Synthesis and antimicrobial activity of 2-substituted [4-(1,3,4-oxadiazol- 2-yl methyl)] phthalazin-1(2H)-one derivatives

Article abstract of DOI:10.1016/j.ejmech.2010.08.005

A series of new 2-substituted [4-(1,3,4-oxadiazol-2-yl)methyl]phthalazin- 1(2H)-one derivatives 7a-h to 9a-h were designed and synthesized from methyl (4-oxo-3,4-dihydrophthalazin-1-yl)acetate (4), which in was turn prepared from phthalic anhydride. The structure of synthesized new compounds were characterized by spectral data and screened for their antimicrobial activities against various bacteria and fungi strains. Several of these compounds showed antimicrobial activity.

Full text of DOI:10.1016/j.ejmech.2010.08.005

European Journal of Medicinal Chemistry 45 (2010) 4983e4989
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antimicrobial activity of 2-substituted
[4-(1,3,4-oxadiazol-2-yl methyl)] phthalazin-1(2H)-one derivatives
,
,
c
a
Ajjanna M. Sridhara a b, Kallam R. Venugopala Reddy b , Jathi Keshavayya , Palusa Sanath Kumar Goud ,
*
Bankavadi C. Somashekar a, Prosenjit Bose a, Sanenahalli K. Peethambar d, Satish Kumar Gaddam a
a Advinus Therapeutics Pvt. Ltd., 21 & 22, Peenya II phase, Bangalore, 560 058 Karnataka, India
b Department of Studies in Industrial Chemistry, Kuvempu University, Jnana Sahyadri, Shankaragatta, 577 451 Karnataka, India
c Department of Studies in Chemistry, Kuvempu University, Jnana Sahyadri, Shankaragatta, 577 451 Karnataka, India
d Department of Biochemistry, Kuvempu University, Jnana Sahyadri, Shankaragatta, 577 451 Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new 2-substituted [4-(1,3,4-oxadiazol-2-yl)methyl]phthalazin-1(2H)-one derivatives 7aeh to
9aeh were designed and synthesized from methyl (4-oxo-3,4-dihydrophthalazin-1-yl)acetate (4), which
in was turn prepared from phthalic anhydride. The structure of synthesized new compounds were
characterized by spectral data and screened for their antimicrobial activities against various bacteria and
fungi strains. Several of these compounds showed antimicrobial activity.
Received 25 April 2010
Received in revised form
21 July 2010
Accepted 1 August 2010
Available online 12 August 2010
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
Phthalazin-1(2H)-one
1,3,4-Oxadiazole
(3-Oxo-2-benzofuran-1(3H)-ylidene) acetic
acid
(4-Oxo-3,4-dihydrophthalazin-1-yl)acetic
acid
Biological assays
Antibacterial
Antifungal
1. Introduction
established drug molecules like Hydralazine [12,13], Budralazine
[14,15], Azelastine [16,17], Ponalrestat [18] and Zopolrestat [19] are
Nitrogen containing heterocyclic molecules constitutes the
largest portion of chemical entities, which are part of many natural
products, fine chemicals, and biologically active pharmaceuticals.
Phthalazin-1(2H)-ones and 1,3,4-oxadiazoles are important
building blocks in the construction of new molecular systems for
biologically active molecules [1e3]. The development of new and
efficient methodologies for synthesis of potentially bioactive
phthalazin-1(2H)-one derivatives is important.
Phthalazin-1(2H)-ones are of considerable interest due to their
antidiabetic [4], antiallergic [5], Vasorelaxant [6], PDE4 inhibitors
[7], VEGF (vascular endothelial growth factor) receptor tyrosine
kinases for the treatment of cancer [8,9], antiasthmatic agents with
dual activities of thromboxane A2 (TXA2) synthetase inhibition and
bronchodialation [10], herbicidal [11], like activities. A number of
prepared from the corresponding phthalazinones.
Disubstituted-1,3,4-oxadiazoles have been found to exhibit
diversebiological activities suchas antibacterial[20], antifungal [21],
antitubercular [22], insecticidal [23], herbicidal [24], analgesic [25],
anti-inflammatory [26], anticonvulsant [27] and anticancer [28].
The diverse biological activities of phthalazin-1(2H)-one, and
1,3,4-oxadiazole pharmacophores encouraged us to envisage the
combination of both groups in a compact system. A new series of
phthalazine-oxadiazoles substituted with heterocyclic moieties at
C-2 position were developed by adopting efficient and well-versed
methodologies (Fig. 1).
1,3,4-oxadiazoles were in turn substituted with different alkyl,
aryl and heterocyclic groups. For preliminary research we selected
2-chloro-1,3-thiazol-5-ylmethyl, 6-chloropyridin-3-ylmethyl, and
N-ethylmorpholine substituents as the heterocyclic groups. The
incorporation of these substances is fundamentally due to
their diverse biological, chemical characteristics and they are
frequently used in medicine and in industry [29e31]. Encouraged by
* Corresponding author. Tel.: þ91 8282 256228; fax: þ91 8282 256255.
E-mail address: venurashmi30@rediffmail.com (K.R. Venugopala Reddy).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.08.005

4984
A.M. Sridhara et al. / European Journal of Medicinal Chemistry 45 (2010) 4983e4989
The antimicrobial data showed that, by changing the phthala-
R1
zine substitution from 6-chloropyridin-3-ylmethyl to 2-chloro-1,3-
thiazol-5-ylmethyl the activity increased but decreased by
changing to 4-ethylmorpholine substitution. Compound 8g which
has thiazole and thiophene substitutions was the most active.
O
1,3,4-Oxadiazole
N
N
N
N
phthalazin-1(2H)-one
4. Conclusions
R
In this article we report the synthesis of (7aeh to 9aeh), new
phthalazine-oxadiazoles substituted at C2 positionwith heterocyclic
moieties, starting from commercially available phthalic anhydride.
Investigation of their antimicrobial activity revealed that phthala-
zine with a 2-chloro-1,3-thiazol-5-ylmethyl substitutionand an
oxadiazole with a thiophene substitution (8g) was the most active
compound although it was significantly less than that of positive
control. The fact that the compounds prepared in this study are
chemically unrelated to the current medication suggests that the
further work is clearly warranted.
O
Fig. 1. 2-Substituted phthalazin-1(2H)-one oxadiazoles scaffold.
these observations it was envisagedto integratethe 1,3,4-oxadiazole
moiety with a phthalazineframe work to study a potential additive
effect of the combined molecule towards antimicrobial activity.
2. Chemistry
The key intermediate in the synthesis of new phthalazinone
oxadiazoles 7aeh to 9aeh is methyl (4-oxo-3,4-dihydroph-
thalazin-1-yl) acetate (4), which was prepared from phthalic
anhydride in good yield [32,33] (Scheme 1).
N-alkylation of compound 4 with different hetero alkyl halides
in presence of base gave 3-substituted methyl (4-oxo-3,4-dihy-
drophthalazin-1-yl)acetates 5aec. The N-alkylation has been
confirmed by Mass, IR, and NMR spectral studies. Addition of
hydrazine hydrate to compounds 5aec in presence of ethanol as
solvent afforded hydrazides 6aec in good yield. Cyclization of
hydrazides 6aec with different acids in presence of phosphorous
oxychloride gave 2-substituted [4-(1,3,4-oxadiazol-2-yl)methyl]
phthalazin-1(2H)-one derivatives (Scheme 2).
5. Experimental protocols
5.1. Chemistry
All chemicals used for the synthesis were of reagent grade and
were procured from Sigma Aldrich Chemical Co, Bangalore; SDFCL,
Mumbai; and the intermediates were prepared as per the known
literature procedure. 1H and 13C NMR spectra were recorded on
400 MHz Varian-AS NMR spectrometer using TMS as an internal
standard. IR spectra were recorded by using PerkinElmer Spectrum
100 Series FTeIR spectrometer. Mass spectra were recorded on
Agilent 1200 Series LC/MSD VL system. Melting points were deter-
mined by using Buchi melting point B-545 instrument and are
uncorrected. All the reactions were monitored by thin layer chro-
matography (TLC) using precoated silica 60 F254, 0.25 mm aluminum
plates (Merck). The crude compounds were purified by using
CombiFlashÒ CompanionÒ flash chromatography system, Teledyne
Isco, Inc USA. Purity of compounds was assessed by HPLC method.
