Synthesis and anti-TMV activity of novel β-amino acid ester derivatives containing quinazoline and benzothiazole moieties

Article abstract of DOI:10.1016/j.bmcl.2014.05.073

Here, a series of β-amino acid ester derivatives containing quinazoline and benzothiazoles was synthesized and evaluated for anti-tobacco mosaic virus (TMV) activity. The compounds 3n, 3o, 3p and 3q showed good antiviral activity against TMV at a concentration of 500 μg/mL, with curative rates of 55.55%, 52.32%, 52.77% and 50.91%, respectively, and protection rates of 52.33%, 55.96%, 54.21% and 50.98%, respectively. These values were close to those of the commercially available antiviral agent ningnanmycin (which has curative and protection rates of 55.27% and 52.16%, respectively). To our knowledge, this is the first report of the anti-TMV activity of β-amino acid ester derivatives containing quinazoline and benzothiazoles moieties; the results indicate that these novel compounds can potentially be used as protective agents against TMV diseases.

Full text of DOI:10.1016/j.bmcl.2014.05.073

Accepted Manuscript
Synthesis and Anti-TMV Activity of Novel β-Amino Acid Ester Derivatives
Containing Quinazoline and Benzothiazole Moieties
Han Xiao, Pei Li, Deyu Hu, Bao-An Song
PII:
S0960-894X(14)00582-4
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.05.073
BMCL 21687
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 April 2014
19 May 2014
21 May 2014
Please cite this article as: Xiao, H., Li, P., Hu, D., Song, B-A., Synthesis and Anti-TMV Activity of Novel β-Amino
Acid Ester Derivatives Containing Quinazoline and Benzothiazole Moieties, Bioorganic & Medicinal Chemistry
Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.05.073
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Synthesis and Anti-TMV Activity of Novel β-Amino Acid Ester
Derivatives Containing Quinazoline and Benzothiazole Moieties
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Han Xiaoa,b, Pei Lia, Deyu Hua, Bao-An Songa*
aState Key Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Center for Research and Development of Fine Chemicals,
Guizhou University, Guiyang 550025, P. R. China
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bSchool of Chemistry and Environmental Science, Guizhou Minzu University,
Guiyang 550025, P. R. China
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ABSTRACT: Here, a series of β-amino acid ester derivatives containing quinazoline
and benzothiazoles was synthesized and evaluated for anti-tobacco mosaic virus
(TMV) activity. The compounds 3n, 3o, 3p and 3q showed good antiviral activity
against TMV at a concentration of 500 µg/mL, with curative rates of 55.55%, 52.32%,
52.77% and 51.2%, respectively, and protection rates of 52.33%, 55.96%, 54.2% and
50.98%, respectively. These values were close to those of the commercially available
antiviral agent ningnanmycin (which has curative and protection rates of 55.27% and
52.1%, respectively). To our knowledge, this is the first report of the anti-TMV
activity of β-amino acid ester derivatives containing quinazoline and benzothiazoles
moieties; the results indicate that these novel compounds can potentially be used as
protective agents against TMV diseases.
Keywords: β-amino acid esters, Benzothiazoles, Quinazoline moiety, Synthesis,
Anti-TMV activity.
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Abbreviations used
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NMR, nuclear magnetic resonance; TMV, tobacco mosaic virus.
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Plant viruses cause diseases often referred to as plant cancers. Tobacco mosaic
virus (TMV) is a positive-sense, single-stranded RNA virus with a broad host range
and effects that vary according to the host species, which include plants such as
tobacco, tomato and many ornamental plants in the Solanaceae family. TMV diseases
diminish the quality and yield of crops and undermine global agricultural production,
resulting in an estimated loss of one billion U.S. dollars each year.1,2 The application
of traditional agrochemicals has had only limited success, and leaves high levels of
residue that have detrimental environmental and ecological effects. Thus, effective
and environmentally safe antiviral agents are urgently needed and their development
remains an ongoing challenge.
Quinazoline derivatives belonging to the N-containing heterocyclic compounds
have a variety of proven biological activities,3 including antitumorigenic,4
anti-inflammatory,5 antihypertensive,6 antimicrobial7 and sterilization.8 These
properties can be attributed to different active groups linked to the quinazoline rings
by synthetic methods;9–13 applications for these compounds can be found in the areas
of biology, pesticide development and medicine.14 Benzothiazole derivatives likewise
have antibacterial, antimicrobial, antihelmintic, antitumorigenic and antiinflammatory
activities15–17 that have many potential applications.18
β-amino acid esters and their derivatives also possess diverse biological
properties, such as antitumor, immune-stimulating and antiphlogistic activities.19–21
These esters are found in many natural products and have been widely used as
peptidomimetics in the synthesis of enzyme inhibitors, antiviral and antibacterial
drugs. These compounds are also used as third-generation pesticides, with potent
effects on fungi, insects and weeds; they are also easily broken down, leaving little
harmful residue. Various applications for β-amino acid esters in drug synthesis and
plant protection have been explored.22–27
We recently reported a series of amino acid ester derivatives containing
benzothiazole moieties (Fig. 1) that demonstrated protective effects against TMV.28
Based on this work, in the present study, a novel family of bioactive molecules were
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developed by introducing a quinazoline fragment to the amino acid ester backbone.
