, 2H), 6.07 (d,
2H), 4.56 (s, 2H), HR-FABMS calcd for C20H17N6O2
(M+ + H): 373.1408, found: 373.1408.
N1-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-
1,2,4-triazol-3-yl)benzene-1,4-diamine-4-nitrobenzene-
sulfonamide (5a): Yellow solid (33%), mp 227–229 ꢀC; 1H
NMR (400 MHz, CDCl3) δ 10.1 (s, 1H), 9.49 (s, 1H), 8.41
(d, J = 3.6 Hz, 1H), 8.36–8.34 (m, 2H), 8.04 (t, J = 6.0 Hz,
1H), 7.92–7.90 (m, 2H), 7.71 (d, J = 4.0 Hz, 1H), 7.49–7.45
(m, 3H), 6.97–6.91 (m, 5H), 6.06 (s, 2H). MS (ESI) m/z:
558.11 (M + H)+.
2-(4-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-
1,2,4-triazol-3-ylamino)phenylamino)ethanol (6c): Brown
oil (30%); 1H NMR (400 MHz, CDCl3) δ 10.8 (s, 1H), 10.2
(s, 1H), 8.86 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 8.06–8.02
(m, 1H), 7.71–7.69 (m, 1H), 7.60–7.40 (m, 2H), 7.28–7.26
(m, 1H), 7.08–7.01 (m, 1H), 6.97–6.91 (m, 1H), 6.71–6.50
N1-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-yl)benzene-1,4-diamine-4-methoxybenzenesulfo-
namide (5b): White solid (25%), mp 225–228 ꢀC; 1H NMR
Bull. Korean Chem. Soc. 2015, Vol. 36, 43–51
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Antitubercular Activities of the Novel 1,2,4-Triazole Derivatives
KOREAN CHEMICAL SOCIETY
(m, 3H), 6.07 (s, 2H), 1.23–1.15 (m, 4H). HR-FABMS calcd
for C22H21N6O3 (M+ + H): 417.1670, found: 417.1666.
Procedure for the Synthesis of (E)-N1-(4-(Pyridin-4-yl)
benzylidene)-N4-(5-(benzo[d][1,3]dioxol-6-yl)-1-(pyridin-
2-yl)-1H-1,2,4-triazol-3-yl)benzene-1,4-diamine (7). To a
solution of N1-(5-(benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-
yl)-1H-1,2,4-triazol-3-yl)benzene-1,4-diamine 4 (1 mmol),
4-(pyridin-4-yl)benzaldehyde (1.5 mmol) in 15 mL ethanol
was added and refluxed overnight. After cooling to room tem-
perature, the mixture was quenched with ice cold water and
extracted with ethyl acetate. The organic layer was washed
with water, dried over Na2SO4, and the solvent was removed
in vacuo. The crude product was purified by column chroma-
tography using hexane and ethyl acetate (5:5) as an eluent.
(E)-N1-(4-(Pyridin-4-yl)benzylidene)-N4-(5-(benzo[d]
[1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl)ben-
zene-1,4-diamine(7):Brown solid (30%), mp142–144 ꢀC; 1H
NMR(400 MHz,CDCl3)δ9.70(s,1H),8.74(s,1H),8.68–8.66
(m,2H),8.45(d,J=2.0 Hz,1H),8.11–8.04(m,3H),7.97(d,J=
8.4 Hz, 2H), 7.80–7.75 (m, 2H), 7.52–7.49 (m, 2H), 7.37–7.35
(s, 2H), 7.01–6.94 (m, 3H), 6.08 (s, 2H). HR-FABMS calcd for
C32H24N7O2 (M+ + H): 538.1986, found: 538.1987.
General Procedure for the Synthesis of Amide Derivatives
of N1-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-
1,2,4-triazol-3-yl)benzeneamide (8a–8e). A mixture of
N1-(5-(benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-yl)benzene-1,4-diamine4(1 mmol) andarylbenzoyl
chloride (1 mmol) and Indium metal powder (1 mmol) in 10
mL DMF was stirred at room temp for 3–4 h. After stirring,
the mixture was poured into water and extracted with ethyl
acetate. The organic layer was washed with water, dried over
Na2SO4, and the solvent was removed in vacuo. The crude
product was purified by column chromatography using hex-
ane and ethyl acetate (7:3) as an eluent.