HPLC method for compounds 7aeh to 9aeh
3. Results and discussions
Investigation on antibacterial screening data (Table 1) showed
some of the compounds were active against four human pathogenic
bacteria. Compounds 7c, 7d, 7g, 7h, 8c, 8g, 8h, and 9g exhibited
activity against Escherichia coli. Similarly compounds 7g, 7h, 8e and
8g showed activity against Staphylococcus aureus. The compounds
7h and 9h showed activity against Bacillus subtilis. Also the
compounds 7g, 8d, 8e, and 8g showed activity against Salmonella
typhi. From these results it could be generalized that, the chloro,
fluoro, pyridine, and thiophene substituted oxadiazole derivatives
shows higher activity compared to other analogues.
The antifungal results data (Table 2) revealed that, the synthesized
compounds showed variable degree of inhibition against the tested
fungi. Compounds 7g, 8g, and 8h possessed the highest antifungal
activity against Chrysosporium keratinophilum. Compounds 7h, 8g,
8h, and 9h showed activity against Candida albicans, while the
compounds 7g, 7h, 8e, 8d, 8g, 8h, 9g, and 9h showed activity of
Microsporum gypsum. Also the compounds 7g, 8g, 8h, 9g, and 9h
showed activity against Aspergillums niger. From these results it could
be concluded that, the thiophene and pyridine substituted oxadiazole
compounds showed higher activity and the others showed less
activity against the fungi.
HPLC instrument
Mobile phase A
Agilent 1200 series LC system
10 mm Ammonium acetate adjusted
to pH: 3.0 with Acetic acid
Acetonitrile
Mobile phase B
Column
Inertsil ODS-3V 250 ꢀ 4.6 mm, 5
m
particle size
Detector
PDA at 254 nm
Sample concentration 10 mg/mL in methanol
Flow-rate
Gradient
1.0 mL/min
The gradient elution of the mobile phase
was 50% B in 0e2 min, 50e90% in
2e10 min, 90% in 10e20 min, 90e50% in
20e25 min and 50% 25e30 min
Injection volume
20 mL
O
N
O
O
OH
COOH
O
Ac2O / CH3COOK
135-140 0C
Methanol /
NH2NH2.H2O
N
NH
O
O
NH
Methanol /10-20 0C
H2SO4 / Reflux
O
4
O
3
O
O
1
2
Scheme 1. Synthesis of methyl (4-oxo-3,4-dihydrophthalazin-1-yl)acetate.

A.M. Sridhara et al. / European Journal of Medicinal Chemistry 45 (2010) 4983e4989
4985
O
O
N
O
N
N
R1
NH
O
O
O
NH2NH2.H2O
NH2
R-X / DMF /K2CO3
60-65 oC
R1-COOH /
N
N
N
N
N
N
NH
Ethanol / reflux
R
R
R
POCl3 / reflux
O
5a-c
O
O
O
6a-c
4
7a-h to 9a-h
R1: a) Methyl
b) Trifluoromethyl
5a, 6a, 7, R:
5b, 6b, 8, R:
5c, 6c, 9, R:
N
Cl
c) Cyclopropyl
N
d) 4-Fluorophenyl
e) 4-chlorophenyl
f) 2-methylphenyl
g) 3-thiophene
Cl
S
N
h) 6-chloro-pyridin-3-yl
O
Scheme 2. Synthesis of 2-substituted phthalazin-1(2H)-one oxadiazoles 7aeh to 9aeh.
5.2. Preparation of 3-substituted-methyl (4-oxo-3,4-
dihydrophthalazin-1-yl)acetate 5aec
3.64 (s, 3H, CH3), 4.11 (s, 2H, CH2), 5.33 (s, 2H, CH2), 7.48 (d, J ¼ 8.0 Hz,
1H, AreH), 7.79 (dd, J ¼ 8.0, 2.4 Hz, 1H, AreH), 7.80e7.99 (m, 3H,
AreH), 8.30e8.32 (m, 1H, AreH), 8.42 (d, J ¼ 2.4 Hz, 1H, AreH).
A mixture of ester 4 (21.8 gm, 0.10 mol), dimethylformamide
(250 mL), potassium carbonate (41.4 gm, 0.3 mol) and corresponding
hetero alkyl halide (0.11 mol) was heated to 60e65 ꢁC for 6 h. After
completion of reaction, filtered the inorganics, the filtrate obtained
was distilled completely under reduced pressure at 60e65 ꢁC. The
residue obtained was diluted with ice water (500 mL) and stirred for
30 min. The precipitated product was filtered, dried and recrystal-
lized using isopropyl alcohol to yield 5aec as white solid.
5.2.2. Methyl {3-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-oxo-3,4-
dihydrophthalazin-1-yl}acetate (5b)
The compound was obtained by using 2-chloro-5-(chlor-
omethyl)-1,3-thiazole. Yield: 60.3%; M.p.: 171.0e174.4 ꢁC; MS:
m/z ¼ 350.1 (M þ 1); Purity: 99.1%; 1H NMR(400 MHz, DMSO-d6)
d:
3.64 (s, 3H, CH3), 4.13 (s, 2H, CH2), 5.46 (s, 2H, CH2), 7.77 (s, 1H,
AreH), 7.89e7.99 (m, 3H, AreH), 8.31e8.33 (m, 1H, AreH).
5.2.1. Methyl {3-[(6-chloropyridin-3-yl) methyl]e4-oxo-3,4-
dihydrophthalazin-1-yl}acetate (5a)
5.2.3. Methyl{3-[2-(morpholin-4-yl)ethyl]-4-oxo-3,4-
dihydrophthalazine1-yl}acetate (5c)
By using 2-chloro-5-(chloromethyl) pyridine, the title
By using 4-(2-chloroethyl)morpholine hydrochloride, the title
compound was obtained. Yield: 68.3%; M.p.: 178.2e183.5 ꢁC; MS: m/
compound was obtained. Yield: 70.9%; M.p.: 156.8e159.6 ꢁC; MS:
z ¼ 344.1 (M þ 1); Purity: 98.2%; 1H NMR(400 MHz, DMSO-d6)
d:
m/z ¼ 332.2 (M þ 1); Purity: 97.6%; 1H NMR(400 MHz, DMSO-d6)
d:
Table 1
Antibacterial activity of compounds 7aeh to 9aeh.
