Thiazolyl-pyrazole derivatives as potential antimycobacterial agents

Article abstract of DOI:10.1016/j.bmcl.2019.03.020

Mycobacterium tuberculosis (Mtb) is an obligate aerobe that is capable of long-term persistence under conditions of low oxygen tension. A series of thiazolyl-pyrazole derivatives (6a–f, 7a–f, 8c, 8e) were screened for antimycobacterial activity against dormant M. tuberculosis H37Ra (D-MTB) and M. bovis BCG (D-BCG). Nine thiazolyl-pyrazole analogs, 6c, 6e, 7a, 7b, 7c, 7e, 7f, 8c and 8e exhibited promissing minimum inhibitory concentration (MIC) values (0.20–28.25 μg/mL) against D-MTB and D-BCG strains of Mtb. Importantly, six compounds (7a, 7b, 7e, 7f, 8c and 8e) exhibited excellent antimycobacterial activity and low cytotoxicity at the maximum evaluated concentration of >250 μg/mL. Finally, the promising antimycobacterial activity and lower cytotoxicity profile suggested that, these compounds could be further subjected for optimization and development as a lead, which could have the potential to treat tuberculosis.

Full text of DOI:10.1016/j.bmcl.2019.03.020

Accepted Manuscript
Thiazolyl-pyrazole derivatives as potential antimycobacterial agents
Sushma J. Takate, Abhijit D. Shinde, Bhausaheb K. Karale, Hemant Akolkar,
Laxman Nawale, Dhiman Sarkar, Pravin C. Mhaske
PII:
S0960-894X(19)30159-3
https://doi.org/10.1016/j.bmcl.2019.03.020
BMCL 26334
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
31 January 2019
17 March 2019
18 March 2019
Please cite this article as: Takate, S.J., Shinde, A.D., Karale, B.K., Akolkar, H., Nawale, L., Sarkar, D., Mhaske,
P.C., Thiazolyl-pyrazole derivatives as potential antimycobacterial agents, Bioorganic & Medicinal Chemistry
Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.03.020
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Thiazolyl-pyrazole derivatives as potential antimycobacterial agents
a
b
c
c
d
Sushma J. Takate, * Abhijit D. Shinde, Bhausaheb K. Karale, Hemant Akolkar, Laxman Nawale, Dhiman
d
b
Sarkar, Pravin C. Mhaske *
aPost-Graduate Department of Chemistry and Research Centre, New Arts, Commerce and Science College,
Ahmednagar, India 414001, (Affiliated to Savirtibai Phule Pune University)
bPost Graduate Department of Chemistry, S. P. Mandali’s Sir Parashurambhau College, Tilak Road, Pune,
India 411 030, (Affiliated to Savirtibai Phule Pune University)
cDepartment of Chemistry, Rayat Shikshan Santhsa’s Radhabai Kale Mahila Mahavidyalya, Ahmednagar,
India 414001, (Affiliated to Savirtibai Phule Pune University)
dCombiChemBio Resource Centre, National Chemical Laboratory, Pune 411 008, India
Fax: 91-020-24332479; Tel: 91-020-24331978; E-mail: mhaskepc18@gmail.com, sjtakate26@gmail.com
Abstract
Mycobacterium tuberculosis (Mtb) is an obligate aerobe that is capable of long-term persistence
under conditions of low oxygen tension. A series of thiazolyl-pyrazole derivatives (6a-f, 7a-f, 8c,
8
e) were screened for antimycobacterial activity against dormant M. tuberculosis H37Ra (D-MTB)
and M. bovis BCG (D-BCG). Nine thiazolyl-pyrazole analogs, 6c, 6e, 7a,7b, 7c, 7e, 7f, 8c and 8e
exhibited promissing minimum inhibitory concentration (MIC) values (0.20-28.25 µg/mL) against
D-MTB and D-BCG strains of Mtb. Importantly, six compounds (7a, 7b, 7e, 7f, 8c and 8e)
exhibited excellent antimycobacterial activity and low cytotoxicity at the maximum evaluated
concentration of >250 µg/mL. Finally, the promising antimycobacterial activity and lower
cytotoxicity profile suggested that, these compounds could be further subjected for optimization
and development as a lead, which could have the potential to treat tuberculosis.
Keywords: Thiazoles, Pyrazole, Antimycobacterial activity, Cytotoxicity.
Mycobacterium tuberculosis (Mtb) is among the most challenging bacterial infections declared by
1
World Health Organization (WHO). In 2016, WHO projected that globally 10.4 million people
were diagnosed by TB and 1.7 million died from the disease. Amongst these, more than 95% of
1
TB deaths occur in low- and middle-income countries. Even with the availability of first line and
second line anti-TB drugs and the Bacille-Calmette-Guérin (BCG) vaccine, WHO estimated that
there were 6 lakhs new cases with resistance to Rifampicin (the most effective first-line drug), of
1
,2
which 4.9 lakhs had MDR-TB. Due to spontaneous mutations in genes of the pathogenic strains,
1