2H). HR-FABMS calcd for C28H20N7O3 (M+ + H):
502.1622, found: 502.1632.
N-(4-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-
1,2,4-triazol-3-ylamino)phenyl)-2,4-dinitrobenzamide (8d):
Brown solid (30%), mp 220–225 ꢀC; 1H NMR (400 MHz,
CDCl3) δ 10.7 (s, 1H), 9.58 (s, 1H), 9.17 (d, J = 2.4 Hz, 1H),
8.99 (t, J = 2.2 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.10–8.06 (m,
2H), 7.77 (d, J = 7.2 Hz, 1H), 7.70–7.61 (m, 4H), 7.52–7.48
(m, 2H), 7.02–6.94 (m, 2H), 6.08 (s, 2H). HR-FABMS calcd
for C27H19N8O7 (M+ + H): 567.1371, found: 567.1378.
N-(4-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-
1,2,4-triazol-3-ylamino)phenyl)-2-(ethylthio)pyridine-3-
carboxamide (8e): Brown solid (30%), mp 196–200 ꢀC; 1H
NMR (400 MHz, CDCl3) δ 10.2 (s, 1H), 9.48 (s, 1H), 8.54 (d,
J = 3.2 Hz, 1H), 8.43 (d, J = 2.4 Hz, 1H), 8.31 (s, 1H),
8.09–8.04 (m, 2H), 7.85 (d, J = 6.0 Hz, 1H), 7.76 (d, J =
8.0 Hz, 1H), 7.50–7.47 (m, 1H), 7.22 (q, J = 3.6 Hz, 2H),
7.00–6.93 (m, 3H), 6.08 (s, 1H), 1.98 (s, 5H).
MIC Determination Against M. tuberculosis. M. tubercu-
losis H37Rv expressing green fluorescent protein was cul-
tured at 37 ꢀC in Middlebrook 7H9 media until the optical
density at 600 nm reached 0.2.25 The testing compound was
first dissolved in dimethylsulfoxide (DMSO), and serially
diluted by twofold in DMSO. A volume of 2 μL from
each dilution was dispensed in a 96-well microtiter plate.
The culture was diluted in Middlebrook 7H9 media, and
2–5 × 104 Colony-forming unit (CFU) were inoculated to each
test well in a volume of 0.1 mL. After a week's incubation at
37 ꢀC, the fluorescence level of the microtiter plate was
recorded in a microplate fluorometer (BMG Labtech, Orten-
berg, Germany). The lowest compound concentration that
inhibited at least 80% compared to the fluorescence level of
the well without the testing compound was determined as
the MIC of a test compound.
N-(4-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-
1,2,4-triazol-3-ylamino)phenyl)-4-nitrobenzamide (8a):
Results and Discussion
1
Brown solid (30%), mp 244–245 ꢀC; H NMR (400 MHz,
CDCl3) δ 10.4 (s, 1H), 9.53 (s, 1H), 8.44 (d, J = 2.4 Hz,
1H), 8.37–8.35 (m, 2H), 8.19–8.17 (m, 2H), 8.09–8.05 (m,
1H), 7.76 (d, J = 6.4 Hz, 1H), 7.67–7.58 (m, 4H), 7.51–7.48
(m, 1H), 7.00–6.93 (m, 2H), 6.08 (s, 2H). HR-FABMS calcd
for C27H20N7O5 (M+ + H): 522.1520, found: 522.1530.
N-(4-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-1,2,4-
triazol-3-ylamino)phenyl)-2-chloropyridine-4-carboxamide
(8b): Brown solid (30%), mp 265–266 ꢀC; 1H NMR (400 MHz,
CDCl3)δ 10.3 (s, 1H), 9.52 (s, 1H), 8.93 (d, J = 2.8 Hz, 1H), 8.44
(d, J= 2.0 Hz, 1H), 8.35–8.32 (dd, J=2.4,2.4Hz,1H),8.09–8.05
(m, 2H), 7.77–7.57 (m, 5H), 7.51–7.48 (m, 2H), 7.00–6.93 (m,
2H), 6.09 (s, 2H). HR-FABMS calcd for C26H19ClN7O3 (M+ +
H): 512.1232, found: 512.1242.