Zone of Inhibition measured in mm
Staphylococcus aureus ꢂ S.D.* Bacillus subtilis ꢂ S.D.*
100 g/mL 50 g/mL 100 g/mL 50
Escherichia coli ꢂ S.D.*
100 g/mL 50
Salmonella typhi ꢂ S.D.*
100 g/mL 50 mg/mL
Synthesized
compounds
m
m
g/mL
m
m
m
mg/mL
m
7a
7b
7c
7d
7e
7f
7g
7h
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
9c
9d
9e
9f
3.5 ꢂ 0.7
8.0 ꢂ 0.0
11.5 ꢂ 0.7
10.0 ꢂ 0.0
8.0 ꢂ 0.0
7.0 ꢂ 0.0
15.5 ꢂ 0.0
12.5 ꢂ 0.7
5.5 ꢂ 0.7
6.5 ꢂ 0.7
11.5 ꢂ 0.7
9.0 ꢂ 0.0
9.0 ꢂ 0.0
6.0 ꢂ 0.0
16.0 ꢂ 0.0
12.0 ꢂ 0.0
2.5 ꢂ 0.7
3.5 ꢂ 0.7
5.0 ꢂ 0.7
2.0 ꢂ 0.0
7.0 ꢂ 0.0
5.5 ꢂ 0.7
8.5 ꢂ 0.7
5.5 ꢂ 0.7
18.5 ꢂ 0.7
1.5 ꢂ 0.7
6.0 ꢂ 0.0
7.0 ꢂ 0.0
8.0 ꢂ 0.0
5.0 ꢂ 0.0
4.5 ꢂ 0.7
10.0 ꢂ 0.0
7.5 ꢂ 0.7
2.5 ꢂ 0.7
3.0 ꢂ 0.0
9.0 ꢂ 0.0
5.0 ꢂ 0.0
5.0 ꢂ 0.0
6.0 ꢂ 0.0
10.0 ꢂ 0.0
8.0 ꢂ 0.0
0.0
1.5 ꢂ 0.7
6.0 ꢂ 0.0
4.5 ꢂ 0.7
6.0 ꢂ 0.0
4.5 ꢂ 0.7
6.5 ꢂ 0.7
11.5 ꢂ 0.7
10.5 ꢂ 0.7
1.0 ꢂ 0.0
7.0 ꢂ 0.0
4.5 ꢂ 0.7
9.0 ꢂ 0.0
10.0 ꢂ 0.0
2.0 ꢂ 0.0
10.0 ꢂ 0.0
7.0 ꢂ 0.0
3.5 ꢂ 0.7
0.0
1.5 ꢂ 0.7
1.0 ꢂ 0.0
8.0 ꢂ 0.0
3.5 ꢂ 0.7
5.0 ꢂ 0.0
7.0 ꢂ 0.7
16.5 ꢂ 0.7
0.0
0.0
0.0
0.0
4.0 ꢂ 0.0
3.0 ꢂ 0.0
3.5 ꢂ 0.7
0.0
2.5 ꢂ 0.7
7.0 ꢂ 0.0
6.0 ꢂ 0.0
7.5 ꢂ 0.7
7.5 ꢂ 0.7
3.0 ꢂ 0.0
15.5 ꢂ 0.0
6.5 ꢂ 0.7
4.5 ꢂ 0.7
5.5 ꢂ 0.7
7.5 ꢂ 0.7
9.0 ꢂ 0.0
9.5 ꢂ 0.7
5.0 ꢂ 0.0
12.0 ꢂ 0.0
5.0 ꢂ 0.0
4.5 ꢂ 0.7
2.5 ꢂ 0.7
6.5 ꢂ 0.7
5.0 ꢂ 0.0
4.5 ꢂ 0.7
5.0 ꢂ 0.0
7.5 ꢂ 0.7
6.5 ꢂ 0.7
20.5 ꢂ 0.7
1.0 ꢂ 0.0
4.0 ꢂ 0.0
3.0 ꢂ 0.0
3.0 ꢂ 0.0
4.0 ꢂ 0.0
1.0 ꢂ 0.0
10.0 ꢂ 0.0
2.5 ꢂ 0.7
2.5 ꢂ 0.7
3.0 ꢂ 0.0
4.0 ꢂ 0.0
5.0 ꢂ 0.0
5.0 ꢂ 0.0
3.0 ꢂ 0.0
7.0 ꢂ 0.0
3.0 ꢂ 0.0
1.5 ꢂ 0.7
0.0
2.5 ꢂ 0.7
3.5 ꢂ 0.7
3.0 ꢂ 0.0
2.5 ꢂ 0.7
4.5 ꢂ 0.7
3.5 ꢂ 0.7
12.0 ꢂ 0.0
3.5 ꢂ 0.7
1.0 ꢂ 0.0
4.0 ꢂ 0.0
1.0 ꢂ 0.0
4.5 ꢂ 0.7
7.0 ꢂ 0.0
7.5 ꢂ 0.7
0.0
4.0 ꢂ 0.0
2.0 ꢂ 0.0
5.0 ꢂ 0.0
7.0 ꢂ 0.0
0.0
2.0 ꢂ 0.0
6.5 ꢂ 0.7
5.0 ꢂ 0.0
7.0 ꢂ 0.0
2.5 ꢂ 0.7
6.0 ꢂ 0.0
8.0 ꢂ 0.0
3.0 ꢂ 0.0
5.0 ꢂ 0.0
5.5 ꢂ 0.7
4.5 ꢂ 0.0
5.5 ꢂ 0.7
5.0 ꢂ 0.0
8.0 ꢂ 0.0
6.0 ꢂ 0.0
1.0 ꢂ 0.0
5.00 ꢂ 0.0
5.5 ꢂ 0.7
6.0 ꢂ 0.0
4.0 ꢂ 0.0
4.5 ꢂ 0.7
6.0 ꢂ 0.0
9.0 ꢂ 0.0
14.5 ꢂ 0.7
4.0 ꢂ 0.0
5.5 ꢂ 0.7
1.00 ꢂ 0.0
3.0 ꢂ 0.0
2.0 ꢂ 0.0
2.0 ꢂ 0.0
3.0 ꢂ 0.0
2.0 ꢂ 0.0
4.0 ꢂ 0.0
4.0 ꢂ 0.0
0.0
2.0 0 ꢂ 0.0
3.5 ꢂ 0.7
3.0 ꢂ 0.0
2.0 ꢂ 0.0
2.5 ꢂ 0.7
3.0 ꢂ 0.0
4.5 ꢂ 0.7
10.5 ꢂ 0.7
7.0 ꢂ 0.0
4.0 ꢂ 0.0
0.0
0.0
0.0
0.0
1.5 ꢂ 0.7
0.0
0.0
3.0 ꢂ 0.0
2.5 ꢂ 0.7
3.5 ꢂ 0.7
1.5 ꢂ 0.7
15.0 ꢂ 1.4
5.0 ꢂ 0.0
1.5 ꢂ 0.7
3.5 ꢂ 0.7
3.5 ꢂ 0.7
12.5 ꢂ 0.7
9g
9h
Amoxicillin
*S.D ¼ Standard deviation.

4986
A.M. Sridhara et al. / European Journal of Medicinal Chemistry 45 (2010) 4983e4989
Table 2
Antifungal activity of compounds 7aeh to 9aeh.