there are increasing reports of multi-drug resistant tuberculosis (MDR-TB) and the extensively
drug resistant tuberculosis (XDR-TB).3,4 This increase in antibiotic resistance has encouraged the
search for new compounds, which can be termed as active against both the acute as well as chronic
forms of tuberculosis.5-8
The hybrid architecture of two or more bioactive pharmacophore scaffolds is one of the
9
powerful tools used in the new drug discovery. In recent years, the thiazole ring clubbed with
1
0
other azole rings are privileged scaffolds for the generation of new lead molecules. The synthesis
of thiazole and pyrazole nucleus containing heterocycles have received considerable notice due to
their promising antimycobacterial activity (Figure 1). The large number of natural products and
1
1
synthetic compounds containing thiazole ring are reported for promising antibacterial, antitumor,
antimalarial and antiviral activities.12,13 Thiazole and its derivatives are important structures in
medicinal chemistry that are capable of producing a rich spectrum of biological activities such as
antimycobacterial,14-21 antimicrobial,22-29 anti-inflammatory,30-33 antiviral, CNS active agents,
34
35
and anticancer activities.36,37 Pyrazole nucleus containing compounds are reported for
antitubercular, anticancer, anti-inflammatory antipyretic and antimicrobial activities.38-42 Further
chalcones derived from thiazole and pyrazole are also known for their antitubercular and
antimicrobial activity.43-46 Thiazole clubbed with pyrazole have displayed antitubercular,10,47-48
anti-inflammatory and antimicrobial49-51 activities. Chromone derivatives are reported for potential
antimycobacterial activity.52-54 These reports facilitated the structural diversity and biological
importance of thiazole and pyrazole, which have made them attractive targets for synthesis.
F
R
O
CH3
N
C2H5
N
N
H
S
R2
Ar
S
NH
S
N
N
R
R1
N
N
O
R
N
N
H
N
N
N
O
R
N
Ph
N
S
N
O
R2
CH3
S
CH3
HO
N
N
N
F
H C
3
N
N
N
S
NH
Ar
N
N
H C
3
S
N
H
N
S
F
Figure 1: Thiazole and pyrazole derivatives as antitubercular agents.
2

Keeping in mind, the biological significance of thiazole and pyrazole derivatives and in
continuation of our search for new antitubercular agents,14-17,31 we report herein the clubbed
thiazolyl-pyrazole derivatives as potential antimycobacterial agents.
The synthesis of 1-(substituted phenyl)-3-(3-(2,4-dimethylthiazol-5-yl)-1-(4-fluorophenyl)-
1
3
H-pyrazol-4-yl)prop-2-en-1-one, 6a-f and 2-(3'-(2,4-dimethylthiazol-5-yl)-1'-(4-fluorophenyl)-
,4-dihydro-1'H,2H-[3,4'-bipyrazol]-5-yl)phenol, 7a-f (scheme 1) were achieved as per our
5
1
previous report. 1-(2,4-Dimethylthiazol-5-yl)ethanone, 3 on condensation with 4-fluorophenyl
hydrazine in EtOH followed by reaction with DMF-POCl in DMF resulted the formation of 3-
3
(2,4-dimethylthiazol-5-yl)-1-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde, 4. Aldehyde 4 on
condensation with 2-hydroxyacetophenones, 5a-f furnished 3-(3-(2,4-dimethylthiazol-5-yl)-1-(4-
fluorophenyl)-1H-pyrazol-4-yl)-1-(2-hydroxyphenyl)prop-2-en-1-one derivatives, 6a-f. Chalcones
6
a-f on cyclization reaction with hydrazine hydrate in absolute ethanol furnished 2-(3'-(2,4-
dimethylthiazol-5-yl)-1'-(4-fluorophenyl)-3,4-dihydro-1'H,2H-[3,4'-bipyrazol]-5-yl)phenols,7a-f.
CH3
H N
2
CHO
N
F
1.
HN
CH3
S
O
O
H C
3
DMF,
rt, 6h
S
EtOH, reflux
N
N N
+
H C
NH2
H C
3
CH3
3
O
S
Br
H C
2. DMF-POCl3, DMF,
0 oC-rt, 6h
3
1
2
3
4
F
R1
R2
R3
OH
EtOH, KOH
rt, 48h
CH3
R4
O
F
F
5
a-f
Compound R1 R2 R3 R4
R1
R2
OH
O
5,6,7a
5,6,7b
5,6,7c
5,6,7d
5,6,7e
5,6,7f
H
H
H
Cl
H
H
H
H
H
H
Br
Cl
H
H
N
NH NH H O
N
N
2
2. 2
R1
OH
N
Me H
EtOH, reflux, 2h
R3
R2
CH3
NH
R4
Cl
H
H
N
S
S
H C
3
Me Cl
R3
R4
N
N
Me Cl Me
CH3
H C
3
6a-f
7
a-f
Scheme 1: Synthetic route of compounds 6a-f and 7a-f
3

