Synthesis and biological evaluation of substituted 4,6-diarylpyrimidines and 3,5-diphenyl-4,5-dihydro-1H-pyrazoles as anti-tubercular agents

Article abstract of DOI:10.1016/j.bmcl.2014.04.094

Various substituted 4,6-diarylpyrimidin-2-amine (4), 4,6-diaryl-2- (heteroaryl)pyrimidine (6) and 1-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl) ethanone (7) derivatives were synthesized in good yields using simple methodology. The synthesized compounds (4-7)

Full text of DOI:10.1016/j.bmcl.2014.04.094

Accepted Manuscript
Synthesis and biological evaluation of substituted 4,6-diarylpyrimidines and
3,5-diphenyl-4,5-dihydro-1H-pyrazoles as anti-tubercular agents
Vinay Pathak, Hardesh K. Maurya, Sandeep Sharma, Kishore K Srivastava, Atul
Gupta
PII:
S0960-894X(14)00451-X
http://dx.doi.org/10.1016/j.bmcl.2014.04.094
BMCL 21587
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 February 2014
7 April 2014
23 April 2014
Please cite this article as: Pathak, V., Maurya, H.K., Sharma, S., Srivastava, K.K., Gupta, A., Synthesis and biological
evaluation of substituted 4,6-diarylpyrimidines and 3,5-diphenyl-4,5-dihydro-1H-pyrazoles as anti-tubercular
agents, Bioorganic & Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.04.094
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Bioorganic & Medicinal Chemistry Letters - (2014) -–-
Synthesis and biological evaluation of substituted 4,6-diarylpyrimidines and 3,5-diphenyl-4,5-dihydro-
1H-pyrazoles as anti-tubercular agents
Vinay Pathaka, Hardesh K. Mauryaa, Sandeep Sharmab, Kishore K Srivastavab, Atul Guptaa,*
a Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Kukrail Road, Lucknow-226015, India
b Division of Microbiology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow 226 031, India
ARTICLE INFO
ABSTRACT
Various substituted 4,6-diarylpyrimidin-2-amine (4), 4,6-diaryl-2-(heteroaryl)pyrimidine (6) and 1-(3,5-diaryl-4,5-dihydro-1H-
pyrazol-1-yl)ethanone (7) derivatives were synthesized in good yields using simple methodology. The synthesized compounds (4-
7) were evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain. Compounds 4a, 6b,
7b, and 7c exhibited significant anti-tubercular activity at MIC values 25, 25, 12.5 and 12.5 µM concentration. In vitro cytotoxicity
data using non cancerous hepatic monocytes (THP-1) cells indicated that most active compounds 7b and 7c were safe as their MIC
values were much lower than their cytotoxic values.
Article History
Received
Revised
Accepted
Available Online
Keywords
4,6-diarylpyrimidine
pyrazole
©2014 Elsevier Ltd. All rights reserved
anti-tubercular
H37Rv
THP-1 cells
Tuberculosis (TB) remains a major global health problem as per
eighteenth global report on tuberculosis (TB) published by WHO in
2013.1 According to this report, an estimated 8.6 million people
developed TB and 1.3 million died from the disease in 2012. The
majority of cases worldwide in 2012 were in the South-East Asia (29%),
African (27%) and Western Pacific (19%) regions. India and China
alone accounted for 26% and 12% of total cases, respectively. 1
HO
O
O
OH
O
O
NHNH2
S
NH2
OH
O
NH
H3CO
H2
N
OH
OH
O
OH
HO
HO
HO
NH2
N
N
N
O
NH
OH
N
O
O
H3C
NH2
N
ethionamide (iv)
OHC
Isonizid (iii)
O
O
CH3
NH2
N
OH
OH
Globally in 2012, data from drug resistance surveys and continuous
surveillance among notified TB cases suggest that 3.6% of newly
diagnosed TB cases and 20% of those previously treated for TB had
MDR-TB. 84,000 people with confirmed MDR-TB (i.e. resistance to
both rifampicin, the most powerful TB drug and isoniazid), plus 10,000
with rifampicin resistance detected using Xpert MTB/ RIF. The largest
increases between 2011 and 2012 were in India, South Africa and
Ukraine.1 Thus, as resistant strains of Mycobacterium tuberculosis
(MTB) have slowly emerged; treatment failure is a main reality.
