Synthesis and biological evaluation of 1,3,4-oxadiazole bearing dihydropyrimidines as potential antitubercular agents

Article abstract of DOI:10.1007/s00044-015-1485-7

A series of 5-(4-acetyl-5-(aryl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-(2-fluorophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-ones (4a-l) were synthesized in very good yields (56-78 %). Biginelli adduct 1 synthesized in the first step was reacted with hydrazi

Full text of DOI:10.1007/s00044-015-1485-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1485-7
ORIGINAL RESEARCH
Synthesis and biological evaluation of 1,3,4-oxadiazole bearing
dihydropyrimidines as potential antitubercular agents
1
1
1
1
1
N. C. Desai
•
A. R. Trivedi
•
H. V. Vaghani
•
H. C. Somani
•
K. A. Bhatt
Received: 25 March 2015 / Accepted: 8 December 2015
Ó Springer Science+Business Media New York 2015
Abstract A series of 5-(4-acetyl-5-(aryl)-4,5-dihydro-1,3,4-
oxadiazol-2-yl)-4-(2-fluorophenyl)-6-methyl-3,4-dihydropy-
rimidin-2(1H)-ones (4a-l) were synthesized in very good
yields (56–78 %). Biginelli adduct 1 synthesized in the first
step was reacted with hydrazine hydrate to furnish carbohy-
drazide intermediate 2 which on further reaction with different
Introduction
Tuberculosis (TB) is a highly infectious airborne disease
caused by pathogenic bacterium Mycobacterium tubercu-
losis (MTB). This pathogen is responsible for over two
million lives each year and dwells hidden in as many as
two billion people (WHO, 2013). In addition, emergence of
new virulent forms of TB such as multi-drug-resistant
tuberculosis (MDR-TB) and extremely drug-resistant
tuberculosis (XDR-TB) and its synergy with human
immunodeficiency virus (HIV) has fueled its epidemic
nature (Zumla et al., 2013). There is an urgent need to
develop newer, potent and safer antitubercular agents
which are less prone to resistance. (Palomino and Martin,
2013; Nguyen and Jacobs, 2012; Nzila et al., 2011). To
cater this need, researchers around the world are actively
involved in the development of antitubercular agents with
improved biological properties and novel mode of action
(Manvar et al., 2010, 2011, 2013, 2014; Upadhyay et al.,
2012; Virsdoia et al., 2010). One of the best tools to
develop newer and effective antitubercular agents is to
design hybrid molecules by molecular hybridization of
different bioactive substances (Dartois and Barry, 2013;
Patani and LaVoie, 1996).
0
aryl aldehydes yielded 4-(2-fluorophenyl)-6-methyl-N -(aryl)-
2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazides (3a-l).
These intermediates 3a-l were cyclized with the help of acetic
anhydride to give the titled compounds 4a-l. All the newly
synthesized compounds 4a-l were screened for their in vitro
antitubercular activity against Mycobacterium tuberculosis
H Rv (Mtb) using Lowenstein–Jensen method. Compounds
37
4
c, 4f, 4h, 4i and 4j inhibited more than 90 % of mycobacterial
growth. Minimum inhibitory concentration (MIC) for com-
pound 4i was found to be equipotent (MIC: 0.20 lg/ml) to the
reference drug isoniazid. Structure activity relationship
revealed that the presence of electronwithdrawing group/atoms
at para position of phenyl ring remarkably enhanced the anti-
tubercular activity of synthesized compounds.
Keywords 3,4-Dihydropyrimidin-2(1H)-ones Á
1
,3,4-Oxadiazoles Á Antitubercular activity: Á
Lowenstein–Jensen method Á
Mycobacterium tuberculosis H Rv
7
3,4-Dihydropyrimidin-2(1H)-one (DHPM) derivatives
have attracted considerable amount of attention due to the
wide range of pharmacological properties such as calcium
channels blockers, anticancer, antiviral, antioxidant and
anti-inflammatory activity (Inca et al,. 2006; Prashantha
Kumar et al., 2009; H e´ lio et al., 2006; Zamanova et al.,
2010; Sushilkumar and Devanand, 2004). Dihydropyrim-
idines are potential inhibitors of dihydrofolate reductase
3
&
N. C. Desai
dnisheeth@rediffmail.com
1
Division of Medicinal Chemistry, Department of Chemistry,
UGC NON-SAP & DST-FIST Sponsored), Maharaja
(DHFR), a promising drug target for the development of
(
anti-infective agents. Although DHFR does not represent a
novel target, there is still enthusiasm for the development
Krishnakumarsinhji Bhavnagar University, Mahatma Gandhi
Campus, Bhavnagar, Gujarat 364 002, India
123

Med Chem Res
of DHFR inhibitors, particularly with regard to mycobac-
teria (Suling et al., 1998; Li et al., 2000; Suling and
Maddry, 2001; Gerum et al., 2002; El-Hamamsy et al.,
fluorophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-ones
(4a-l) is outlined in Scheme 1. Initially, ethyl 4-(2-fluo-
rophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (1) was synthesized Biginelli reaction of urea,
ethylacetoacetate and 2-fluorobenzaldehyde in methanol
with catalytic amount of HCl. Compound 1 was further
reacted with hydrazine hydrate in the presence of catalytic
amount of con. H SO to furnish 4-(2-fluorophenyl)-6-
2
007). On the other hand, 1,3,4-oxadiazoles are an
important class of heterocyclic compounds with an array of
biological and pharmacological properties such as
antibacterial, antitubercular, vasodilatory, antifungal,
cytotoxic, anti-inflammatory, analgesic hypolipidemic,
anticancer and ulcerogenic activities (Suresh Kumar et al.,
2
4
methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbohy-
drazide (2). In the next step, intermediate 2 was reacted
with different aryl aldehydes in the presence of catalytic
2
010; Shirote and Bhatia, 2011; Prakash et al., 2010;
Padmavathi et al., 2009; Akhter et al., 2009; Idrees et al.,
009; Jayashankar et al., 2009; Kumar et al., 2009;
0
2
amount of glacial acetic acid to yield N -arylidene-4-(2-
Bhandari et al., 2008). Further, 1,3,4-oxadiazole hetero-
fluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrim-
idine-5-carbohydrazide (3a-l) intermediates. Finally, these
intermediates were condensed with acetic anhydride to
produce the targeted compounds 4a-l. Designed series of
cycles are very good bioisosteres of amides and esters and
possess
a
phenomenal pharmacokinetic property,
lipophilicity that influences the drug’s ability to reach the
target by transmembrane diffusion and may demonstrate
potent activity against resistant TB by inhibiting the
biosynthesis of lipids (Ouellet et al., 2008; Seward et al.,
1
13
molecules 4a-l were characterized by IR, H NMR,
NMR and mass spectrometry techniques before evaluating
for in vitro antitubercular activity.
C
2
006; Ahsan et al., 2011). Recognizing these facts and in
The IR spectrum of compounds 4a-l showed the
stretching vibrations of carbonyl group around 1729–
continuation to our endeavors toward the development of
-
1767 cm and the absorption bands of –NH group around
1
anti-infective agents (Desai et al., 2012a, b, 2013a, b, c,
-
1
2
015), it was envisaged that the design and synthesis of
3210–3267 cm . Strongly intense absorption bands were
observed around 1538–1594, 1529–1567 and 1136–
such novel compounds which include advantage of dual
pharmacophore of DHPMs and 1,3,4-oxadiazoles in single
molecular framework are worth the attempt.