N-(4-(5-(Benzo[d][1,3]dioxol-6-yl)-1-(pyridin-2-yl)-1H-
1,2,4-triazol-3-ylamino)phenyl)-4-cyanobenzamide (8c):
Brown solid (30%), mp >250 ꢀC; 1H NMR (400 MHz,
CDCl3) δ 10.3 (s, 1H), 9.52 (s, 1H), 8.44 (d, J = 2.4 Hz,
1H), 8.11–8.00 (m, 5H), 7.76 (d, J = 8.0 Hz, 1H), 7.65–7.57
(m, 3H), 7.51–7.48 (m, 2H), 7.00–6.93 (m, 2H), 6.08 (s,
Chemistry. Two-step synthesis of 1,2,4-triazole as previously
reported was employed in this study. Scheme 1 outlines the syn-
thetic procedure of compounds 1a–o and 2a–d. Phenylben-
zoylthiourea derivatives were prepared by reactions between
commercially available benzoyl isothiocyanate and substituted
anilines. The benzoylthiourea thus formed was reacted
O
O
S
n
+
S
a
( )
n
N
C
H2N
( )
N
N
H
H
R
R
NHNH2
N
N
n
( )
N
N
H
N
R
b
N
1, n=0
2, n=1
Scheme 1. Reagents and conditions. (a) iPr2NEt, CH3CN, rt, 8 h; (b)
EDCI, DMF, rt, overnight.
Bull. Korean Chem. Soc. 2015, Vol. 36, 43–51
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BULLETIN OF THE
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Antitubercular Activities of the Novel 1,2,4-Triazole Derivatives
KOREAN CHEMICAL SOCIETY
a
b
O
O
+ KSCN
NCS
Cl
NHNH2
H
N
R
N
N
N
O
HN
N
S
c
HN
R
N
3a-g
Scheme 2. Reagents and conditions. (a) Dry acetone, (b) different aromatic amines, (c) EDCI, DMF, rt, overnight.
NH2
Table 1. Chemical structures and antitubercular activities of
NHNH2
compounds 1a–2d.
NH2
N
O
O
S
NH2
a
O
O
NCS
O
O
N
H
NH
b
N
n
(
)
N
H
O
S
O
HN
NH2
H
N
O
N
HN
N
R
Cl
N
N
S
O
N
R
O
N
R
O
N
N
O
N
O
5a-d
N
c
N
1a-1o; n = 0
2a-2d; n = 1
4
H2
C
H
r
B
R
HN
N
N
R
C
Compound
R
MIC (μM)
H2
N
d
O
N
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
4-F
4-CH3
>200
200
O
O
N
C
H
R
e
>200
>200
200
O
6a-c
4-OCH3
2-OCH3
3-OCH3
4-OCH2CH3
2,6-(CH3)2
2-CH2CH3
3-CH2CH3
4-Cl
R
Cl
f
HN
N
N
R
N
O
N
100
>200
200
O
N
H
7
HN
N
N
R
>200
>200
>200
>200
200
N
O
O
1j
1k
1l
N
O
N
4-Br
1m
1n
1o
2a
2b
2c
2d
2-OCH2CH3
3-OCH2CH3
4-NH2
H
4-F
8a-d
200
Scheme 3. Reagents and conditions. (a) Reflux 5 h, (b) DMF, EDCI,
rt, overnight, (c) NaH, DMF, 100 ꢀC, overnight, (d) CSCO3, DMF,
120 ꢀC, (e) EtOH, reflux, (f ) indium metal, DMF, rt, 30 min.