However, various drugs such as streptomycin (i), rifampicin (ii),
isoniazid (iii), ethionamide (iv), ethambutol (v) and pyrazinamide (vi)
etc (Fig. 1) are used for the treatment of TB. Since, these drugs are
taking more than six month treatment; therefore, there is a need for
regular efforts to search new chemical entities which can serve better
treatment against tuberculosis. Some nitrogenous derivatives such as
pyrimidine and pyrazole analogs (vii & viii) are reported to be highly
effective against Mycobacterium tuberculosis in in vitro model at 0.78
and 0.35 µg/mL concentration respectively (Fig. 1).2
N
Streptomycin (i)
Rifampicin (ii)
Cl
F
O
O
N
OH
CN
NH2
O
N
H
N
N
N
Et
N
Cl
F
S
N
Et
N
H
N
NH
N
H
N
F
OH
Pyrazinamide (vi)
Chloropyrimidine (vii)
Pyrazole analog (viii)
Ethambutol (v)
Figure 1. Lead anti-tubercular agents
In the recent past, 2-amino-4,6-diarylpyrimidine derivatives3-5 have
been reported to exhibit diverse biological activities such as
antiplatelet,3 reverse-transecriptase inhibitory,4 antifungal and
antibacterial activities5 whereas another nitrogenous molecule, 3,5-
diaryl-1H-pyrazole derivatives6-7 have presented potential aryl-N-
acetyltransferase inhibitory6 and cytotoxic activities.7 Recently, we
could explore the anti-tubercular activity of conformationally rigid 2-
amino-4,6-diarylpyrimidine (ix)8
derivatives (x)8 on cyclic framework, Fig. 2.
and 3,5-diaryl-1H-pyrazole
On the other side, structure activity relationship (SAR) study of some
biologically active natural products such as combretastatin (xi),7,9
phenastatin (xii)9 and podophyllotoxin (xiii)9 revealed that
________________
Corresponding author. Tel.:+91-522-2718556, E-mail:atisky2001@yahoo.co.in

trimethoxyphenyl group present in these molecules is mainly
responsible for their potent cyctotoxic activity,9 Fig. 2.
In our strategy to see the effect of size of pyrimidine ring on
biological efficacy of compound 4 and 6, we further synthesized 1-(3,5-
diaryl-4,5-dihydro-1H-pyrazol-1-yl)ethanone (7) from the reaction of
chalcones (3) with hydrazine hydrate in presence of acetic acid at reflux
temperature following reported methods which yielded desired
compounds 52-72% in yield as shown in Scheme 3 (Table 1).11-15
Figure 2.
Scheme 3. Synthesis 1-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)ethanone (7)16
Table 1. Structure, melting point and yield of synthesized compounds16
Inspired from our previous findings on
2-amino-4,6-
diarylpyrimidine8 and 3,5-diaryl-1H-pyrazole fragment containing
molecules8 and observed impact of trimethoxyphenyl group on
biological cytotoxic activities,9 we further designed some 2-amino-4,6-
diarylpyrimidine derivatives (4 and 6) and 3,5-diaryl-1H-pyrazole
derivatives (7) as potential anti-tubercular agents. The proposed
molecules will have a trimethoxyphenyl fragment (phenyl ring B of 4,
scheme 1) to important cytotoxic activity, along with a diatomic five and
six member heterocyclic ring.