-
1178 cm due to stretching vibrations of –C=N, –C=C
1
1
and –C–F groups, respectively. In H NMR spectra of 4a-l,
characteristic signal of secondary amine showed a broad
singlet around 5.67–6.14 ppm exchangeable with D O. The
2
Results and discussion
intense singlet peak around 2.03–2.35 ppm corresponded
to the methyl protons of the free –COCH group in 1,3,4-
3
Chemistry
oxadiazole ring. Aromatic and –CH=N protons appeared in
the region at 6.99–8.10 ppm. The singlet around 6.87–
6.99 ppm assigned to –CH proton further confirmed the
The reaction sequence for the preparation of 5-(4-acetyl-5-
1
3
(
aryl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-(2-
formation of 1,3,4-oxadiazole ring. C NMR spectrum of
2 2 2 2 4
Scheme 1 Synthetic protocol for the title compounds. Reagents and condition: a HC1, MeOH, Reflux; 2h; b NH NH H O, H SO , 1,4-dioxane,
Reflux, 3h; c Aryl aldehydes, EtOH, AcOH, Reflux; 5–6 h; d (CH CO) O, Reflux, 2h
3
2
1
23

Med Chem Res
compounds 4a-l displayed characteristic signal of carbonyl
carbon in 1,3,4-oxadiazole ring around 158.2–158.9 ppm.
Carbons of –C=N in oxadiazole ring showed a chemical
shift around 160.9–161.7 ppm. Chemical shift around
demonstrated high inhibitory activity against MTB, indi-
cating that the electronic properties of the substituents have
major influence on the antimycobacterial activity. It is a
well-known fact that strong electron withdrawing substi-
tution such as nitro, chloro and fluoro at the para position
of the aromatic ring increases the overall lipophilicity of
molecule and hence facilitates diffusion of a molecule
through the biological membranes to reach its site of
action, which in turn may provide a positive influence on
antitubercular activity (Jorge et al. 2009; Testa et al. 2000).
9
5.6–101.0 ppm was assigned to a –CH carbon in the
oxadiazole ring. Aromatic carbons were observed in the
range of 114.0–142.5 ppm. In mass spectra, molecular ion
peak is in agreement with proposed molecular weight and
elemental analysis.
Antimycobacterial activity
Experimental
Compounds 4a-l were initially screened for their in vitro
antimycobacterial activity against M. tuberculosis H Rv
3
7
All reactions except those in aqueous media were carried out
by standard techniques for the exclusion of moisture.
Melting points were determined on an electro-thermal
melting point apparatus by open capillary method and were
reported uncorrected. TLC on silica gel plates (Merck, 60,
F254) was used for monitoring of the reactions. Column
chromatography on silica gel (Merck, 70–230 mesh and
strain using Lowenstein–Jensen method exactly as descri-
bed previously (Kathrotiya and Patel 2013). Results of the
antitubercular studies are given in Table 1. Compounds
exhibiting C90 % inhibition in the initial screen were
retested at lower concentration (MIC) in Lowenstein–Jen-
sen medium to determine the actual MIC. In the prelimi-
nary screening, compounds 4c, 4f, 4h, 4i and 4j inhibited
MTB with 90–100. In the secondary level, compounds 4c
and 4f inhibited MTB with MIC of 3.12 lg/mL and com-
pound 4i with MIC of 0.20 lg/mL. Among all these
230–400 mesh ASTH for flash chromatography) was
applied when necessary to isolate and purify the reaction
products. Yields refer to purified products and are not
optimized. Elemental analysis (% C, H, N) was carried out
by a Perkin-Elmer 2400 CHN analyzer. IR spectra of all
compounds were recorded on a Perkin-Elmer FT-IR spec-
compounds, compound 4i having 4-NO substituent at the
2
phenyl ring of 1,3,4-oxadiazole substitution was found to
be the most potent compound of the series with MIC
equivalent to the standard drug isoniazid. Preliminary
in vitro results provide an excellent lead for further
development of these molecules as novel antitubercular
agents. It is interesting to note that substituents with elec-
tronic withdrawing group/atoms such as nitro, chloro and
fluoro at para position of 1,3,4-oxadiazolyl phenyl ring
-1
trophotometer in KBr, and frequencies are reported in cm .
1
H NMR spectra were run on Varian Gemini 400 MHz and
13
C NMR spectra on Varian Mercury-400, 100 MHz in
DMSO-d as a solvent and tetramethylsilane (TMS) as an
6
internal standard. Chemical shifts are reported as units
(ppm) values. LCMS spectra were scanned on a Shimadzu
LCMS 2010 spectrometer. Anhydrous reactions were car-
ried out in oven-dried glassware in nitrogen atmosphere.
Table 1 In vitro antitubercular activity of 4a-l against M. tubercu-
losis H37Rv
Preparation of ethyl 4-(2-fluorophenyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (1)
Entry
% Inhibition
MIC (lg/mL)
Compound ethyl 4-(2-fluorophenyl)-6-methyl-2-oxo-
,2,3,4-tetrahydropyrimidine-5-carboxylate (1) was pre-
pared according to the literature method with some minor
modifications. Urea (0.5 mol), ethylacetoacetate
0.75 mol) and 2-fluorobenzaldehyde (0.75 mol) were
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
36
62
98
69
71
99
56
99
99
98
39
48
99
–
1
–
3.12
–
(
–
mixed in methanol (25 ml). Catalytic amount of HCl was
added to the reaction mixture and refluxed for 2 h. The
progress of reaction was monitored by TLC. After com-
pletion of reaction, the reaction mass was cooled and
white/yellowish crystals were separated. Almost pure pro-
duct obtained as white/cream solid was filtered and dried. It
was further crystallized using methanol. Yield: 85 %; mp
3.12
–
g
h
12.5
0.20
100
–
i
j
k
l
–
2
20–221 °C; Anal. calcd. for C H N O : C-60.42,
1
4 15 2 3
Isoniazid
0.20
H-5.43, N-10.07; Found: C-60.20, H-5.55, N-10.12.
123

Med Chem Res
Preparation of 4-(2-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-i (2)
116.6 (–C=C–F in phenyl ring), 125.3 (Ar–C), 127.0 (Ar–
C) (2), 128.4 (Ar–C), 129.3 (2) (Ar–C), 130.4 (Ar–C),
130.7 (Ar–C), 130.9 (Ar–C), 134.4 (Ar–C), 149.4 (–
Compound (1) (0.01 mol) dissolved in 1,4-dioxane
(
NHN=CH–), 155.3 (–CO pyrimidine ring), 155.7 (–C–
20 mL), and to this, hydrazine hydrate (99 %) (0.01 mol)
CH ), 161.3 (–C–F), 163.4 (–CONH–); LCMS: m/z 352
3
?
[M] ; Anal. calcd. for C H F N O : C, 61.16; H, 4.40;
was added followed by the addition of a catalytic amount
2
1 18 2 4 3
of conc. H SO and allowed to stir for 3 h at 100 °C. After
N, 13.59; Found: C, 63.67; H, 4.83; N, 14.65.
2
4
completion of reaction, crude mass was allowed to cool
and poured on crushed ice. Product obtained as yellowish
precipitate was filtered and dried. Purification was done by
crystallization using ethanol (95 %).