>200
>200
200
>200
200
4-OCH3
4-CH3
with 2-hydrazinopyridine and EDCI at room temperature to
give 1,2,4-triazole-3-amino derivatives. The biphenyl-
isothiocyanate was prepared from biphenyl benzoyl and
KSCN. Then benzoylthiourea derivatives were prepared from
the reaction with various anilines, and cyclized to afford 1,2,4-
triazole derivatives 3a–g as shown in Scheme 2. The prepara-
tion of the compounds 4, 5a–d, 6a–c, and 8a–e are shown in
Scheme 3. The preparation of 1,2,4-triazoles from isothiocy-
anate was carried out by similar procedure. Afterward, the
aminogroupincompound4wasfurther reacted togivesulfon-
amide (5a–d), benzyl (6a–c), and amide (8a–e) derivatives.
Biological Activity. The antitubercular activities of the
synthesized compounds are shown in Tables 1-5. Table 1
shows that among the eighteen 5-phenyl-1,2,4-triazole com-
pounds, two compounds (3e and 8d) showed mild antituber-
cular activity. Isonicotinylhydrazine (INH) was used as a
positive standard to evaluate the antitubercular activities of
the compounds. MIC of INH was 0.228 μM in the test.
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Antitubercular Activities of the Novel 1,2,4-Triazole Derivatives
KOREAN CHEMICAL SOCIETY
Table 2. Chemical structures and antitubercular activities of
compounds 3a–3f.
Table 4. Chemical structures and antitubercular activities of
compounds 6a–6c and 7.
H
N
N
R
HN
N
R
N
N
N
O
N
N
O
N
Compound
R
MIC (μM)
3a
3b
3c
3d
3e
3f
Phenyl
4-Nitrophenyl
2,4-Dimethoxyphenyl
2,6-Dimethylphenyl
2-Nitro-4-hydroxyphenyl
4-Chloropyridin-2-yl
>200
>200
>200
>200
12.5
Compound
R
MIC (μM)
CN
6a
>200
H
N
>200
Table 3. Chemical structures and antitubercular activities of
compounds 4 and 5a–5d.
CN
H
HN
N
R
6b
6c
>200
50
N
N
O
N
OH
O
H
N
N
N
Compound
R
MIC (μM)
4
-NH2
200
H
O
7
100
N
S
O
N
5a
5b
>200
>200
NO2
H
O
S
N
Various substitutions (-Br, -Cl, -methoxy, -ethoxy, -amino)
at the 4 position of phenyl group of 5-phenyl-1,2,4-triazole-3-
amino moiety showed no activity. Only 4-F compounds (1b
and 2b) showed mild activity with an MIC value 200 μM.
Compounds 1e, 1f, 1 m, and 1n having 2-methoxy, 2-ethoxy,
3-methoxy, or 3-ethoxy substituents on the ring, respectively,
showed mild activity with MIC values of 100 μM. The activity
of 5-biphenyl-1,2,4-triazole compounds is shown in Table 2.
Only one compound, 3e, which has 2-nitro-4-hydroxy phenyl
group in its 1,2,4-triazole-3-amino moiety, exhibited the anti-
tubercular activity with an MIC value 12.5 μM and it was the
highest among the synthesized compounds. The other active
compound 8d, with an MIC value of 12.5 μM, has a 3,4-
nitro-phenyl group in its structure. However, compounds
3b, 5a, and8a, whichhave4-nitrophenylgroupinitsstructure,
showed no activity. This result suggests that 1,2,4-triazole-3-
amine derivatives need a 2-nitro or 3-nitro group in their
O
O
H
O
N
S
O
5c
100
N
H
O
N
S
S
O
5d
>200
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KOREAN CHEMICAL SOCIETY
Conclusion
Table 5. Chemical structures and antitubercular activities of
compounds 8a–8e.
In this study, a series of 1,2,4-triazole-3-amine derivatives
were synthesized and evaluated for their antitubercular activ-
ity. Compounds 3e and 8d appeared to be most potent (MIC
12.5 μM) among the synthesized compounds. These com-
pounds have common characteristics in that 2-nitro or 3-nitro
groups are present in the structures. These results indicate that
compounds 3e and 8d can be used as model compounds for
further development of new antitubercular drugs which have
1,2,4-triazole moieties.
HN
N
R
N
O
N
O
N
Compound
R
MIC (μM)
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KOREAN CHEMICAL SOCIETY
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