Com. Structure
Mp (oC)
Yield (%)
4a10
173-174
66
4b10
4c10
4da
155-156
149-150
133-134
64
53
51
In our approach, synthesis of target molecules was started using 1-
arylethanone (1) and arylaldehyde (2) as starting materials following
reported procedure.10 Reaction of 1 with arylaldehyde (2) using base
KOH in methanol with stirring for 24-25 h at room temperature
produced chalcones (3) in 67-85 % yields. Chalcones (3) on further
reaction with guanidine hydrochloride in the presence of sodium hydride
and DMF at reflux temperature gave 4,6-diarylpyrimidin-2-amines (4)
in 51-66 % yield, Scheme 1.
202-203
175-176
189-190
55
57
62
4e
4f
4ga
152-153
67-68
37
35
45
6a
6b
6c
Scheme 1. Synthesis of 4,6-diarylpyrimidin-2-amines (4)16
In anticipation to study structure activity relationship (SAR) of 4,6-
diarylpyrimidin-2-amines (4), we have also synthesized novel 4,6-
diaryl-2-(heteroaryl)pyrimidine (6) from chalcone (3) and
heteroarylamidines (5) in the presence of sodium hydride and DMF at
reflux temperature in 35 to 45 % yield as shown in Scheme 2 (Table 1).
185-186
172-173
39
6d
6e
248-249
148-149
40
56
O
N
N
7a11,12
Scheme 2. Synthesis of 4,6-diaryl-2-(heteroaryl)pyrimidine (6)16
OMe
OMe
MeO
OMe
2

anti-tubercular activity at MIC 25 and 50 µM respectively while
compounds 4e, 4f and 4d were inactive at 100 µM concentration (MIC
value).
7b11,13
143-144
63
The 2-heteroaryl substituted 4,6-diaryl-pyrimidine derivatives, 6a and
6b exhibited considerable anti-tubercular activity at MIC 25 and 100
µM respectively. However, compounds 6c, 6d and 6e in this series were
found to be inactive at 100 µM concentrations (MIC value).
Similarly, the 3,5-diarylpyrazole derivatives, 7a, 7b and 7c exhibited
significant anti-tubercular activity at MIC 50, 12.5 and 12.5 µM
respectively whereas compounds 7e and 7f were found active at MIC
100 µM and 7d was found inactive at 100 µM.
7c11
141-142
163-164
52
72
7d
Structure activity relationship (SAR) of compounds 4-7 revealed that
in case of 4,6-diarylpyrimidine derivatives 4 and 6, methoxy group in
phenyl ring A of 4,6-diarylpyrimidin-2-amines (e.g. 4a, Scheme 1) had
impact on anti-tubercular activity. Additional methoxy group in phenyl
ring A or replacement of methoxy groups by methylenedioxy brought
decline in biological activity of compounds. Similarly, replacement of
methoxy group of phenyl ring A of 4a by halogen atoms (F, Cl, and Br)
attenuated anti-tubercular activity. Further, substitution of 2-amino
group of 4a by pyridinyl fragment such as pyridin-2-yl, pyridin-3-yl and
pyridin-4-yl could not bring further enhancement in biological activity
of compound 4a.
The biological activity of compounds 7a-f showed that ring
contraction of pyrimidine ring of 4,6-diarylpyrimidine derivatives 4a-c
and 4e-g had incremental effect on their anti-tubercular activity e.g.
compounds 7b, 7c, 7e and 7f had better activity over compound 4b, 4c,
4f and 4g. Interestingly, in contrast to compound 4a, replacement of
methoxy group in phenyl ring A of 7a (Scheme 3) by halogen atoms (F,
Cl and Br) had profound effect on its anti-tubercular activity.
In view of good anti-tubercular activity of compounds 4a-b, 6a-b,
7a-c and 7e-f, their cytoxicity was evaluated in vitro using MTT assay
in non cancerous hepatic monocytes (THP-1) cells.9 In this assay,
cytotoxicity concentration (CC50) values of 4a-b, 7b-c was 100 µM and
compounds 6a, 7a, 7e-f had 200 µM (Table 2). However, compound 6b
presented CC50 value of 50 µM.