0
N -(2-fluorobenzylidene)-4-(2-fluorophenyl)-6-methyl-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (3b)
Light yellow crystal; Yield: 76 %; mp 179–180 °C; IR
4
-(2-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-
(KBr) m
3248, 3060, 2964, 1743, 1547, 1535,
max
-
1 1
tetrahydropyrimidine-5-carbohydrazide (2)
1140 cm ; H NMR (DMSO-d , 400 MHz): d = 2.36 (s,
6
3H, –CH ), 5.59 (s, 1H, –CH pyrimidine ring), 6.15 (s, 1H,
3
Light yellow solid; Yield: 69 %; mp 198–199 °C; IR (KBr)
mmax 3452, 3342, 3071, 1513, 1685 cm
–NH–C–Ph), 7.06–7.47 (m, 8H, Ar–H), 7.48 (s, 1H, –NH–
N=CH), 7.54 (s, 1H, –NH–N=CH–), 8.45 (s, 1H, –NH–C–
-
1
1
;
H NMR
1
3
(
DMSO-d , 400 MHz): d = 1.97 (s, 2H, NH D O exch.),
Me); C NMR (DMSO-d , 100 MHz): d = 16.4 (–CH ),
6
2,
2
6
3
2
.35 (s, 3H, –CH ), 5.60 (s, 1H, –CH), 5.87 (s, 1H, –
3
51.5 (–CH pyrimidine), 99.7 (–C=C–CH pyrimidine ring),
3
NHNH ), 6.05 (s, 1H, –NHCPh), 6.18 (s, 1H, –NHCCH ),
2
115.3 (2), 116.8 (–C=C–F in phenyl ring), 125.1 (Ar–C),
130.7 (Ar–C), 130.9 (Ar–C), 131.4 (Ar–C), 131.7 (Ar–C),
132.4 (Ar–C), 132.7 (Ar–C), 149.7 (–NHN=CH–), 155.7 (–
3
1
.94 (d, 2H, Ar–H), 7.23 (d, 2H, Ar–H); C NMR
3
6
(
DMSO-d , 100 MHz): d = 162.5 (–CONH–), 161.5 (–C–
6
F), 155.9 (–C–CH ), 150.8 (–NHN=CH–), 114.6–132.4
3
CO pyrimidine ring), 156.4 (–C–CH ), 161.7 (–C–F), 161.9
3
?
(–C–F), 163.7 (–CONH–); LCMS m/z 370 [M] ; Anal.
(
Ar–C), 101.2 (–C=C–CH pyrimidine ring), 52.9 (–CH
3
?
pyrimidine), 16.2 (–CH ); LCMS: m/z 262 [M] ; Anal.
3
calcd. for C H F N O : C, 61.16; H, 4.40; N, 13.59;
21 18 2 4 3
calcd. for C H FN O : C, 54.54; H, 4.96; N, 21.20.
1
Found: C, 63.67; H, 4.83; N, 14.65.
2
13
4 2
Found: C, 54.92; H, 4.55; N, 21.12.
0
N -(4-fluorobenzylidene)-4-(2-fluorophenyl)-6-methyl-2-
0
General procedure for the preparation of N -benzylidene-
-(2-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-
oxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (3c)
4
tetrahydropyrimidine-5-carbohydrazides (3a-l)
Light orange crystal; Yield: 69 %; mp 212–213 °C; IR
(
KBr) m
3247, 3065, 2982, 1747, 1560, 1533,
max
-
1 1
A mixture of different aldehydes (0.01 mol) and 4-(2-flu-
orophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-
1145 cm ; H NMR (DMSO-d , 400 MHz): d = 2.42 (s,
6
3H, –CH ), 5.65 (s, 1H, –CH pyrimidine ring), 6.23 (s,
3
5
-carbohydrazide (0.01 mol) (2) was dissolved in ethanol.
1H, –NH–C–Ph), 7.12–7.54 (m, 8H, Ar–H), 7.56 (s, 1H, –
NH–N=CH), 7.64 (s, 1H, –NH–N=CH–), 8.37 (s, 1H, –
A catalytic amount of glacial acetic acid was added into the
reaction mixture and refluxed for 5–6 h at 78 °C by using
reflux condenser equipped with magnetic stirrer. After
completion of reaction, crude mass was cooled to room
temperature and the crystals formed were filtered off and
recrystallized from alcohol (95 %) to give product (3a-l).
1
3
NH–C–Me); C NMR (DMSO-d , 100 MHz):d = 16.7
6
(–CH ), 51.8 (–CH pyrimidine), 100.4 (–C=C–CH
3
3
pyrimidine ring), 114.9 (2), 116.4 (–C=C–F in phenyl
ring), 125.7 (Ar–C), 130.4 (Ar–C), 130.8 (Ar–C), 131.6
(Ar–C), 131.9 (Ar–C), 132.5 (Ar–C), 132.9 (Ar–C), 149.9
(
–NHN=CH–), 155.8 (–CO pyrimidine ring), 156.8 (–C–
0
N -benzylidene-4-(2-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-
CH ), 161.9 (–C–F), 162.5 (–C–F), 164.4 (–CONH–);
3
?
LCMS m/z 370 [M] ; Anal. calcd. for C H F N O : C,
tetrahydropyrimidine-5-carbohydrazide (3a)
2
1 18 2 4 3
6
1.16; H, 4.40; N, 13.59; Found: C, 63.67; H, 4.83; N,
Light brown crystal; Yield: 72 %; mp 240–241 °C; IR
14.65.
(
KBr) m
3254, 3052, 2975, 1759, 1544, 1529,
max
1
-
1
0
1
3
–
137 cm ; H NMR (DMSO-d , 400 MHz): d = 2.42 (s,
H, –CH ), 5.52 (s, 1H, –CH pyrimidine ring), 6.05 (s, 1H,
3
4-(2-fluorophenyl)-N -(2-hydroxybenzylidene)-6-methyl-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (3d)
6
NH–C–Ph), 7.04–7.49 (m, 9H, Ar–H), 7.46 (s, 1H, –NH–
N=CH), 7.55 (s, 1H, –NH–N=CH–), 8.21 (s, 1H, –NH–C–
3
Light gray crystal; Yield: 65 %; mp 267–268 °C; IR (KBr)
mmax 3234, 3039, 2987, 1765, 1540, 1533, 1145 cm ; H
1
-1 1
Me); C NMR (DMSO-d , 100 MHz): d = 16.8 (–CH ),
6
3
5
1.7 (–CH pyrimidine), 99.4 (–C=C–CH pyrimidine ring),
3
NMR (DMSO-d , 400 MHz):d = 2.47 (s, 3H, –CH ), 4.67
6
3
1
23

Med Chem Res
0
(
s, 1H, –OH), 5.54 (s, 1H, –CH pyrimidine ring), 5.98 (s,
H, –NH–C–Ph), 7.01–7.39 (m, 8H, Ar–H), 7.53 (s, 1H, –
NH–N=CH), 7.57 (s, 1H, –NH–N=CH–), 8.43 (s, 1H, –
4-(2-fluorophenyl)-6-methyl-N -(4-nitrobenzylidene)-2-
1
oxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (3g)
1
3
NH–C–Me); C NMR (DMSO-d , 100 MHz):d = 17.4 (–
CH ), 52.4 (–CH pyrimidine), 99.7 (–C=C–CH pyrimidine
3
Light orange crystal; Yield: 63 %; mp 287–288 °C; IR
(KBr) mmax 3265, 3042, 2967, 1751, 1537, 1523,
6
3
-1 1
1129 cm ; H NMR (DMSO-d
ring), 115.5 (2), 116.9 (–C=C–F in phenyl ring), 125.2 (Ar–
C), 127.4 (Ar–C), 129.5 (Ar–C) (2), 130.3 (Ar–C), 130.8
6
, 400 MHz): d = 2.47 (s,
3H, –CH ), 5.74 (s, 1H, –CH pyrimidine ring), 5.98 (s, 1H,
3
(
Ar–C), 131.6 (Ar–C), 150.2 (–NHN=CH–), 155.3 (–CO
–NH–C–Ph), 6.44 (s, 1H, –NH–N=CH), 7.04–7.57 (m, 8H,
pyrimidine ring), 155.9 (–C–CH ), 158.5 (–C–OH), 161.6
3
Ar–H), 7.59 (s, 1H, –NH–C–Me), 7.85 (s, 1H, –NH–
?