The synthesis and characterization of 32 β-amino acid ester derivatives containing
quinazoline and benzothiazoles units have been described. These compounds were
screened for potential bioactivity and preliminary structure-activity relationships were
examined. The bioassays showed that the compounds have variable inhibitory effects
against TMV.
Figure 1
The method used to generate β-amino acid ester derivatives containing
quinazoline and benzothiazoles units has been previously described29 and is outlined
in Scheme 1. Compounds 3a to 3af were synthesized from 4-chloroquinethiazole in
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three steps. The physical characteristics, as well as H and 13C nuclear magnetic
resonance (NMR) and elemental analysis data for all synthesized compounds, are
reported in the Appendix. The results for the representative compound 3n are shown
below.
Scheme 1
Dimethyl 2-(((6-chlorobenzo[d]thiazol-2-yl)amino)(4-((7-chloroquinazolin -4-yl)
1
oxy)phenyl) methyl)malonate (3n): white solid; m.p., 136–139 °C; yield, 51%; H
NMR (500 MHz, CDCl3): δ (ppm) 8.75 (s, 1H, ArH), 8.34 (d, 1H, J = 10 Hz, ArH),
8.01 (d, 1H, J = 10 Hz, ArH), 7.94–7.92 (m, 1H, ArH), 7.68–7.65 (m, 1H, ArH), 7.57
(d, 1H, J = 5 Hz, ArH), 7.55 (d, 1H, J = 5 Hz, ArH), 7.28–7.27 (m, 3H, ArH),
7.11–7.08 (m, 1H, ArH), 7.04 (s, 1H, NH), 5.83 (s, 1H, CH), 4.09 (d, 1H, J = 5 Hz,
CH), 3.74 (d, 6H, J = 10 Hz, CH3). 13C NMR (125 MHz, CDCl3): δ (ppm) 168.6,
167.3, 166.7, 166.0, 154.2, 152.2, 152.1, 151.8, 136.2, 134.3, 131.0, 130.9, 128.9,
128.1, 128.0, 122.8, 126.0, 123.6, 122.3, 122.1, 120.9, 119.5, 116.5, 57.4, 56.7, 53.3,
53.0. Anal. Calcd for C27H20Cl2N4O5S: C, 55.58; H, 3.46; N, 9.60. Found: C, 55.23; H,
3.85; N, 10.02.
The inhibitory effects of the synthesized β-amino acid ester derivatives on TMV
activities were evaluated in vivo. As a positive control, the activity of the commercial
antiviral agent ningnanmycin was assessed under the same conditions.30,31
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preliminary screen demonstrated that the inhibitory effects of these compounds
against TMV was variable (Table 1). Compounds 3n, 3o, 3p and 3q showed high
anti-TMV activity at a concentration of 500 µg/mL, with curative rates of 55.55%,
52.32%, 52.77% and 51.2%, respectively, values that were comparable to that of
ningnanmycin (55.27%). A strong protective effect was also observed for these four
compounds, with rates of 52.33%, 55.96%, 54.21% and 50.98%, respectively, which
was similar to the protection rate of ningnanmycin (52.1%).
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Table 1
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Four conclusions can be drawn from the data presented in Table 1. First, when
the R-group was -H, regardless of the R1 and R2 moieties, compounds showed little
variation in anti-TMV activity and only moderate curative effects, with rates not
exceeding 48%. Second, when R and R1 were substituted with -Cl, -CH3, -C2H5,
n-C3H7 or -CH2C6H5 as R2, the compounds had similar anti-TMV activities, with
curative rates of 55.55%, 52.32%, 52.77%, and 51.2%, respectively. Third, compared
to compounds that had the same substituents for R1 and R2, the activities of -Cl
derivatives were superior to those of -H derivatives, such that 3n > 3d, 3p > 3e and
3p > 3f. Last, when R1 was -CH3, the antiviral activity was consistently lower than
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those of compounds with -Cl as R1 irrespective of the functional groups at R and R2.
,
Thus, introducing an electron-withdrawing group in the quinazoline ring can enhance
the inhibition ratio of the compound.