Zone of Inhibition measured in mm
Chrysosporium
Candida albicans ꢂ S.D.*
Microsporum gypsum ꢂ S.D.*
Aspergillus flavus ꢂ S.D.*
100 g/mL 50 g/mL
keratinophilum ꢂ S.D.*
100 g/mL 50
0.0
Synthesized compounds
m
m
g/mL
100
mg/mL
50
m
g/mL
100
m
g/mL
50
m
g/mL
m
m
7a
7b
7c
7d
7e
7f
7g
7h
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
9c
9d
9e
9f
9g
9h
0.0
3.5 ꢂ 0.7
4.5 ꢂ 0.7
8.5 ꢂ 0.7
4.5 ꢂ 0.7
5.5 ꢂ 0.7
3.00 ꢂ 0.0
7.5 ꢂ 0.7
11.5 ꢂ 0.7
2.5 ꢂ 0.7
3.5 ꢂ 0.7
5.5 ꢂ 0.7
5.5 ꢂ 0.7
6.5 ꢂ 0.7
3.5 ꢂ 0.7
8.50 ꢂ 0.7
10.5 ꢂ 0.7
2.5 ꢂ 0.7
3.5 ꢂ 0.7
4.5 ꢂ 0.7
5.5 ꢂ 0.7
3.5 ꢂ 0.7
1.5 ꢂ 0.7
7.50 ꢂ 0.7
10.5 ꢂ 0.7
19.5 ꢂ 0.7
1.0 ꢂ 0.0
1.5 ꢂ 0.7
5.5 ꢂ 0.7
2.5 ꢂ 0.7
3.0 ꢂ 0.0
0.0
5.5 ꢂ 0.7
8.5 ꢂ 0.7
1.0 ꢂ 0.0
0.5 ꢂ 0.7
3.5 ꢂ 0.7
2.5 ꢂ 0.7
3.0 ꢂ 0.0
0.0
4.5 ꢂ 0.7
9.5 ꢂ 0.7
1.0 ꢂ 0.0
0.5 ꢂ 0.7
2.5 ꢂ 0.7
2.5 ꢂ 0.7
1.0 ꢂ 0.0
0.0
4.5 ꢂ 0.7
6.5 ꢂ 0.7
15.0 ꢂ 0.0
2.00 ꢂ 0.0
5.0 ꢂ 0.0
7.5 ꢂ 0.7
6.5 ꢂ 0.7
4.0 ꢂ 0.0
3.0 ꢂ 0.0
11.0 ꢂ 0.0
7.00 ꢂ 0.0
3.5 ꢂ 0.7
5.5 ꢂ 0.7
7.0 ꢂ 0.0
8.5 ꢂ 0.7
4.0 ꢂ 0.0
3.0 ꢂ 0.0
9.5 ꢂ 0.7
7.5 ꢂ 0.0
3.5 ꢂ 0.7
4.0 ꢂ 0.0
6.0 ꢂ 0.0
7.5 ꢂ 0.7
3.0 ꢂ 0.0
2.0 ꢂ 0.0
10.5 ꢂ 0.7
9.5 ꢂ 0.0
17.0 ꢂ 0.0
0.0
5.0 ꢂ 0.0
2.5 ꢂ 0.7
5.0 ꢂ 0.0
4.0 ꢂ 0.0
5.0 ꢂ 0.0
4.0 ꢂ 0.0
7.5 ꢂ 0.7
6.5 ꢂ 0.7
3.0 ꢂ 0.0
4.5 ꢂ 0.7
6.0 ꢂ 0.0
5.0 ꢂ 0.0
5.0 ꢂ 0.0
2.0 ꢂ 0.0
8.5 ꢂ 0.7
8.0 ꢂ 0.7
3.5 ꢂ 0.7
5.5 ꢂ 0.7
5.0 ꢂ 0.0
4.0 ꢂ 0.0
1.0 ꢂ 0.0
3.0 ꢂ 0.0
9.5 ꢂ 0.7
8.0 ꢂ 0.7
17.5 ꢂ 0.7
1.0 ꢂ 0.0
0.0
4.5 ꢂ 0.7
2.5 ꢂ 0.7
1.5 ꢂ 0.7
3.0 ꢂ 0.0
1.5 ꢂ 0.7
10.5 ꢂ 0.7
6.5 ꢂ 0.7
2.5 ꢂ 0.7
5.5 ꢂ 0.7
3.5 ꢂ 0.7
2.5 ꢂ 0.7
4.5 ꢂ 0.7
3.5 ꢂ 0.7
11.5 ꢂ 0.7
8.5 ꢂ 0.7
0.0
4.5 ꢂ 0.7
2.5 ꢂ 0.7
5.5 ꢂ 0.7
1.5 ꢂ 0.7
2.5 ꢂ 0.7
6.5 ꢂ 0.7
4.5 ꢂ 0.7
14.0 ꢂ 0.0
1.0 ꢂ 0.0
0.5 ꢂ 0.7
0.0
3.0 ꢂ 0.0
4.5 ꢂ 0.7
4.0 ꢂ 0.7
1.0 ꢂ 0.0
1.0 ꢂ 0.0
6.5 ꢂ 0.7
4.0 ꢂ 0.0
0.0
3.0 ꢂ 0.0
4.5 ꢂ 0.7
4.0 ꢂ 0.7
1.0 ꢂ 0.0
1.0 ꢂ 0.0
6.5 ꢂ 0.7
4.0 ꢂ 0.0
0.0
2.0 ꢂ 0.0
3.5 ꢂ 0.7
4.0 ꢂ 0.7
1.0 ꢂ 0.0
1.0 ꢂ 0.0
7.5 ꢂ 0.7
4.0 ꢂ 0.0
14.0 ꢂ 1.0
2.5 ꢂ 0.7
2.0 ꢂ 0.7
2.5 ꢂ 0.7
1.0 ꢂ 0.0
4.0 ꢂ 0.0
3.5 ꢂ 0.0
1.0 ꢂ 0.0
1.5 ꢂ 0.7
3.5 ꢂ 0.7
2.0 ꢂ 0.7
2.5 ꢂ 0.7
1.0 ꢂ 0.0
3.5 ꢂ 0.7
4.0 ꢂ 0.0
1.0 ꢂ 0.0
2.5 ꢂ 0.7
2.5 ꢂ 0.7
2.0 ꢂ 0.7
0.0
1.0 ꢂ 0.0
0.0
6.5 ꢂ 0.7
4.5 ꢂ 0.7
0.0
2.0 ꢂ 0.0
0.5 ꢂ 0.7
0.0
2.0 ꢂ 0.0
0.0
5.5 ꢂ 0.7
5.5 ꢂ 0.7
0.0
2.0 ꢂ 0.0
0.5 ꢂ 0.7
2.5 ꢂ 0.7
0.0
0.0
1.5 ꢂ 0.7
6.5 ꢂ 0.7
4.5 ꢂ 0.7
13.5 ꢂ 0.7
3.5 ꢂ 0.7
1.5 ꢂ 0.7
11.0 ꢂ 1.0
Metronidazole
*S.D ¼ Standard deviation.
2.42 (m, 4H, moreCH2eNeCH2e), 2.65e2.68 (t, J ¼ 6.8 Hz, 2H,
eCH2), 3.50 (m, 4H, moreCH2eOeCH2e), 3.64 (s, 3H, CH3), 4.10 (s,
2H, CH2), 4.23e4.25 (t, J ¼ 6.8 Hz, 2H, eCH2), 7.86e7.95 (m, 3H,
AreH), 8.28e8.30 (m, 1H, AreH).
1H
NMR(400
MHz,
DMSO-d6)
d
:
2.44
(m,
4H,
moreCH2eNeCH2e), 2.66e2.69 (t,
J
¼
6.8 Hz, 2H, CH2),
3.51e3.53 (m, 4H, moreCH2eOeCH2e), 3.78 (s, 2H, CH2),
4.22e4.25 (t, J ¼ 6.8 Hz, 2H, CH2), 4.26e4.27 (brs, 2H, NH2),
7.84e7.89 (m, 1H, AreH), 7.92e7.93 (m, 2H, AreH), 8.27e8.29
(m, 1H, AreH), 9.34 (brs, 1H, NH).
5.3. Preparation of 3-substituted (4-oxo-3,4-dihydrophthalazin-1-
yl)acetohydrazide 6aec
A mixture of esters 5(aec) (0.05 mol) and hydrazine hydrate
(0.10 mol) in ethanol (200 mL) were heated under reflux for 10 h.
After completion of reaction, cooled to room temperature, the
precipitated product was filtered and washed with cold ethanol to
give corresponding hydrazides 6aec as white solid.
5.4. General procedure for the synthesis of 2-substituted [4-(1,3,4-
oxadiazol-2-yl) methyl] phthalazin-1(2H)-one derivatives 7(aeh) to
9(aeh)
A solution of hydrazide 6aec (0.1 mmol), and corresponding
acid (0.1 mmol) in phosphorous oxychloride (5 mL), was refluxed
for 6e8 h. After cooling, the excess phosphorous oxychloride was
evaporated under reduced pressure. The residue obtained was
diluted with ice water (50 mL), neutralised with saturated sodium
bicarbonate, and extracted with ethyl acetate (50 mL ꢀ 3). The
combined organic layer was dried over anhydrous sodium sulphate.
After filtration, the solvent was evaporated to get crude product,
which was purified by using CombiFlashÒ CompanionÒ flash
chromatography system using ethyl acetate/hexane as mobile
phase to get the corresponding phthalazin-1(2H)-one oxadiazole
derivatives 7aeh to 9aeh.