–C–F), 163.4 (–CONH–); LCMS m/z368 [M] ; Anal.
13
(
N=CH–); C NMR (DMSO-d
6
, 100 MHz): d = 16.8 (–
pyrimidine
ring), 116.7 (–C=C–F in phenyl ring), 124.4 (Ar–C) (2),
26.1 (Ar–C), 128.3 (Ar–C) (2), 130.4 (Ar–C), 130.8 (Ar–
C), 131.3 (Ar–C), 140.4, 147.7 (–C–NO ), 149.4 (–
calcd. for C H F N O : C, 61.16, H, 4.40, N, 13.59;
21 18 2 4 3
CH ), 51.8 (–CH pyrimidine), 99.9 (–C=C–CH
3 3
Found: C, 63.67; H, 4.83; N, 14.65.
1
0
4
-(2-fluorophenyl)-N -(4-hydroxybenzylidene)-6-methyl-2-
2
oxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (3e)
NHN=CH–), 155.3 (–CO pyrimidine ring), 155.8 (–C–
CH ), 161.4 (–C–F), 163.3 (–CONH–); LCMS m/z397
3
?
[M] ; Anal. calcd. for C21
Light brown crystal; Yield: 68 %; mp 232–233 °C; IR
H
18
F
2
N
4
O
3
: C, 61.16; H, 4.40;
(
KBr) m
3237, 3067, 2984, 1746, 1567, 1519,
N, 13.59; Found: C, 63.67; H, 4.83; N, 14.65.
max
-
1 1
1
129 cm ; H NMR (DMSO-d , 400 MHz): d = 2.49 (s,
6
0
3
H, –CH ), 5.23 (s, 1H, –OH), 5.59 (s, 1H, –CH pyrimidine
3
4-(2-fluorophenyl)-6-methyl-N -(2-nitrobenzylidene)-2-
ring), 6.04 (s, 1H, –NH–C–Ph), 7.11–7.47 (m, 8H, Ar–H),
oxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (3h)
7
8
1
1
.68 (s, 1H, –NH–N=CH), 7.74 (s, 1H, –NH–N=CH–),
3
1
.32 (s, 1H, –NH–C–Me);
C
NMR (DMSO-d6,
Light gray crystal; Yield: 76 %; mp 194–195 °C; IR (KBr)
m
-1 1
max 3267, 3055, 2967, 1770, 1557, 1547, 1130 cm ; H
00 MHz): d = 16.6 (–CH ), 52.7 (–CH pyrimidine),
3
00.3 (–C=C–CH pyrimidine ring), 115.3 (2), 116.5 (–
3
NMR (DMSO-d , 400 MHz): d = 2.38 (s, 3H, –CH ), 5.69
6
3
C=C–F in phenyl ring), 125.5 (Ar–C), 127.7 (Ar–C), 129.9
Ar–C) (2), 130.6 (Ar–C), 131.2 (Ar–C), 131.8 (Ar–C),
49.4 (–NHN=CH–), 155.8 (–CO pyrimidine ring), 156.5
(s, 1H, –CH pyrimidine ring), 6.04 (s, 1H, –NH–C–Ph),
6.49 (s, 1H, –NH–N=CH), 7.13–7.67 (m, 8H, Ar–H), 7.72
(
1
3
1
(s, 1H, –NH–C–Me), 7.92 (s, 1H, –NH–N=CH–);
NMR (DMSO-d , 100 MHz): d = 16.4 (–CH ), 52.4 (–CH
pyrimidine), 102.2 (–C=C–CH pyrimidine ring), 116.4 (–
C
(
–C–CH ), 158.7 (–C–OH), 161.4 (–C–F), 163.9 (–CONH–
3
?
; LCMS m/z368 [M] ; Anal. calcd. for C H F N O : C,
6
3
)
3
2
1 18 2 4 3
6
1
1.16; H, 4.40; N, 13.59; Found: C, 63.67; H, 4.83; N,
4.65.
C=C–F in phenyl ring), 124.6 (Ar–C) (2), 127.4 (Ar–C),
128.7 (Ar–C) (2), 130.5 (Ar–C), 130.9 (Ar–C), 131.6 (Ar–
C), 140.2 (Ar–C), 147.9 (–C–NO ), 149.7 (–NHN=CH–),
2
0
N -(4-chlorobenzylidene)-4-(2-fluorophenyl)-6-methyl-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (3f)
155.5 (–CO pyrimidine ring), 156.2 (–C–CH ), 161.7 (–C–
3
?
F), 163.5 (–CONH–); LCMS m/z 397 [M] ; Anal. calcd.
for C H F N O : C, 61.16; H, 4.40; N, 13.59; Found: C,
1 18 2 4 3
2
Light yellow crystal; Yield: 59 %; mp 276–277 °C; IR
63.67; H, 4.83; N, 14.65.
(
KBr) m
3278, 3043, 2976, 1763, 1549, 1533,
max
1
-
1
0
1
3
–
131 cm ; H NMR (DMSO-d , 400 MHz): d = 2.36 (s,
H, –CH ), 5.65 (s, 1H, –CH pyrimidine ring), 5.95 (s, 1H,
3
4-(2-fluorophenyl)-6-methyl-N -(3-nitrobenzylidene)-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (3i)
6
NH–C–Ph), 7.01–7.51 (m, 8H, Ar–H), 7.57 (s, 1H, –NH–
C–Me), 7.72 (s, 1H, –NH–N=CH), 7.91 (s, 1H, –NH–
1
Light brown crystal; Yield: 81 %; mp 222–223 °C; IR
(KBr) mmax 3242, 3039, 2969, 1767, 1548, 1539,
3
N=CH–); C NMR (DMSO-d , 100 MHz): d = 17.4 (–
6
-
1 1
1141 cm ; H NMR (DMSO-d
CH ), 52.7 (–CH pyrimidine), 100.3 (–C=C–CH pyrim-
3
6
, 400 MHz): d = 2.42 (s,
3H, –CH ), 5.49 (s, 1H, –CH pyrimidine ring), 5.78 (s, 1H,
3
idine ring), 117.4 (–C=C–F in phenyl ring), 124.7(Ar–C),
29.5(Ar–C)(2), 130.4 (Ar–C) (2), 130.7 (Ar–C), 131.5
3
1
–NH–C–Ph), 6.34 (s, 1H, –NH–N=CH), 7.03–7.58 (m, 8H,
Ar–H), 7.81 (s, 1H, –NH–C–Me), 7.99 (s, 1H, –NH–
(
(
Ar–C), 131.8 (Ar–C), 132.4 (Ar–C), 134.5 (Ar–C), 135.6
–C–Cl), 149.7 (–NHN=CH–), 155.5 (–CO pyrimidine
1
3
N=CH–); C NMR (DMSO-d
CH ), 51.3 (–CH pyrimidine), 102.4 (–C=C–CH
3
, 100 MHz): d = 17.4 (–
6
ring), 156.2 (–C–CH ), 161.7 (–C–F), 163.7 (–CONH–);
3
3
pyrim-
?