The thiazolyl-pyrazole chalcones 6c and 6e showed good anti-tubercular activity and were
further cyclized to chromen-4-one derivatives 8c and 8e, respectively (Scheme 2).
CH3
N
CH3
N
H C
3
H C
3
S
S
O
N
N
O
DMSO / I2
reflux
N
N
O
R3
R3
F
HO
R2
R2
2
3
2
3
8c: R = H, R = Me
6
c: R = H, R = Me
F
2
3
2
3
8e: R = Me, R = Cl
6
e: R = Me, R = Cl
Scheme 2: Synthetic route of chromen-4-one derivatives 8c and 8e
The synthesized thiazolyl-pyrazole derivatives were screened for in vitro antimycobacterial
activity against avirulent strain of D-MTB (ATCC 25177) and D-BCG (ATCC 35743) in liquid
medium. The convincing antimycobacterial activity of thiazolyl-pyrazole compounds in our
preliminary screen studies (Table S1) leads us to determine minimum inhibition concentration
(MIC). To investigate this class of compounds further, we screened thirteen thiazolyl-pyrazole
analogs for inhibition of D-MTB and D-BCG growth in MIC by using an established XTT
Reduction Menadione assay (XRMA) method.55-58 The MIC of anti-TB drug, Rifampicin was
determined by using the XRMA method and this was used as a reference. The result of
antimycobacterial activity is presented in Table 1 and Table S2 (IC and MIC).
5
0
4

Table 1: In vitro-ex vivo antimycobacterial activity expressed by MIC in µg/mL (µM) of
compounds 6a-f, 7a-f, 8c and 8e against two strains of Mtb
F
CH3
N
CH3
N
H C
3
H C
3
S
S
O
N
N
O
N
R4
N
R1
OH
N
N
O
R3
R3
R2
F
HO
NH
N
S
R2
R2
R3
R4
N
R1
F
6
a-f
7a-f
8c and 8e
Comp. R1 R2 R3 R4 Ex vivo (D-MTB)
In vitro (D-MTB)
MICc
In vitro (D-BCG)
MICc
MICc
6
a
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
Br
Cl
H
H
H
H
H
>30
>30
>30
6
b
>30
>30
>30
6
c
Me
Cl
7.43(17.14)
>30
14.13(32.69)
>30
7.01(16.17)
>30
6
d
6
e
Me Cl
3.54(7.56)
23.24(49.66)
>30
3.21(6.85)
>30
6
f
Me Cl Me >30
7
a
H
H
H
H
Br
Cl
H
H
H
H
H
1.51(2.95)
0.7(1.50)
14.95(33.41)
ndb
2.96(5.79)
1.16(2.48)
20.76(46.38)
nd
0.20(0.39)
0.72(1.54)
28.25(63.12)
nd
7
b
7
c
Me
Cl
7
d
7
e
Me Cl
4.14(8.59)
4.65(9.65)
2.5(5.04)
2.54(5.89)
1.72(3.69)
0.75(0.91)
2.3(4.77)
2.26(4.55)
0.51(1.18)
1.33(2.85)
0.81(0.98)
7
f
Me Cl Me 0.61(1.23)
8
8
c
e
H
Me
H
H
0.53(1.23)
1.37(2.94)
Me Cl
RPa
a
b
c
RP: Rifampicin; nd: Not determined; MIC: minimum inhibitory concentration.
The analysis of antimycobacterial activity data revealed that the thiazolyl-pyrazole
anagoges 6c, 6e, 7a, 7b, 7c, 7e, 7f, 8c and 8e exert a statistically significant 90% decrease in
growth of D-MTB and D-BCG. From the structure activity relationship of compounds 6a-f, 7a-f,
8
c and 8e, it has noticed that substituent like Br, Cl, and CH on phenyl ring significantly influence
3
the antimycobacterial activity.
5