7e14
141-142
119-120
65
64
7f15
a Commercially available
The synthesized compounds were characterized by the use of
different spectroscopic techniques viz NMR (1H NMR, 13C NMR, Dept
135), IR and mass spectrometry.16
Compounds 4, 6 and 7 (Table 1) were evaluated for their anti-
tubercular activity against Mycobacterium tuberculosis H37Rv strain
using micro plate alamar blue assay (MABA) and results are reported in
Table 2. Out of eighteen compounds viz 4a-g, 6a-e and 7a-f with high
log p values, eleven compounds 4a-d, 6a-b, 7a-c and 7e-f were found to
be active (Table 2). In order to assess lipophilic nature of compounds
and compare it with standard anti-tubercular drugs, their lipophilicity
was calculated using ChemBioDraw Ultra 11.0 which is expressed in
the terms log P value, Table 2.
Table 2.
In vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain using
micro plate alamar blue assay (MABA) and in vitro cytotoxicity in THP-1 cells (CC50
)
Compounds
Log Pa
MIC (µM)
CC50 (µM)
Since, theoretically, MIC values are approximately double of IC50
values therefore considering the in-vitro anti-tubercular and cytotoxic
activities of compounds (MIC Vs IC50 values), the most active
compound 7b and 7c are considered to be eight times selective towards
tubercular Vs healthy cells whereas compound 4a and 7a are four times
selective with significant high log p values and were found to be safe
with respect to their MIC values.
In conclusion, we have synthesized trimethoxy benzene moiety
containing diarylpyrimidin-2-amine derivatives (4 and 6) and 1-(3,5-
diaryl-4,5-dihydro-1H-pyrazol-1-yl)ethanone (7) in moderate to good
yields. Compounds 4a, 6b, 7b and 7c exhibited significant anti-
tubercular activity at MIC values 25, 25, 12.5 and 12.5 µM
concentration respectively in in vitro assay against Mycobacterium
tuberculosis H37Rv strain. The biological activity profile of most active
derivatives 7b and 7c showed significant anti-tubercular activity with
eight times selectivity towards tubercular Vs healthy cells and safe with
respect to their MIC values.
3.50
4.45
25
50
100
100
4a
4b
4c
4d
4e
4f
4.18
3.78
3.25
3.40
3.66
5.02
5.44
5.02
4.77
4.93
2.34
2.09
3.02
2.09
2.25
2.50
-0.60
2.61
-4.11
4.74
3.40
50
-
50
-
>100
>100
>100
100
25
-
200
-
4g
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
7f
200
50
-
>100
>100
>100
50
-
400
200
100
100
200
200
200
-
Overall, out of three pharmacophores studied viz 4, 6 and 7,
diarylpyrazole derivatives (7) have further scope for investigation as
novel anti-tubercular agents for better treatment of MTB.
12.5
12.5
>100
100
100
0.2
Acknowledgements
A.G. and V.P. acknowledge the financial support received from CSIR-
CIMAP networking project (BSC-203). H.K.M. acknowledges DST,
New Delhi, India for financial support as DST fast track young scientist
fellowship [No. SR/FT/CS-20/2011]. Authors are also thankful to
Director, CSIR-CIMAP and CSIR-CDRI for their support.
Isonizid8
Rifampicin8
2.0
-
Streptomycin8
vii (Fig. 1)2a
viii (Fig. 1)2b
6.0
-
Supplementary data
0.78 b
0.35 b
-
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.bmcl.............These data
include experimental methods, spectral data and scan copy of some
compounds, MOL files and InChiKeys of compounds described in this
article.
-
aliphophilicity was calculated using ChemBioDraw Ultra 11.0, b µg/mL
The anti-tubercular activity results of synthesized compounds (4-7)
revealed that 4,6-diarylpyrimidin-2-amines, 4a and 4b-d exhibited good
3

(CH), 153.88 (2xAr), 163.81, 189.09 (C=O); MS (C19H20O5): 329 [MH+].