LCMS m/z 386 [M] ; Anal. calcd. for C H F N O : C,
idine ring), 115.9 (–C=C–F in phenyl ring), 125.7 (Ar–C)
(2), 127.9 (Ar–C), 128.8 (Ar–C) (2), 130.8 (Ar–C), 131.4
2
1 18 2 4 3
6
1
1.16; H, 4.40; N, 13.59; Found: C, 63.67; H, 4.83; N,
4.65.
(Ar–C), 131.9 (Ar–C), 140.7 (Ar–C), 147.5 (–C–NO ),
2
123

Med Chem Res
1
3
1
50.3 (–NHN=CH–), 155.4 (–CO pyrimidine ring), 155.9
(s, 1H, –NH–N=CH), 8.24 (s, 1H, –NH–N=CH–);
C
(
–C–CH ), 161.5 (–C–F), 163.9 (–CONH–); LCMS m/z
3
NMR (DMSO-d , 100 MHz):d = 16.6 (–CH ), 51.7 (–CH
pyrimidine), 99.5 (–C=C–CH pyrimidine ring), 116.4 (–
3
6
3
?
97 [M] ; Anal. calcd. for C H F N O : C, 61.16; H,
3
2
1
18
2
4
3
4
.40; N, 13.59; Found: C, 63.67; H, 4.83; N, 14.65.
C=C–F in phenyl ring), 125.0 (Ar–C), 128.7 (Ar–C), 129.7
(
Ar–C) (2), 130.4 (Ar–C), 130.7 (Ar–C), 131.4 (Ar–C),
0
4
-(2-fluorophenyl)-N -(4-methoxybenzylidene)-6-methyl-2-
132.4 (Ar–C), 133.7 (2) (–C–Cl), 140.5 (–NHN=CH–),
oxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (3j)
155.7 (–CO pyrimidine ring), 155.9 (–C–CH ), 161.7 (–C–
3
?
F), 163.9 (–CONH–); LCMS m/z 421 [M] ; Anal. calcd.
Light pink crystal; Yield: 70 %; mp 237–238 °C; IR (KBr)
mmax 3252, 3057, 2979, 1767, 1549, 1531, 1145 cm ; H
for C H F N O : C, 61.16; H, 4.40; N, 13.59; Found: C,
21 18 2 4 3
-
1 1
63.67; H, 4.83; N, 14.65.
NMR (DMSO-d , 400 MHz): d = 2.53 (s, 3H, –CH ), 3.78
6
3
(
s, 3H, –OCH ), 5.47 (s, 1H, –CH pyrimidine ring), 5.73 (s,
3
General procedure for the preparation of 5-(4-acetyl-5-
aryl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-(2-fluorophenyl)-
6-methyl-3,4-dihydropyrimidin-2(1H)-ones (4a–l)
1
H, –NH–C–Ph), 6.98–7.45 (m, 8H, Ar–H), 7.52 (s, 1H, –
NH–C–Me), 7.67 (s, 1H, –NH–N=CH), 8.32 (s, 1H, –NH–
3
N=CH–); C NMR (DMSO-d , 100 MHz): d = 16.9 (–
1
6
CH ), 51.5 (–CH pyrimidine), 57.8 (–OCH ), 100.4 (–
3
Acetic anhydride (0.02 mol) was added to compounds
(3a-l) (0.01 mol), and the reaction mass was refluxed for
2 h using reflux condenser. After completion of reaction,
the reaction mixture was poured into ice-cold water. The
precipitate was filtered off, washed with water, dried and
recrystallized from DMF–ethanol to give product (4a-l).
3
C=C–CH pyrimidine ring), 114.7 (Ar–C) (2), 117.3 (–
3
C=C–F in phenyl ring), 125.2 (Ar–C), 127.4 (Ar–C), 129.4
(
Ar–C) (2), 130.4 (Ar–C), 130.7 (Ar–C), 131.4 (Ar–C),
49.7 (–NHN=CH–), 155.7 (–CO pyrimidine ring), 156.5
–C–CH ), 159.7 (–C–OCH ), 161.8 (–C–F), 164.4 (–
1
(
3
3
?
CONH–); LCMS m/z 382 [M] ; Anal. calcd. for C H
1 18-
2
F N O : C,61.16; H,4.40; N,13.59; Found: C, 63.67; H,
4 3
5-(4-acetyl-5-phenyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-
(2-fluorophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one
2
4
.83; N, 14.65.
(4a)
0
4
-(2-fluorophenyl)-N -(2-methoxybenzylidene)-6-methyl-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (3k)
Light pink crystal; Yield: 72 %; mp 240–241 °C; IR (KBr)
-
1 1
mmax 3210, 3095, 2924, 1751, 1594,1557, 1140 cm ; H
NMR (DMSO-d , 400 MHz): d = 2.09 (s, 3H, –COCH ),
2.45 (s, 3H, –CH ), 5.56 (s, 1H, –CH pyrimidine ring), 5.93
Yellowish orange crystal; Yield: 60 %; mp 262–263 °C; IR
6
3
(
KBr) m
3259, 3059, 2981, 1749, 1554, 1534,
max
3
-
1 1
1
143 cm ; H NMR (DMSO-d , 400 MHz): d = 2.48 (s,
(s, 1H, –NH–C–Ph), 6.98 (s, 1H, –CH oxadiazole ring),
1
6
3
3
H, –CH ), 3.57 (s, 3H, –OCH ), 5.54 (s, 1H, –CH
3
7.09–7.39 (m, 9H, Ar–H), 7.91 (s, 1H, –NH–C–Me);
C
3
pyrimidine ring), 5.81 (s, 1H, –NH–C–Ph), 7.03–7.38 (m,
H, Ar–H), 7.59 (s, 1H, –NH–C–Me), 7.74 (s, 1H, –NH–
NMR (DMSO-d , 100 MHz): d = 16.3 (–CH ), 23.2 (–
COCH ), 55.3 (–CH pyrimidine), 93.5 (–C=C–CH
3 3
6
3
8
1
N=CH), 8.24 (s, 1H, –NH–N=CH–); C NMR (DMSO-d6,
3
pyrimidine ring), 101.0 (–CH of oxadiazole ring), 116.7 (–
C=C–F in phenyl ring), 127.5 (Ar–C) (2), 128.4 (Ar–C)
(2), 128.7 (Ar–C), 128.9 (Ar–C) (2), 130.2 (Ar–C), 134.3
(Ar–C), 140.7, 155.5 (–CO pyrimidine ring), 156.2 (–C–
CH ), 158.2 (–COCH ), 160.9 (–C=N oxadiazole ring),
1
00 MHz): d = 17.4 (–CH ), 52.4 (–CH pyrimidine), 58.5
3
(
–OCH ), 100.7 (–C=C–CH pyrimidine ring), 115.6 (Ar–
3 3
C) (2), 116.7 (–C=C–F in phenyl ring), 125.8 (Ar–C),
28.5 (Ar–C), 129.7 (Ar–C) (2), 130.6 (Ar–C), 130.9 (Ar–
1
3
3
?
C), 131.2 (Ar–C), 149.5 (–NHN=CH–), 155.5 (–CO
pyrimidine ring), 156.3 (–C–CH ), 160.3 (–C–OCH ),
161.5 (–C–F); LCMS m/z 394 [M] ; Anal. calcd. for C
21-
H FN O : C, 63.95; H, 4.86; N, 14.21; Found: C, 63.07;
19 4 3
3
3
?