5.3.1. 2-{3-[(6-chloropyridin-3-yl) methyl]-4-oxo-3, 4-
dihydrophthalazin-1-yl} acetohydrazide (6a)
By using compound 5a, the title compound was obtained. Yield:
86.9%; M.p.: 206.2e210.0 ꢁC; MS: m/z ¼ 344.1 (M þ 1); Purity: 99.3%;
1H NMR: (400 MHz, DMSO-d6)
d: 3.79 (s, 2H, CH2), 4.27 (brs, 2H,
NH2), 5.34 (s, 2H, CH2), 7.48e7.50 (d, J ¼ 8.4 Hz,1H, AreH), 7.80e7.83
(dd, J ¼ 8.4, 2.4 Hz, 1H, AreH), 7.86e7.98 (m, 3H, AreH), 8.28e8.30
(m,1H, AreH), 8.43e8.44 (d, J ¼ 2.4 Hz,1H, AreH), 9.35 (brs,1H, NH).
5.3.2. 2-{3-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-oxo-3,4-
dihydrophthalazin-1-yl}acetohydrazide (6b)
The title compound was obtained from 5b. Yield: 83.2%; M.p.:
214.9e218.5 ꢁC; MS: m/z ¼ 350.1 (M þ 1); Purity: 98.5%; 1H NMR
(400 MHz, DMSO-d6): 3.80 (s, 2H, CH2), 4.28 (brs, 2H, NH2), 5.46 (s,
2H, CH2), 7.78 (s, 1H, AreH), 7.86e7.98 (m, 3H, AreH), 8.30e8.32
(m, 1H, AreH), 9.38 (s, 1H, NH).
5.4.1. 2-[(6-chloropyridin-3-yl)methyl]-4-[(5-methyl-1,3,4-
oxadiazol-2-yl)methyl]phthalazin-1(2H)-one (7a)
White solid; Yield: 62.2%; Purity ¼ 98.8%; M.p.: 175.9e179.4 ꢁC;
MS: m/z ¼ 368.1 (M þ 1); IR (KBr) cmꢃ1: 2924, 1718, 1656, 1587; 1H
NMR (400 MHz, DMSO-d6)
d: 2.50 (s, 3H, CH3), 4.49 (s, 2H,
eCeCH2eCe), 5.34 (s, 2H, eNeCH2eCe), 7.27e7.29 (d, J ¼ 8.4 Hz,1H,
AreH), 7.78e7.84 (dd, J ¼ 8.4, 2.4 Hz, 1H, AreH), 7.86e7.88 (m, 3H,
AreH), 8.44e8.46 (m, 1H, AreH), 8.49 (d, J ¼ 2.4 Hz, 1H, AreH); 13C
5.3.3. 2-{3-[2-(morpholin-4-yl)ethyl]-4-oxo-3,4-
dihydrophthalazin-1-yl}acetohydrazide (6c)
By using 5c, the title compound was obtained. Yield: 88.6%;
NMR (100 MHz, DMSO-d6) d: 164.7, 163.7, 158.7, 150.1, 149.9, 141.9,
M.p.: 187.0e191.7 ꢁC; MS: m/z ¼ 332.2 (M þ 1); Purity: 99.1%;
140.0,134.3,132.9,132.7,128.9,127.6,127.0,126.0,124.7, 50.9,29.1,10.9.

A.M. Sridhara et al. / European Journal of Medicinal Chemistry 45 (2010) 4983e4989
4987
5.4.2. 2-[6-(chloropyridin-3-yl)methyl]-4-{[5-(trifluoromethyl)-
5.4.7. 2-[(6-chloropyridin-3-yl)methyl]-4-{[5-(thiophen-3-yl)-
1,3,4-oxadiazol-2-yl]methyl} phthalazin-1(2H)-one (7b)
1,3,4-oxadiazol-2-yl]methyl} phthalazin-1(2H)-one (7g)
White solid; Yield: 43.2%; Purity ¼ 99.0%; M.p.: 117.5e119.8 ꢁC;
White solid; Yield: 72.9%; Purity ¼ 99.2%; M.p.: 154.2e157.1 ꢁC;
MS: m/z ¼ 422.1 (M þ 1); IR (KBr) cmꢃ1: 2830, 1719, 1652, 1599;
MS: m/z ¼ 436.1 (M þ 1); IR (KBr) cmꢃ1: 2924, 1790, 1653, 1585; 1H
1H NMR (400 MHz, CDCl3)
d: 4.64 (s, 2H, eCeCH2eCe), 5.31 (s,
NMR (400 MHz, DMSO-d6) d: 4.78 (s, 2H, eCeCH2eCe), 5.30 (s, 2H,
2H, eNeCH2eC), 7.27e7.28 (d, J ¼ 8.4 Hz, 1H, AreH), 7.72e7.74
eNeCH2eCe), 7.35e7.37 (m, 1H, AreH), 7.56e7.57 (m, 1H, AreH),
7.71e7.73 (m, 1H, AreH), 7.91e8.09 (m, 4H, AreH), 8.26 (m, 1H,
AreH), 8.32e8.34 (m, 1H, AreH), 8.37 (m, 1H, AreH); 13C NMR
(100 MHz, DMSO-d6) d: 163.1, 161.8, 158.7, 149.9, 141.8, 139.9, 134.4,
132.9, 132.5, 129.5, 129.0, 128.8, 127.6, 127.1, 126.0, 125.8, 124.7,
124.6, 123.7, 50.8, 29.1.
(dd, J ¼ 8.4, 2.4 Hz, 1H, AreH), 7.81e7.88 (m, 3H, AreH), 8.48e8.49
(d, J ¼ 2.4 Hz, 2H, AreH); 13C NMR (100 MHz, CDCl3)
d: 165.8, 163.3,
158.4, 151.5, 150.2, 142.9, 141.2, 135.3, 132.9, 132.2, 128.5, 128.0,
126.8, 125.2, 124.9, 124.2, 50.8, 29.2.
5.4.3. 2-[(6-chloropyridin-3-yl)methyl]-4-[(5-cyclopropyl-1,3,4-
oxadiazol-2-yl)methyl] phthalazin-1(2H)-one (7c)
5.4.8. 2-[(6-chloropyridin-3-yl)methyl]-4-{[5-(6-chloropyridin-3-
yl)-1,3,4-oxadiazol-2-yl] methyl}phthalazin-1(2H)-one (7h)
White solid; Yield: 79.5%; Purity ¼ 97.9%; M.p.: 188.6e190.2 ꢁC;
MS: m/z ¼ 465.1(M þ 1); IR (KBr) cmꢃ1: 2896, 1789, 1658, 1593; 1H
White solid; Yield: 43.2%; Purity ¼ 97.6%; M.p.: 158.9e161.8 ꢁC;
MS: m/z ¼ 394.1 (M þ 1); IR (KBr) cmꢃ1: 2923, 1718, 1656, 1587; 1H
NMR (400 MHz, CDCl3) d: 0.98e1.09 (m, 4H, eCH2eCH2), 2.06e2.12
NMR (400 MHz, CDCl3) d: 4.63 (s, 2H, eCeCH2eCe), 5.34 (s, 2H,
(m, 1H, AlkeCH), 4.46 (s, 2H, eCeCH2eCe), 5.33 (s, 2H,
eNeCH2eC), 7.27e7.29 (d, J ¼ 8.4 Hz, 1H, AreH), 7.76e7.78 (dd,
J ¼ 8.4, 2.4 Hz, 1H, AreH), 7.79e7.88 (m, 3H, AreH), 8.44e8.47
(m, 1H, AreH), 8.50 (d, J ¼ 2.4 Hz, 1H, AreH); 13C NMR (100 MHz,
eNeCH2eCe), 7.22e7.24 (d, J ¼ 8.0 Hz, 1H, AreH), 7.51e7.53
(d, J ¼ 8.4 Hz, 1H, AreH), 7.74e7.76 (dd, J ¼ 8.0, 2.4 Hz, 1H, AreH),
7.80e7.92 (m, 3H, AreH), 8.20e8.23 (dd, J ¼ 8.0, 2.4 Hz, 1H, AreH),
8.47e8.48 (d, J ¼ 2.4 Hz, 2H, AreH), 8.49 (m, 1H, AreH) 8.99e9.00
CDCl3) d: 163.2, 161.8, 158.7, 149.8, 141.9, 139.9, 134.3, 132.9, 132.6,
(d, J ¼ 2.4 Hz, 1H, AreH); 13C NMR (100 MHz, CDCl3)
d: 164.9, 164.2,
129.5, 129.0, 128.9, 127.6, 126.0, 124.8, 50.8, 29.2, 17.0, 11.5.