In summary, a series of new β-amino acid ester derivatives, compounds 3a to 3af,
containing quinazoline and benzothiazole moieties, were synthesized via an addition
reaction of imines 2a to 2f with malonate in CH2Cl2. Functional assays indicated that
compounds 3n, 3o, 3p and 3q had strong protective and curative effects against TMV,
similar to those of ningnanmycin, with -Cl derivatives being superior to -H
derivatives. These novel β-amino acid ester derivatives can potentially be used as
protective agents against TMV disease in plants.
Acknowledgements
This study was supported by the National Key Program for Basic Research (no.
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2010CB126105) and the National Natural Science Foundation of China (no.
21132003).
Appendices
Additional data for this article, including detailed information on the synthesis,
characterization, and methods for testing the bioactivity of the compounds can be
found in the online version at http://dx.doi.org/10.1016/j.bmcl.
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Figure legend
Figure 1. Compounds with putative TMV inhibitory activity.
Scheme legend
Scheme 1. Synthesis of compounds 3a to 3af.
Table legend
Table 1. Inhibitory effects of β-amino acid ester derivatives against TMV.
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Figure 1. Compounds with putative TMV inhibitory activity.
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Scheme 1. Synthesis of compounds 3a to 3af.
N
O
R
O
OH
Cl
N
N
+
R
K2CO3
N
OHC
CHO
1
N
O
R
N
N
R
N
R1
R1
Toluene
EtOH,
S
S
N
+
NH2
N
C
H
O
N
OHC
2
1
R1
N
R
S
NH
O
N
N
CH
R2
R1
O
O
O
S
N
C
R2
R2
O
+
O
O
O
R2
O
O
H
N
N
R
2
N
R: -H, 7-Cl, 6-CH3, 8-CH3
R1: -H, -Cl, -OCH3, -CH3
3a-3af
R2: -CH3, -C2H5, n-C3H7, -CH2C6H5
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Table 1. Inhibitory effects of β-amino acid ester derivatives against TMV.
Concentration Curative
Protection
rate (%)
Comps
R
R1
R2
(µg/mL)
500
rate (%)
-H
-H
-H
-H
-Cl
-Cl
-Cl
-CH3
43.47 3.01 44.21 2.09
43.02 4.11 39.27 4.78
40.14 2.46 41.04 3.77
43.68 3.23 29.08 4.32
45.10 2.99 39.70 3.09
46.33 1.97 42.33 3.39
48.09 4.06 45.96 2.67
44.76 4.89 34.21 4.03
35.10 4.23 40.98 4.99
48.30 4.75 49.27 4.06
32.11 3.81 31.04 4.67
41.87 4.56 36.88 4.94
43.66 2.79 49.70 3.18
55.55 4.93 52.33 3.43
52.32 3.44 55.96 3.99
52.77 3.90 54.21 4.04
50.91 4.17 50.98 4.75
41.89 3.02 39.27 4.11
42.96 3.55 44.21 3.86
46.60 2.23 40.98 4.39
41.88 4.38 39.27 4.84
46.47 1.90 41.04 4.57
36.56 4.22 46.88 3.02
38.58 4.89 44.21 3.85
41.67 4.65 50.98 3.67
46.57 3.21 49.27 3.35
46.93 4.94 41.04 4.32
45.36 4.35 49.08 3.09
44.97 3.78 39.27 4.34
38.76 3.09 41.04 4.76
31.98 4.88 39.70 2.99
34.85 3.76 42.33 3.45
55.27 2.36 52.16 3.67
3a
-H
500
3b
n-C3H7
-H
-CH2C6H5 500
3c
-H
-CH3
500
500
3d
-H
3e
n-C3H7
-H
-CH2C6H5 500
3f
-H
-OCH3 -CH3
-OCH3 -C2H5
500
500
500
3g
-H
3h
-H
-OCH3
3i
n-C3H7
-H
-OCH3 -CH2C6H5 500
3j
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
-H
-CH3
500
500
3k
-H
3l
n-C3H7
-H
-CH2C6H5 500
3m
-Cl
-Cl
-Cl
-Cl
-CH3
500
500
500
3n
-C2H5
n-C3H7
3o
3p
-CH2C6H5 500
3q
-OCH3 -CH3
-OCH3 -C2H5
500
500
500
3r
3s
-OCH3
3t
n-C3H7
-OCH3 -CH2C6H5 500
3u
-CH3
-CH3
-CH3
-CH3
500
500
3v
3w
n-C3H7
-CH2C6H5 500
3x
6-CH3 -H
6-CH3 -H
-CH3
500
500
500
500
500
500
500
500
500
3y
-C2H5
3z
6-CH3 -OCH3 -CH3
6-CH3 -OCH3 -C2H5
3aa
3ab
8-CH3 -H
8-CH3 -H
8-CH3 -Cl
-CH3
-C2H5
-CH3
-C2H5
3ac
3ad
3ae
8-CH3
-Cl
3af
---
Ningnanmycin
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Graphical abstract
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