61.4 (–C–F), 163.7 (–CONH–); LCMS m/z 382 [M] ;
1
H, 4.83; N, 14.65.
Anal. calcd. for C H F N O : C, 61.16; H, 4.40; N,
1 18 2 4 3
2
1
3.59; Found: C, 63.67; H, 4.83; N, 14.65.
5-(4-acetyl-5-(2-fluorophenyl)-4,5-dihydro-1,3,4-
oxadiazol-2-yl)-4-(2-fluorophenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (4b)
0
N -(2,6-dichlorobenzylidene)-4-(2-fluorophenyl)-6-methyl-
2
-oxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (3l)
Light brown crystal; Yield: 58 %; mp 254–255 °C; IR
Light gray crystal; Yield: 79 %; mp 292–293 °C; IR (KBr)
(KBr)
m
3220, 3087, 2916, 1745, 1578,1567,
max
-1 1
-
1
1
mmax 3267, 3057, 2990, 1776, 1560, 1545, 1156 cm ; H
NMR (DMSO-d , 400 MHz): d = 2.34 (s, 3H, –CH ), 5.34
1149 cm ; H NMR (DMSO-d , 400 MHz): d = 2.15 (s,
6
3H, –COCH ), 2.45 (s, 3H, –CH ), 5.56 (s, 1H, –CH
3
6
3
3
(
s, 1H, –CH pyrimidine ring), 6.05 (s, 1H, –NH–C–Ph),
pyrimidine ring), 5.89 (s, 1H, –NH–C–Ph), 6.98 (s, 1H, –
CH oxadiazole ring), 6.99–7.41 (m, 8H, Ar–H), 7.85 (s,
6
.84–7.34 (m, 7H, Ar–H), 7.64 (s, 1H, –NH–C–Me), 8.45
1
23

Med Chem Res
1
3
1
H, –NH–C–Me);
C NMR (DMSO-d , 100 MHz):
6
61.46; H, 4.67; N, 13.65; Found: C, 61.48; H, 4.51; N,
13.19.
d = 16.7 (–CH ), 24.3 (–COCH ), 53.5 (–CH pyrimidine),
3
3
9
5.7 (–C=C–CH pyrimidine ring), 97.0 (–CH of oxadia-
3
zole ring), 116.9 (–C=C–F in phenyl ring), 117.5 (Ar–C),
5-(4-acetyl-5-(4-hydroxyphenyl)-4,5-dihydro-1,3,4-
oxadiazol-2-yl)-4-(2-fluorophenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (4e)
1
1
1
24.5 (Ar–C), 124.8 (Ar–C), 125.3 (Ar–C), 128.7(Ar–C),
29.9 (Ar–C), 130.7 (Ar–C), 131.3 (Ar–C), 131.5 (Ar–C),
55.8 (–CO pyrimidine ring), 156.7 (–C–CH ), 158.5 (–
3
COCH ), 161.3 (–C=N oxadiazole ring), 161.5, 161.8 (–C–
3
Light yellow crystal; Yield: 75 %; mp 286–287 °C; IR
?
F); LCMS m/z 412 [M] ; Anal. calcd. for C H F N O :
(KBr) m
3456, 3245, 3078, 2950, 1729, 1578, 1539,
max
1 1
2
1
18
2
4
3
-
C, 61.16; H, 4.40; N, 13.59; Found: C, 61.14; H, 4.70; N,
1178 cm ; H NMR (DMSO-d , 400 MHz): d = 2.29 (s,
6
1
3.56.
3H, –COCH ), 2.39 (s, 3H, –CH ), 5.56 (s, 1H, –CH
3
3
pyrimidine ring), 5.78 (s, 1H, –NH–C–Ph), 6.99 (s, 1H, –
5
-(4-acetyl-5-(4-fluorophenyl)-4,5-dihydro-1,3,4-
CH oxadiazole ring), 7.08–7.45 (m, 8H, Ar–H), 8.04 (s,
1
3
oxadiazol-2-yl)-4-(2-fluorophenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (4c)
1H, –NH–C–Me);
C NMR (DMSO-d , 100 MHz):
6
d = 18.2 (–CH ), 24.6 (–COCH ), 53.8 (–CH pyrimidine),
3
3
94.5 (–C=C–CH pyrimidine ring), 96.5 (–CH of oxadia-
3
Light gray crystal; Yield: 69 %; mp 160–161 °C; IR (KBr)
mmax 3235, 3078, 2934, 1745(–CO stret.), 1580,1561,
zole ring), 116.4 (–C=C–F in phenyl ring), 120.6 (Ar–C),
123.7 (Ar–C), 124.3 (Ar–C), 126.5 (Ar–C), 127.9 (Ar–C),
128.5 (Ar–C), 129.8 (Ar–C), 130.4 (Ar–C), 131.9 (Ar–C),
-
1 1
1
136 cm ; H NMR (DMSO-d , 400 MHz): d = 2.26 (s,
6
3
H, –COCH ), 2.34 (s, 3H, –CH ), 5.39 (s, 1H, –CH
3
154.8 (–CO pyrimidine ring), 156.7 (–C–CH ), 158.4 (–
3
3
pyrimidine ring), 5.76 (s, 1H, –NH–C–Ph), 6.87 (s, 1H, –
CH oxadiazole ring), 7.10–7.49 (m, 8H, Ar–H), 7.92 (s,
COCH ), 161.6 (–C=N oxadiazole ring), 161.8, 162.5 (–C–
3
?
F); LCMS m/z 410 [M] ; Anal. calcd. for C H FN O : C,
2
1
19
4 4
1
3
1
H, –NH–C–Me);
C NMR (DMSO-d , 100 MHz):
6
61.46, H, 4.67, N, 13.65; Found: C, 61.62, H, 4.84, N,
13.16.
d = 16.9 (–CH ), 24.4 (–COCH ), 53.8 (–CH pyrimidine),
3
3
9
4.5 (–C=C–CH pyrimidine ring), 98.8 (–CH of oxadia-
3
zole ring), 118.8 (–C=C–F in phenyl ring), 120.8 (Ar–C),
5-(4-acetyl-5-(4-chlorophenyl)-4,5-dihydro-1,3,4-
oxadiazol-2-yl)-4-(2-fluorophenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (4f)
1
1
1
23.8 (Ar–C), 124.4 (Ar–C), 125.7 (Ar–C), 127.5 (Ar–C),
28.4 (Ar–C), 129.4 (Ar–C), 130.3 (Ar–C), 130.5 (Ar–C),
55.6 (–CO pyrimidine ring), 156.8 (–C–CH ), 158.4 (–
3
COCH ), 161.2 (–C=N oxadiazole ring), 161.5, 161.7 (–C–
3
Light yellow crystal; Yield: 57 %; mp 257–258 °C; IR
?
F); LCMS m/z 412 [M] ; Anal. calcd. for C H F N O :
(KBr) m
3252, 3082, 2962, 1734, 1584, 1543,
2
1
18
2
4
3
max
-
1 1
C, 61.16; H, 4.40; N, 13.59; Found: C, 61.17; H, 4.27; N,
1157 cm ; H NMR (DMSO-d , 400 MHz): d = 2.32 (s,
6
1
3.68.