163.5, 152.1, 150.6, 149.4, 141.2, 139.8, 133.1, 134.1, 132.2, 131.6, 128.0,
127.1, 126.3, 124.7, 123.1, 122.6, 50.1, 29.1.
5.4.4. 2-[(6-chloropyridin-3-yl)methyl]-4-{[5-(4-fluorophenyl)-
1,3,4-oxadiazol-2-yl]methyl} phthalazin-1(2H)- one (7d)
5.4.9. 2-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-[(5-methyl-1,3,4-
oxadiazol-2-yl)methyl] phthalazin-1(2H)-one (8a)
White solid; Yield: 70.4%; Purity
¼
99.1%; M.p.:
White solid; Yield: 62.6%; Purity ¼ 98.5%; M.p.: 163.2e165.9 ꢁC;
184.6e186.5 ꢁC; MS: m/z ¼ 448.1 (M þ 1); IR (KBr) cmꢃ1: 2930,
MS: m/z ¼ 374.0 (M þ 1); IR (KBr) cmꢃ1: 3070, 1655, 1591, 1457; 1H
1719, 1657, 1591; 1H NMR (400 MHz, CDCl3):
d 4.61 (s, 2H,
NMR (400 MHz, DMSO-d6)
d: 2.52 (s, 3H, CH3), 4.52 (s, 2H,
eCeCH2eCe), 5.35 (s, 2H, eNeCH2eCe), 7.19e7.25 (m, 2H, AreH),
7.24e7.26 (d, J ¼ 8.0 Hz, 1H, AreH), 7.74e7.76 (dd, J ¼ 8.0, 2.4 Hz,
1H, AreH), 7.77e7.83 (m, 2H, AreH), 7.85e7.99 (m, 3H, AreH),
8.46e8.48 (m, 1H, AreH), 8.51e8.52 (d, J ¼ 2.4 Hz, 1H, AreH); 13C
eCeCH2eCe), 5.43 (s, 2H, eNeCH2eCe), 7.76 (s, 1H, AreH),
7.78e7.94 (m, 3H, AreH), 8.32e8.34 (m, 1H, AreH); 13C NMR
(100 MHz, DMSO-d6) d: 164.2, 163.5, 152.9, 140.2, 135.1, 134.2, 132.3,
131.7, 128.1, 127.1, 126.3, 124.6, 123.1, 122.6, 50.2, 29.3.
NMR (100 MHz, CDCl3):
d 165.2, 164.7, 163.7, 150.7, 150.1, 149.9,
141.9, 140.0, 134.2, 134.3, 132.9, 132.7, 128.9, 127.6, 126.7, 124.7,
123.2, 122.7, 49.8, 29.2.
5.4.10. 2-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-{[5-(trifluoromethyl)-
1,3,4-oxadiazol-2-yl] methyl}phthalazin-1(2H)-one (8b)
White solid; Yield: 50.1%; Purity ¼ 98.7%; M.p.: 140.3e143.5 ꢁC;
MS: m/z ¼ 428.0 (M þ 1); IR (KBr) cmꢃ1: 2830, 1657, 1591, 1417; 1H
5.4.5. 4-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-2-[(6-
chloropyridin-3-yl)methyl] phthalazin-1 (2H)-one (7e)
NMR (400 MHz, DMSO-d6) d: 4.54 (s, 2H, eCeCH2eCe), 5.44 (s, 2H,
eNeCH2eCe), 7.76 (s, 1H, AreH), 7.71e7.96 (m, 3H, AreH),
White solid; Yield: 70.2%; Purity ¼ 98.7%; M.p.: 168.3e170.1 ꢁC;
8.32e8.34 (m, 1H, AreH); 13C NMR (100 MHz, DMSO-d6):
d
165.8,
MS: m/z ¼ 464.1 (M þ 1); IR (KBr) cmꢃ1: 2928, 1718, 1658, 1592; 1H
164.0, 158.4, 152.0, 140.9, 140.7, 135.5, 135.1, 134.0, 132.6, 128.6,
127.5, 127.1, 125.1, 46.8, 29.5.
NMR (400 MHz, CDCl3)
d: 4.61 (s, 2H, eCeCH2eCe), 5.35 (s,
2H, eNeCH2eCe), 7.19e7.21 (d, J ¼ 8.0 Hz, 1H, AreH), 7.49e7.51
(d, J ¼ 8.1 Hz, 2H, AreH), 7.74e7.77 (dd, J ¼ 8.0, 2.4 Hz, 1H, AreH),
7.79e7.83 (d, J ¼ 8.1 Hz, 2H, AreH), 7.85e7.93 (m, 3H, AreH),
8.46e8.48 (m, 1H, AreH), 8.51e8.52 (d, J ¼ 2.4 Hz 1H, AreH); 13C
5.4.11. 2-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-[(5-cyclopropyl-
1,3,4-oxadiazol-2-yl)methyl] phthalazin-1(2H)-one (8c)
White solid; Yield: 32.0%; Purity ¼ 98.3%; M.p.: 129.1e132.7 ꢁC;
NMR (100 MHz, CDCl3) d: 164.8, 164.1, 163.6, 150.6, 150.0, 149.2,
MS: m/z ¼ 400.1 (M þ 1); IR (KBr) cmꢃ1: 2833, 1660, 1561, 1420; 1H
141.1, 139.1, 133.2, 134.2, 132.8, 131.7, 128.9, 127.2, 126.6, 125.6, 124.8,
123.1, 122.6, 50.1, 29.1.
NMR (400 MHz, DMSO-d6) d: 0.89e1.01 (m, 4H, eCH2eCH2e), 1.45
(m, 1H, AlkeCH), 4.57 (s, 2H, eCeCH2eCe), 5.49 (s, 2H,
eNeCH2eCe), 7.77 (s, 1H, AreH), 7.89e8.99 (m, 3H, AreH),
8.31e8.33 (m, 1H, AreH); 13C NMR (100 MHz, DMSO-d6)
d: 165.2,
5.4.6. 2-[(6-chloropyridin-3-yl)methyl]-4-{[5-(2-methylphenyl)-
1,3,4-oxadiazol-2-yl]methyl} phthalazin-1(2H)-one (7f)
164.5, 158.2, 152.9, 140.2, 140.1, 135.6, 135.2, 134.1, 132.6, 128.6,
127.5, 127.1, 46.8, 29.5, 17.0, 11.5.