References and Notes
b) 4,6-diarylpyrimidin-2-amines (4): In a 50 mL R.B. flask, chalcone (3, 2.0 mmol)
and guanidine hydrochloride (4.0 mmol) in the presence of base NaH (3.0 mmol)
were stirred in DMF (20 ml) at 160-170 oC. After the completion of reaction,
mixture was diluted with water and extracted with ethyl acetate. The organic layer
was separated, dried over anhydrous sodium sulphate and concentrated to give crude
material which on column chromatography on basic alumina using chloroform in
hexane (40 to 50%) as eluent gave desired compound (4). 4-(benzo[d][1,3]dioxol-5-
yl)-6-(4-methoxyphenyl)pyrimidin-2-amine (4g): Pale yellow solid; yield 62%; Rf:
0.5 (10% methanol in CHCl3 ); mp 189-190 oC; IR (KBr, νmax/cm-1): 3361.92 (NH2);
1H NMR (CDCl3+DMSO-d6, 300 MHz, δ ppm): 3.80 (s, 3H, OCH3), 5.57 (s, 2H,
NH2), 5.97 (s, 2H, CH2), 6.84 (d, J=8.1 Hz, 1H, Ar-H), 6.92 (d, J=8.7 Hz, 2H, Ar-H
), 7.25 (s, 1H, CH), 7.53-7.58 (m, 2H, ArH), 7.98 (d, 2H, J=8.7, ArH); 13C NMR
(CDCl3+DMSO-d6, 75 MHz, δ ppm): 54.54 (OMe), 100.65 (OCH2), 101.23 (ArH),
106.42 (CH) 107.45 (ArH), 113.16 (2xArH), 120.68 (ArH), 127.71 (2xArH), 129.24,
131.22, 147.33, 148.69, 160.69, 162.83, 164.00, 164.30; MS (C18H15N3O3): 322.2
[MH+].
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c) 4,6-diarylpyrimidin-2-amines (6): In a 50 mL R.B. flask, chalcone (3, 2 mmol)
and amidine ( 5, 2 mmol) in the presence of base NaH (3 mmol) were stirred in DMF
(10 ml) at 135-140 oC. After the completion of reaction, reaction mixture was poured
in cold water with vigorous stirring and neutralized it with N/5 HCl solution. The
precipitate was filtered and dried. The crude was purified by column
chromatography with a mixture of chloroform-methanol to give the desired product
6. 4-(4-methoxyphenyl)-2-(pyridin-3-yl)-6-(3,4,5-trimethoxyphenyl)pyrimidine (6a):
creamy solid; Rf: 0.7 (EtOAc); mp 152-153 oC; 1H NMR (CDCl3, 300 MHz, δ ppm):
3.91 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.02 (s, 6H, 2xOCH3), 7.75 (d, J=9.0 Hz,
2H, ArH), 7.44-7.48 (m, 1H, ArH), 7.50 (s, 2H, ArH), 7.70 (s, 1H, ArH), 8.25 (d,
J=9.0 Hz, 2H, ArH), 8.72-8.75 (m, 1H, ArH), 8.89-8.92 (m, 1H, ArH), 9.87 (s, 1H,
ArH); 13C NMR (CDCl3, 75 MHz, δ ppm): 55.85 (OMe), 56.81 (2xOMe), 61.40
(OMe) 105.03 (2xArH), 109.98 (ArH), 114.73 (2xArH), 123.66 (ArH), 129.20
(2xArH), 129.83, 133.05, 134.05, 136.00 (ArH), 141.24, 150.56 (ArH), 151.57
(ArH), 154.05 (2xAr), 162.56, 162.87, 164.60, 164.75.; MS (C25H23N3O4) : 430.3
[MH+].