3H, –COCH ), 2.43 (s, 3H, –CH ), 5.62 (s, 1H, –CH
3
3
pyrimidine ring), 5.82 (s, 1H, –NH–C–Ph), 6.87 (s, 1H, –
CH oxadiazole ring), 7.12–7.39 (m, 8H, Ar–H), 7.83 (s,
5
-(4-acetyl-5-(2-hydroxyphenyl)-4,5-dihydro-1,3,4-
1
3
oxadiazol-2-yl)-4-(2-fluorophenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (4d)
1H, –NH–C–Me);
C NMR (DMSO-d , 100 MHz):
6
d = 16.4 (–CH ), 23.5 (–COCH ), 54.4 (–CH pyrimidine),
3
3
93.7 (–C=C–CH pyrimidine ring), 95.7 (–CH of oxadia-
3
Light orange crystal; Yield: 56 %; mp 189–190 °C; IR
zole ring), 116.5 (–C=C–F in phenyl ring), 120.3 (Ar–C),
123.6 (Ar–C), 124.8 (Ar–C), 126.4 (Ar–C), 127.7 (Ar–C),
128.4 (Ar–C), 129.3 (Ar–C), 130.7 (Ar–C), 131.6 (Ar–C),
(
KBr) m
3445, 3226, 3067, 2945, 1739, 1584, 1556,
max
1 1
-
1
158 cm ; H NMR (DMSO-d , 400 MHz): d = 2.35 (s,
6
3
H, –COCH ), 2.46 (s, 3H, –CH ), 5.43 (s, 1H, –CH
3
154.5 (–CO pyrimidine ring), 156.4 (–C–CH ), 158.7 (–
3
3
pyrimidine ring), 5.67 (s, 1H, –NH–C–Ph), 6.94 (s, 1H, –
CH oxadiazole ring), 7.04–7.39 (m, 8H, Ar–H), 7.84 (s,
COCH ), 161.3 (–C=N oxadiazole ring), 161.4, 162.8 (–C–
3
?
F); LCMS m/z 428 [M] ; Anal. calcd. for C H FClN O :
2
1
18
4 3
1
3
1
H, –NH–C–Me);
C NMR (DMSO-d , 100 MHz):
6
C, 58.82; H, 4.23; N, 13.06; Found: C, 58.31; H, 4.57; N,
13.76.
d = 16.4 (–CH ), 23.4 (–COCH ), 53.6 (–CH pyrimidine),
3
3
9
4.7 (–C=C–CH pyrimidine ring), 97.3 (–CH of oxadia-
3
zole ring), 117.5 (–C=C–F in phenyl ring), 120.4 (Ar–C),
5-(4-acetyl-5-(2-nitrophenyl)-4,5-dihydro-1,3,4-oxadiazol-
2-yl)-4-(2-fluorophenyl)-6-methyl-3,4-dihydropyrimidin-
2(1H)-one (4g)
1
1
1
23.4 (Ar–C), 124.6 (Ar–C), 126.3 (Ar–C), 127.7 (Ar–C),
28.7 (Ar–C), 129.5 (Ar–C), 130.6 (Ar–C), 131.7 (Ar–C),
54.6 (–CO pyrimidine ring), 156.4 (–C–CH ), 158.7 (–
3
COCH ), 161.3 (–C=N oxadiazole ring), 161.2, 162.3 (–C–
3
Light yellow crystal; Yield: 59 %; mp 234–235 °C; IR
(KBr) mmax 3247, 3072, 2968, 1743, 1538, 1551,
?
F); LCMS m/z 410[M] ; Anal. calcd. for C H FN O : C,
2
1
19
4 4
123

Med Chem Res
-
1 1
1
162 cm ; H NMR (DMSO-d , 400 MHz): d = 2.23 (s,
(–C=N oxadiazole ring), 162.7 (–C–F); LCMS m/z 439
?
[M] ; Anal. calcd. for C H FN O : C, 57.40; H,4.13;
6
3
H, –COCH ), 2.42 (s, 3H, –CH ), 5.53 (s, 1H, –CH
3
3
21 18
5 5
pyrimidine ring), 6.04 (s, 1H, –NH–C–Ph), 6.91 (s, 1H, –
N,15.94; Found: C, 57.70; H, 4.77; N, 15.60.
CH oxadiazole ring), 7.20–8.10 (m, 8H, Ar–H), 8.15 (s,
1
3
1
H, –NH–C–Me);
C NMR (DMSO-d , 100 MHz):
6
5-(4-acetyl-5-(2,6-dichlorophenyl)-4,5-dihydro-1,3,4-
oxadiazol-2-yl)-4-(2-fluorophenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (4j)
d = 16.7 (–CH ), 23.4 (–COCH ), 55.7 (–CH pyrimidine),
3
3
9
4.4 (–C=C–CH pyrimidine ring), 96.3 (–CH of oxadia-
3
zole ring), 115.7 (–C=C–F in phenyl ring), 124.6 (Ar–C)
(
(
2), 125.2 (Ar–C), 126.7 (Ar–C) (2), 130.5 (Ar–C), 131.2
Light brown crystal; Yield: 78 %; mp 198–199 °C; IR
Ar–C), 131.5 (Ar–C), 141.9, 148.5 (C–NO ), 155.8 (–CO
2
(KBr) m
3246, 3058, 2979, 1729, 1557, 1537,
max
-
1 1
pyrimidine ring), 156.5 (–C–CH ), 158.9 (–COCH ), 161.3
3
1148 cm ; H NMR (DMSO-d , 400 MHz): d = 2.14 (s,
3
6
(
–C=N oxadiazole ring), 162.8 (–C–F); LCMS m/z 439
3H, –COCH ), 2.54 (s, 3H, –CH ), 5.59 (s, 1H, –CH
3
3
?
M] ; Anal. calcd. for C H FN O : C, 57.40; H, 4.13; N,
[
pyrimidine ring), 6.05 (s, 1H, –NH–C–Ph), 6.88 (s, 1H, –
CH oxadiazole ring), 7.11–7.55 (m, 7H, Ar–H), 7.70 (s,
2
1
18
5 5
1
5.94; Found: C, 57.37; H, 4.23; N, 15.91.
1
3
1H, –NH–C–Me);
C NMR (DMSO-d , 100 MHz):
6
5
2
2
-(4-acetyl-5-(3-nitrophenyl)-4,5-dihydro-1,3,4-oxadiazol-
-yl)-4-(2-fluorophenyl)-6-methyl-3,4-dihydropyrimidin-
(1H)-one (4h)
d = 17.4 (–CH ), 23.4 (–COCH ), 54.6 (–CH pyrimidine),
94.5 (–C=C–CH pyrimidine ring), 95.6 (–CH of oxadiazol
3
3
3
ring), 116.7 (–C=C–F in phenyl ring), 124.8 (Ar–C), 129.7
(Ar–C) (2), 130.3 (Ar–C), 130.8 (Ar–C) (2), 131.5 (Ar–C),
Light yellow crystal; Yield: 59 %; mp 206–207 °C; IR
KBr) m 3254, 3067, 2974, 1756, 1544, 1557,
132.6 (Ar–C), 134.5 (Ar–C) (2), 156.5 (–CO pyrimidine
ring), 157.7 (–C–CH ), 158.2 (–COCH ), 160.6 (–C=N
(
max
1
3
3
-
1
?
oxadiazole ring), 161.3 (–C–F); LCMS m/z 462 [M] ;
1
155 cm ; H NMR (DMSO-d , 400 MHz): d = 2.17 (s,
6
3
H, –COCH ), 2.35 (s, 3H, –CH ), 5.49 (s, 1H, –CH
3
Anal. calcd. for C H Cl FN O : C, 54.44; H, 3.70; N,
21 17
3
2
4 3
pyrimidine ring), 6.14 (s, 1H, –NH–C–Ph), 6.88 (s, 1H, –
CH oxadiazole ring), 7.14–7.89 (m, 8H, Ar–H), 8.04 (s,
12.09; Found: C, 54.71; H, 3.79; N, 12.01.