White solid; Yield: 72.9%; Purity ¼ 98.2%; M.p.: 159.2e162.3 ꢁC;
MS: m/z ¼ 444.1 (M þ 1); IR (KBr) cmꢃ1: 2924, 1792, 1653, 1589; 1H
NMR (400 MHz, CDCl3):
d 2.62 (s, 3H, CH3), 4.62 (s, 2H,
5.4.12. 2-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-{[5-(4-fluorophenyl)-
1,3,4-oxadiazol-2-yl] methyl} phthalazin-1(2H)-one (8d)
eCeCH2eCe), 5.35 (s, 2H, eNeCH2eCe), 7.17e7.19 (d, J ¼ 8.0 Hz,
1H, AreH), 7.32e7.34 (m, 2H, AreH), 7.40e7.43 (m, 1H, AreH),
7.73e7.75 (dd, J ¼ 8.0, 1.6 Hz, 1H, AreH), 7.79e7.95 (m, 4H, AreH),
8.46e8.48 (m, 1H, AreH), 8.51e8.52 (d, J ¼ 1.6 Hz, 1H, AreH); 13C
White solid; Yield: 80.6%; Purity ¼ 98.5%; M.p.: 156.5e158.9 ꢁC;
MS: m/z ¼ 454.1 (M þ 1); IR (KBr) cmꢃ1: 2865, 1660, 1607, 1498; 1H
NMR (400 MHz, DMSO-d6) d: 4.84 (s, 2H, eCeCH2eCe), 5.43 (s, 2H,
NMR (100 MHz, CDCl3) d: 164.8, 164.1, 163.6, 150.6, 150.0, 149.2,
eNeCH2eCe), 7.43e7.50 (m, 2H, AreH), 7.68 (s, 1H, AreH),
7.93e7.97 (m, 1H, AreH), 7.99e8.04 (m, 3H, AreH), 8.11e8.13
(m, 1H, AreH), 8.34e8.36 (m, 1H, AreH); 13C NMR (100 MHz,
141.1, 139.1, 133.2, 134.2, 132.8, 131.7, 128.9, 127.2, 126.8, 126.6, 125.8,
125.0, 124.8, 123.1, 122.9, 50.1, 29.1, 22.2.

4988
A.M. Sridhara et al. / European Journal of Medicinal Chemistry 45 (2010) 4983e4989
DMSO-d6)
d
: 168.7, 167.2, 166.1, 164.8, 163.7, 163.5, 162.6, 158.7,
eCH2eOeCH2e), 4.33e4.36 (t, J ¼ 6.8 Hz, 2H, CH2), 4.65 (s, 2H,
CH2), 7.42e7.88 (m, 3H, AreH), 8.48e8.49 (m, 1H, AreH); 13C NMR
152.8, 141.0, 140.7, 133.9, 132.5, 127.5, 124.4, 116.6, 116.5, 46.6, 29.6.
(100 MHz, CDCl3) d: 164.1, 163.6, 158.7, 150.0, 140.0, 134.3, 132.8,
5.4.13. 4-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-2-[(2-
chloro-1,3-thiazol-5-yl) methyl] phthalazin-1(2H)-one (8e)
132.6, 128.9, 125.9, 124.6, 66.7, 57.6, 53.6, 41.9, 29.1.
White solid; Yield: 76.9%; Purity ¼ 98.7%; M.p.: 163.2e165.2 ꢁC;
5.4.19. 2-[2-(morpholin-4-yl)ethyl]-4-{[5-(cyclopropyl)-1,3,4-
oxadiazol-2-yl]methyl} phthalazin-1(2H)-one (9c)
MS: m/z ¼ 470.1; IR (KBr) cmꢃ1: 2860, 1667, 1620, 1480; 1H NMR
(400 MHz, DMSO-d6) d: 4.84 (s, 2H, eCeCH2eCe), 5.42 (s, 2H,
Semi solid; Yield: 26.9%; Purity ¼ 98.9%; MS: m/z ¼ 382.2
(M þ 1); IR (KBr) cmꢃ1: 2955, 2826, 1781, 1720, 1656; 1H NMR
eNeCH2eCe), 7.24e7.26 (d, J ¼ 8.0 Hz, 2H, AreH), 7.67 (s, 1H,
AreH), 7.71e7.76 (m, 3H, AreH), 8.16e8.18 (d, J ¼ 8.0 Hz, 2H, AreH),
(400 MHz, CDCl3) d: 0.98e1.08 (m, 4H, eCH2eCH2e), 2.06e2.12
8.32e8.34 (m, 1H, AreH); 13C NMR (100 MHz, DMSO-d6)
d: 168.6,
(m, 1H, AlkeCH), 2.55 (m, 4H, eCH2eNeCH2e), 2.80e2.85 (t,
J ¼ 6.8 Hz, 2H, CH2), 3.62e3.66 (m, 4H, eCH2eOeCH2e), 4.31e4.35
(t, J ¼ 6.8 Hz, 2H, CH2), 4.67 (s, 2H, CH2), 7.84e7.89 (m, 1H, AreH),
7.89e7.93 (m, 2H, AreH), 8.27e8.29 (m, 1H, AreH); 13C NMR
(100 MHz, CDCl3) d: 164.3, 163.8, 158.7, 149.8, 141.9, 134.3, 132.9,
132.6, 129.5, 124.8, 66.8, 57.5, 53.3, 41.6, 29.1, 17.1, 10.9.
166.2,166.1, 164.6,163.7, 163.4, 162.6, 158.7,152.5,141.1,140.0,133.2,
128.2, 127.5, 124.4, 116.6, 116.1, 46.9, 29.5.
5.4.14. 2-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-{[5-(2-methylphenyl)-
1,3,4-oxadiazol-2-yl] methyl} phthalazin-1(2H)-one (8f)
White solid; Yield: 80.1%; Purity ¼ 99.5%; M.p.: 134.6e136.9 ꢁC;
MS: m/z ¼ 450.1 (M þ 1); IR (KBr) cmꢃ1: 2924, 2887, 1653, 1589;
5.4.20. 2-[2-(morpholin-4-yl)ethyl]-4-{[5-(4-fluorophenyl)-1,3,4-
oxadiazol-2-yl]methyl} phthalazin-1(2H)-one (9d)
1H NMR (400 MHz, DMSO-d6)
d: 2.62 (s, 3H, CH3), 4.88 (s, 2H,
eCeCH2eCe), 5.45 (s, 2H, eNeCH2eCe), 7.42e7.48 (d, J ¼ 4.0, 2H,
AreH), 7.56 (s, 1H, AreH), 7.83e7.90 (m, 3H, AreH), 8.22e8.25 (m,
2H, AreH), 8.47e8.49 (m, 1H, AreH); 13C NMR (100 MHz, DMSO-
d6) d: 165.2, 160.3, 158.4, 151.5, 142.3, 141.5, 138.0, 136.1, 134.4,
133.0, 132.2, 131.9, 129.4, 129.1, 128.9, 127.4, 126.9, 126.2, 123.0,
46.7, 29.2, 22.1.
White solid; Yield: 76.5%; Purity ¼ 99.2%; M.p.: 150.2e154.3 ꢁC;
MS: m/z ¼ 436.1 (M þ 1); IR (KBr) cmꢃ1: 2956, 2812, 1787, 1653; 1H
NMR (400 MHz, CDCl3) d: 2.51 (m, 4H, eCH2eNeCH2e), 2.78e2.79
(t, J ¼ 6.8 Hz, 2H, CH2), 3.80e3.81 (m, 4H, eCH2eOeCH2e),
4.51e4.55 (t, J ¼ 6.8 Hz, 2H, CH2), 4.61 (s, 2H, CH2), 7.36e7.38
(m, 1H, AreH), 7.47e7.56 (m, 3H, AreH), 7.77e7.93 (m, 2H, AreH),
8.00e8.02 (m, 1H, AreH), 8.45e8.47 (m, 1H, AreH); 13C NMR
(100 MHz, CDCl3) d: 166.1, 164.8, 163.7, 163.5, 162.6, 158.7, 152.8,
141.0, 140.7, 133.9, 132.5, 127.5, 127.0, 126.1, 66.5, 57.5, 53.4, 41.9,
29.4.
5.4.15. 2-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-{[5-(thiophen-3-
yl)-1,3,4-oxadiazol-2-yl]methyl} phthalazin-1(2H)-one (8g)
White solid; Yield: 80.1%; Purity ¼ 99.0%; M.p.: 139.2e140.6 ꢁC;
MS: m/z ¼ 442.1 (M þ 1); IR (KBr) cmꢃ1: 2924, 1653, 1585; 1H NMR
(400 MHz, DMSO-d6) d: 4.82 (s, 2H, CH2), 5.43(s, 2H, eCH2), 7.42e7.43
5.4.21. 2-[2-(morpholin-4-yl)ethyl]-4-{[5-(4-methoxyphenyl)-
1,3,4-oxadiazol-2-yl]methyl} phthalazin-1(2H)-one (9e)
(m, 1H, AreH), 7.53e7.57 (m, 2H, CH2), 7.69 (s, 1H, AreH), 7.75e7.85
(m, 2H, AreH), 7.99e8.22 (m, 2H, AreH); 13C NMR (100 MHz, DMSO-
White solid; Yield: 70.1%; Purity ¼ 97.8%; M.p.: 156.2e158.6 ꢁC;
d6) d: 168.6, 166.2, 166.1, 164.6, 163.7, 163.4, 162.6, 158.7, 152.5, 141.1,
137.6.0, 133.2, 128.2, 127.5, 124.4, 116.6, 116.1, 46.9, 29.5.