The structure activity relationship reported that, among the thiazolyl-pyrazole chalcone
3
3
3
derivatives 6a-f, compounds 6a (R = Br) and 6b (R = Cl) were inactive. Substitution at R by
methyl group in compound 6c exhibited excellent activity against D-MTB (MIC: 14.13 g/mL)
1
3
and D-BCG (MIC: 7.01 g/mL). Further it was noted that substitution at R and R by chlorine in
2
3
compound 6d, decreased the activity. Substitution at R by methyl and R by chlorine in compound
6
e reported good activity against D-MTB (MIC: 23.24 g/mL) and excellent activity against D-
4
BCG (MIC: 3.21 g/mL) whereas substitution of one more methyl group at R in compound 6f,
decreases the activity.
It was noticed that thiazolyl-bispyrazol derivatives, 7a-f were found to be more potent
3
against both strains of Mtb. Compound 7a (R = Br) has shown excellent activity against D-MTB
with MIC 2.96 g/mL. In addition, against D-BCG the compound 7a was found to be fourfold
3
more activity than Rifampicin with MIC 0.20 g/mL. It was also noticed that when R was
substituted by chlorine in compound 7b, it showed comparable activity against D-MTB (MIC: 1.16
3

g/mL) and D-BCG (MIC: 0.72 g/mL) with respect to the standard drug. Substitution at R by
methyl group in compound 7c showed moderate to good activity against both Mtb strains.
2
3
Compound 7e (R = CH , R = Cl) reported an excellent activity against D-MTB (MIC 4.65
3
g/mL) and D-BCG (MIC 2.3 g/mL). Also, it was noticed that, on substitution of one more
4
methyl group at R in compound 7f, the activity increased against D-MTB by two fold (MIC 2.5
g/mL) and retained against D-BCG (MIC 2.26 g/mL).
From the chromen-4-one derivatives 8c and 8e, compound 8c reported excellent activity
against D-MTB (MIC: 2.54 g/mL) and D-BCG (MIC: 0.51 g/mL). Similarly, compound 8e
reported excellent activity against D-MTB (MIC: 1.72 g/mL) and D-BCG (MIC: 1.33 g/mL).
From compounds 8c and 8e it was observed that in chromen-4-one derivatives, methyl group at R3
2
3
is more potent against D-BCG than the methyl group at R and chlorine at R position.
In sharp contrast, it is worth noting that, cyclization of compounds 6a-f into compounds
7
7
a-f and compounds 8c, 8e enhanced the antitubercular activity; particularly compounds 7a, 7b,
e, 7f, 8c and 8e were found to be the most active derivatives.
The efficacy of thiazolyl-bispyrazol derivatives was also examined with an intracellular
5
7
model of Mtb infection as per protocols reported in literature (Khan et al, 2012). The results
gathered in Table 1 show that lead compounds 7a, 7b, 7e, 7f, 8c and 8e exhibits interesting
6