8. Maurya, H. K.; Verma, R.; Saba, A.; Pandey, S.; Pathak, V.; Sharma, S.; Srivastava,
K. K.; Negi, A. S.; Gupta, A. Bioorg. Med. Chem. Lett. 2013, 23, 5844.
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Rao, S. S.; Gahlot, U. S.; Dulawat, S. S.; Vyas, R.; Ameta, K. L.; Verma,
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(a) Nepali, K.; Kadian, K.; Ojha, R.; Dhiman, R.; Garg, A.; Singh, G.;
Buddhiraja, A.; Bedi, P. M. S.; Dhar, K. L. Med. Chem. Res. 2012, 21, 2990; (b)
Nepali, K; Singh, G.; Turan, A.; Agarwal, A.; Sapra, S.; Kumar, R.; Banerjee, U. C.;
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Rostom, S. A. F.; Badr, M. H.; Abd El Razik, H. A.; Ashour, H. M. A.;
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d) 1-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)ethanone (7): In a 50 mL R.B. flask,
chalcone (3, 1.5 mmol) and hydrazine hydrate ( 7.5 mmol) were stirred in acetic acid
(20 mL) at 133-140 oC. On completion of the reaction, mixture was diluted with
water and extracted with ethyl acetate. The organic layer was separated, dried over
anhydrous sodium sulphate and concentrated to give crude material which on
column chromatography on basic alumina using chloroform in hexane (40-50%) as
eluent gave desired compound 7. 1-(3-(benzo[d][1,3]dioxol-5-yl)-5-(4-
methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (7f): white solid; yield 64%;
Rf: 0.64 (10% methanol in CHCl3 ); mp 119-120 oC; IR (KBr, νmax/cm-1): 1646
(C=O); 1H NMR (CDCl3, 300 MHz, δ ppm): 2.40 (s, 3H, CH3), 3.11 (dd, J=4.5 &
17.7 Hz, 1H, CH2), 3.64-3.73 (m, 1H, CH), 3.79 (s, 3H, OCH3), 5.54 (dd, J=4.2 &
11.4 Hz, 1H, CH), 6.04 (s, 2H, CH2), 6.83-6.87 (m, 3H, ArH), 7.10-7.19 (m, 3H,
ArH), 7.28 (s, 1H, ArH); 13C NMR (CDCl3, 75 MHz, δ ppm): 22.34 (CH3) , 42.79
(CH2), 55.67 (OCH3), 55.83 (CH), 101.94 (OCH2), 106.62 (ArH), 108.63, 114.63
(2xArH), 121.99 (ArH), 126.25, 127.31 (2xArH), 134.56, 148.62, 149.94, 153.84,
159.42, 169.03 (C=O); MS (C19H18N2O4): 339 [MH+].
16. a) Representative procedure for synthesis of chalcone (3): 1-arylethanone (1, 10
mmol) and arylaldehyde (2, 10 mmol) in the presence of base KOH (30 mmol) were
stirred in methanol (50 mL) for 24 h at room temperature. After the completion of
reaction, methanol was distilled and the crude was diluted with ethyl acetate and
extracted with water. The organic layer was separated, dried over anhydrous sodium
sulphate and concentrated to give crude material which on recrystallized with
methanol to give desired compound (3) in 70-80 % yields. 1-(4-methoxyphenyl)-3-
(3,4,5-trimethoxyphenyl)prop-2-en-1-one (3a): yellow solid; yield 83%; Rf: 0.34
(30% EtOAc in Hexane); mp 131-132 oC; IR (KBr, νmax/cm-1): 1656 (C=O), 1H NMR
(CDCl3, 300 MHz, δ ppm): 3.87 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.89 (s, 6H,
2xOCH3), 6.85 (s, 2H, ArH), 6.97 (d, 2H, J=9.0 Hz, ArH), 7.36 (d, J=15.6 Hz, 1H,
CH ), 7.65 (d, J=15.3 Hz, 1H, CH), 8.02 (d, J=9.0 Hz, 2H, ArH); 13C NMR (CDCl3,
75 MHz, δ ppm): 55.89 (OCH3), 56.63 (2xOCH3), 61.39 (OCH3), 106.02 (2xArH),
114.24 (2xArH), 121.66 (CH), 130.99, 131.20 (2xArH), 131.54, 140.71, 144.53
4

Graphical Abstract
5