MS: m/z ¼ 448.1 (M þ 1); IR (KBr) cmꢃ1: 2957, 2860, 1787, 1782,
1657; 1H NMR (400 MHz, CDCl3)
d: 2.53 (m, 4H, eCH2eNeCH2e),
2.79e2.82 (t,
J
¼
6.8 Hz, 2H, CH2), 3.64e3.66 (m, 4H,
5.4.16. 4-{[5-(6-chloropyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}-
2-[(2-chloro-1,3-thiazol-5-yl) methyl]phthalazin-1(2H)-one (8h)
White solid; Yield: 64.3%; Purity ¼ 98.8%; M.p.: 181.2e183.0 ꢁC;
MS: m/z ¼ 471.0 (M þ 1); IR (KBr) cmꢃ1: 2896, 1658, 1593, 1520; 1H
eCH2eOeCH2e), 3.86 (s, 3H, CH3), 4.34e4.38 (t, J¼6.8 Hz, 2H, CH2),
4.60 (s, 2H, CH2), 6.96e6.98 (d, J ¼ 8.8 Hz, 2H, AreH), 7.77e7.82
(m, 2H, AreH), 7.92e7.93 (d, J ¼ 8.8 Hz, 2H, AreH), 7.94e7.95 (m,
1H, AreH), 8.46e8.48 (m, 1H, AreH); 13C NMR (100 MHz, CDCl3)
d:
NMR (400 MHz, DMSO-d6) d: 4.66 (s, 2H, eCeCH2eCe), 5.43 (s, 2H,
166.7, 164.5, 163.9, 163.5, 162.6, 158.6, 152.7, 143.8, 142.7, 141.0,
140.7,133.9,130.5,127.5,127.0,126.1, 66.7, 57.5, 53.4, 41.9, 29.3, 22.3.
eNeCH2eCe), 7.68 (s, 1H, AreH), 7.77e7.79 (d, J ¼ 8.0 Hz, 1H,
AreH), 7.90e8.13 (m, 3H, AreH), 8.32e8.34 (m, 1H, AreH),
8.36e8.39 (dd, J ¼ 8.0, 2.2 Hz, 1H, AreH), 8.98 (m, 1H, AreH); 13C
5.4.22. 2-[2-(morpholin-4-yl)ethyl]-4-{[5-(thiophen-3-yl)-1,3,4-
oxadiazol-2-yl]methyl} phthalazin-1(2H)-one (9f)
NMR (100 MHz, DMSO-d6) d: 164.0, 163.1, 159.4, 158.7, 156.9, 152.8,
148.8, 141.0, 134.4, 133.9, 132.4, 132.1, 128.6, 127.6, 124.3, 123.2,
115.2, 114.9, 46.7, 29.6.
White solid; Yield: 49.2%; Purity
¼
99.2%; M.p.:
153.5e156.8 ꢁC MS: m/z ¼ 424.1 (M þ 1); IR (KBr) cmꢃ1: 2815, 1643,
1575, 1453; 1H NMR (400 MHz, CDCl3)
d: 2.52 (m, 4H,
5.4.17. 4-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-[2-
(morpholin-4-yl)ethyl]phthalazin-1(2H)-one (9a)
moreCH2eNeCH2e), 2.78e2.81 (t, J ¼ 6.8 Hz, 2H, CH2), 3.64e3.66
(m, 4H, moreCH2eOeCH2e), 4.34e4.37 (t, J ¼ 6.8 Hz, 2H, CH2), 4.60
(s, 2H, CH2), 7.44e7.45 (m, 1H, AreH), 7.61e7.62 (m, 1H, AreH),
7.77e7.99 (m, 4H, AreH), 8.46e8.49 (m, 1H, AreH); 13C NMR
(100 MHz, CDCl3) d: 163.1, 161.8, 158.7, 149.9, 141.8, 139.9, 134.4,
132.9,132.5,129.5,129.0,128.8,127.6,127.1, 66.2, 57.0, 53.2, 41.8, 29.1.
White solid; Yield: 49.6%; Purity ¼ 98.7%; M.p.: 158.2e160.3 ꢁC;
MS: m/z ¼ 356.1 (M þ 1); IR (KBr) cmꢃ1: 2941, 1787, 1722, 1652; 1H
NMR(400 MHz, CDCl3)
d: 2.35 (s, 3H, CH3), 2.53 (m, 4H,
moreCH2eNeCH2e), 2.77e2.80 (t, J ¼ 6.8 Hz, 2H, eCH2), 3.66 (m,
4H, moreCH2eOeCH2e), 4.34e4.37 (t, J ¼ 6.8 Hz, 2H, eCH2), 4.65
(s, 2H, CH2), 7.87e7.96 (m, 3H, AreH), 8.28e8.30 (d, J ¼ 7.6 Hz, 1H,
AreH); 13C NMR (100 MHz, CDCl3)
d: 164.2,163.7, 158.7, 150.1, 140.0,
5.4.23. 2-[2-(morpholin-4-yl)ethyl]-4-{[5-(5-bromopyridinyl-3-
yl)-1,3,4-oxadiazol-2-yl]methyl} phthalazin-1(2H)-one (9g)
134.3, 132.9, 132.7, 128.9, 124.7, 66.8, 57.7, 53.4, 41.6, 29.2, 10.6.
Off white solid; Yield: 70.9%; Purity
¼
98.7%; M.p.:
145.6e149.1 ꢁC; MS: m/z ¼ 497.1 (M þ 1); IR (KBr) cmꢃ1: 2955,
5.4.18. 2-[2-(morpholin-4-yl)ethyl]-4-{[5-(trifluoromethyl)-1,3,4-
oxadiazol-2-yl]methyl} phthalazin-1(2H)-one (9b)
1653, 1576, 1452; 1H NMR (400 MHz, CDCl3)
d: 2.53 (m, 4H,
White solid; Yield: 31.8%; Purity ¼ 98.3%; M.p.: 139.1e140.5 ꢁC;
moreCH2eNeCH2e), 2.77e2.80 (t, J ¼ 6.4 Hz, 2H, CH2), 3.66 (m, 4H,
moreCH2eOeCH2e), 4.34e4.37 (t, J ¼ 6.4 Hz, 2H, CH2), 4.65 (s, 2H,
CH2), 7.79e7.92 (m, 3H, AreH), 8.45e8.50 (m, 2H, AreH), 8.83 (m,
MS: m/z ¼ 410.1 (M þ 1); IR (KBr) cmꢃ1: 2950, 2816, 1782, 1720,
1656; 1H NMR (400 MHz, CDCl3)
d: 2.52 (m, 4H, eCH2eNeCH2e),
1H, AreH), 9.14 (m, 1H, AreH); 13C NMR (100 MHz, CDCl3)
d: 166.1,
2.78e2.81 (t,
J
¼
6.8 Hz, 2H, CH2), 3.64e3.66 (m, 4H,

A.M. Sridhara et al. / European Journal of Medicinal Chemistry 45 (2010) 4983e4989
4989
164.8, 163.7, 163.5, 162.6, 158.7, 152.8, 150.7, 141.0, 140.7, 133.9,
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The author A.M. Sridhara is thankful to Advinus Therapeutics
Pvt. Ltd. Bangalore, India, and Chairman, Department of Studies in
Industrial Chemistry, Kuvempu University, Shimoga, India for their
help and support to the research.