minimum inhibitory concentration (MIC) values in the range 0.53–4.14ꢀμg/mL in human THP-1
macrophages and was devoid of cytotoxicity in human THP-1 cells (GI : >30 g/mL) (Table S3).
5
0
Interestingly, all lead compounds exert a similar minimum inhibitory effect (D-MTB- ex vivo) on
the antimycobacterial activity (in vitro) of the D-MTB and D-BCG, which also suggests these
compounds showed excellent anti-mycobacterial potential against dormant strains of Mtb.
All compounds were also examined for in vitro cytotoxicity in human cancer cell lines
5
9
(
HeLa, A549 and PANC-1) by the MTT colorimetric assay. The results, expressed as GI /GI
50 90
in the presence of at different concentrations of each compound, are summarized in the Table 2.
Table 2: In vitro cytotoxicity activity of compounds 6a-f, 7a-f, 8c and 8e against three human
cancer cell lines
HeLa (Cervix)
Cell line
A549 (Lung)
Cell line
PANC-1 (Pancreas)
Cell line
Compound
GI50
GI90
GI50
GI90
GI50
GI90
(
µg/mL) (µg/mL)
(µg/mL)
>250
>250
47.77
>250
>250
33.45
81.44
>250
>250
nd
(µg/mL) (µg/mL) (µg/mL)
6
a
4.88
>250
29.88
>250
34.87
59.29
21.62
>250
>250
nd
44.94
>250
77.32
>250
87.29
128.28
43.11
>250
>250
nd
>250
>250
136.87
>250
>250
84.31
154.68
>250
>250
nd
>250
>250
52.41
>250
>250
35.22
76.41
>250
>250
nd
>250
>250
114.87
>250
>250
97.41
115.65
>250
>250
nd
6
b
6c
6
d
6e
6
f
7
a
7
b
7c
7
d
7
7
e
f
>250
25.21
>250
16.68
>100
0.0048
>250
46.87
>250
53.48
>100
0.075
145.68
43.36
>250
>250
>100
0.0035
>250
88.98
>250
>250
>100
0.0706
127.44
41.64
>250
>250
>100
0.1279
>250
77.64
>250
>250
>100
5.715
8
8
c
e
Rifampicin
Paclitaxel
The result of GI and GI (> 250 µg/mL) of compounds 7b, 7c, 7e, 8c and 8e confirmed that
5
0
90
these molecules did not exhibit any significant toxicity effect on the selected cell line.
In this study, the synthesis and the antimycobacterial evaluations of 1-(substituted phenyl)-
7

3
-(3-(2,4-dimethylthiazol-5-yl)-1-(4-fluorophenyl)-1H-pyrazol-4-yl)prop-2-en-1-ones, 6a-f, 2-(3'-
2,4-dimethylthiazol-5-yl)-1'-(4-fluorophenyl)-3,4-dihydro-1'H,2H-[3,4'-bipyrazol]-5-yl)phenols,
a-f, and 2-(3-(2,4-dimethylthiazol-5-yl)-1-(4-fluorophenyl)-1H-pyrazol-4-yl)-4H-substituted
(
7
chromen-4-ones, 8c and 8e were achieved. The cyclization of chalcones 6a-f to pyrazole 7a-f and
chromene-4-ones 8c and 8e enhanced the antimycobacterial activity. These active thiazolyl-
pyrazole derivatives were found to display no manifest cytotoxicity toward HeLa, A549 and
PANC-1 human cells and among them, six compounds (7a, 7b, 7e, 7f, 8c and 8e) exhibited
attractive inhibitory activities against D-MTB and D-BCG strains of Mtb.
Acknowledgments
Authors are thankful to CSIR-NCL, Pune for lending support with their biological activities.
Central Instrumentation facility, Savitribai Phule Pune University, Pune is also acknowledged for
spectral analysis. A D Shinde is grateful to CSIR-for award of JRF, Award No 08/319(0004/)17-
EMR-1.
Conflicts of interest: There are no conflicts to declare
Supplementary data
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1
2

F
F
F
R1
N
N
OH
O
N
R2
R1
R3
OH
R4
N
N
N
R2
R3
O
R2
CH3
R3
CH3
CH3
NH
N
R4
S
S
S
N
N
O
N
7
a-f
6a-f
H3C
H C
H3C
8c and 8e
3
MICµg/mL (µM)
1.16-20.76 (2.48-46.38)
D-BCG M. bovis 0.20-28.25 (0.39-63.12)
MICµg/mL (µM)
14.13-23.24 (32.69-49.66)
3.21-7.01 (6.85-16.17)
MICµg/mL (µM)
1.72-2.54 (3.69-5.89)
0.51-1.33 (1.18-5.85)
D-Mtb H37Ra
6
0.
1
3