1
3
1
H, –NH–C–Me);
C NMR (DMSO-d , 100 MHz):
6
5-(4-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1,3,4-
oxadiazol-2-yl)-4-(2-fluorophenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (4k)
d = 17.4 (–CH ), 24.4 (–COCH ), 55.5 (–CH pyrimidine),
3
3
9
4.7 (–C=C–CH pyrimidine ring), 96.7 (–CH of oxadia-
3
zole ring), 116.6 (–C=C–F in phenyl ring), 124.9 (Ar–C)
(
(
2), 125.5 (Ar–C), 126.4 (Ar–C) (2), 130.7 (Ar–C), 131.4
Light brown crystal; Yield: 72 %; mp 256–257 °C; IR
Ar–C), 131.8 (Ar–C), 142.4, 148.7 (C–NO ), 155.4 (–CO
2
(KBr) m
3267, 3047, 2963, 1761, 1548, 1535,
max
-
1 1
pyrimidine ring), 156.7 (–C–CH ), 158.4 (–COCH ), 161.7
3
1153 cm ; H NMR (DMSO-d , 400 MHz): d = 2.03 (s,
3
6
(
–C=N oxadiazole ring), 162.4 (–C–F); LCMS m/z 439
3H, –COCH ), 2.44 (s, 3H, –CH ), 3.78 (s, 3H, –OCH ),
3
3
3
?
M] ; Anal. calcd. for C H FN O : C, 57.40; H, 4.13; N,
[
5.58 (s, 1H, –CH pyrimidine ring), 6.09 (s, 1H, –NH–C–
Ph), 6.97 (s, 1H, –CH oxadiazole ring), 6.99–7.39 (m, 8H,
2
1
18
5 5
1
5.94; Found: C, 57.69; H, 4.68; N, 15.56.
1
Ar–H), 7.74 (s, 1H, –NH–C–Me); C NMR (DMSO-d6,
3
5
2
2
-(4-acetyl-5-(4-nitrophenyl)-4,5-dihydro-1,3,4-oxadiazol-
-yl)-4-(2-fluorophenyl)-6-methyl-3,4-dihydropyrimidin-
(1H)-one (4i)
100 MHz): d = 16.8 (–CH ), 24.7 (–COCH ), 53.7 (–CH
3
3
pyrimidine), 56.3 (–OCH ), 93.9 (–C=C–CH pyrimidine
3
3
ring), 101.0 (–CH of oxadiazole ring), 114.0 (2), 116.4 (–
C=C–F in phenyl ring), 125.0 (Ar–C), 127.1 (Ar–C) (2),
129.7(Ar–C), 130.6 (Ar–C), 131.3 (Ar–C), 131.6 (Ar–C),
Light yellow crystal; Yield: 66 %; mp 222–223 °C; IR
KBr) m 3247, 3072, 2956), 1767, 1546, 1534,
(
156.3 (–CO pyrimidine ring), 156.7 (–C–CH ), 158.3 (–
3
max
-
1 1
1
167 cm ; H NMR (DMSO-d , 400 MHz): d = 2.17 (s,
COCH ), 161.2 (–C=N oxadiazole ring), 161.7 (–C–F),
3
6
?
162.7 (–C–OCH ); LCMS m/z 424 [M] ; Anal. calcd. for
3
H, –COCH ), 2.39 (s, 3H, –CH ), 5.55 (s, 1H, –CH
3
3
3
pyrimidine ring), 6.18 (s, 1H, –NH–C–Ph), 6.93 (s, 1H, –
C H F N O : C, 61.16; H, 4.40; N, 13.59; Found: C,
21 18 2 4 3
CH oxadiazole ring), 7.18–7.74 (m, 8H, Ar–H), 8.13 (s,
1
63.67; H, 4.83; N, 14.65.
3
1
H, –NH–C–Me);
C NMR (DMSO-d , 100 MHz):
6
d = 17.6 (–CH ), 23.3 (–COCH ), 54.9 (–CH pyrimidine),
5-(4-acetyl-5-(2-methoxyphenyl)-4,5-dihydro-1,3,4-
oxadiazol-2-yl)-4-(2-fluorophenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (4l)
3
3
9
4.3 (–C=C–CH pyrimidine ring), 95.8 (–CH of oxadia-
3
zole ring), 115.9 (–C=C–F in phenyl ring), 124.4 (Ar–C)
(
(
2), 125.7 (Ar–C), 126.7 (Ar–C) (2), 129.3 (Ar–C), 130.7
Ar–C), 131.5 (Ar–C), 142.6, 147.6 (C–NO ), 155.7 (–CO
2
Light brown crystal; Yield: 72 %; mp 240–241 °C; IR
(KBr) mmax 3254, 3052, 2975, 1759, 1544, 1529,
pyrimidine ring), 156.9 (–C–CH ), 158.6 (–COCH ), 160.3
3
3
1
23

Med Chem Res
-
1 1
1
3
5
137 cm ; H NMR (DMSO-d , 400 MHz): d = 2.09 (s,
withdrawing group/atoms such as nitro, chloro and fluoro
at para position of 1,3,4-oxadiazolyl phenyl ring showed
very good antitubercular activity. Compound 4i substituted
with fluoro group emerged as the most potent antituber-
cular agents with MIC equivalent to isoniazid. Conse-
quently, such type of compounds would represent a fertile
matrix for further development of novel and potent anti-
tubercular agents requiring further optimization in order to
discover the scope and limitation of its biological profile.
6
H, –COCH ), 2.47 (s, 3H, –CH ), 3.67 (s, 3H, –OCH ),
3
3
3
.63 (s, 1H, –CH pyrimidine ring), 6.13 (s, 1H, –NH–C–
Ph), 6.95 (s, 1H, –CH oxadiazole ring), 7.02–7.43 (m, 8H,
1
Ar–H), 7.76 (s, 1H, –NH–C–Me); C NMR (DMSO-d6,
3
1
00 MHz): d = 16.8 (–CH ), 24.7(–COCH ), 53.7 (–CH
pyrimidine), 56.3 (–OCH ), 93.9 (–C=C–CH pyrimidine
3
3
3
3
ring), 101.0 (–CH of oxadiazole ring), 114.0 (2), 116.4 (–
C=C–F in phenyl ring), 125.0 (Ar–C), 127.1 (Ar–C) (2),
1
1
29.7 (Ar–C), 130.6 (Ar–C), 131.3 (Ar–C), 131.6 (Ar–C),
Acknowledgments The authors are thankful to the University
Grants Commission, New Delhi, for NON-SAP and UGC-BSR one-
time grant and Department of Science and Technology, New Delhi,
for DST-FIST programs financial support. We would like to express
our sincere gratitude to the Department of Chemistry, Mahatma
Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar Univer-
sity, Bhavnagar, for providing research and library facilities. One of
the authors, Amit R. Trivedi is thankful to UGC for awarding Dr.
D. S. Kothari Post-Doctoral Fellowship.
56.3 (–CO pyrimidine ring), 156.7 (–C–CH ), 158.3 (–
3
COCH ), 161.2 (–C=N oxadiazole ring), 161.7 (–C–F),
3
?
1
62.7 (–C–OCH ); LCMS m/z 424 [M] ; Anal. calcd. for
3
C H F N O : C, 61.16; H, 4.40; N, 13.59; Found: C,
21 18 2 4 3
6
3.67; H, 4.83; N, 14.65.
Biological assay
Antitubercular assay
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