In vitro anti-inflammatory potential and QSAR analysis of oxazolo/thiazolo pyrimidine derivatives

Article abstract of DOI:10.1007/s00044-012-0189-5

Twenty-six different benzylidene oxazolo/thiazolo (3,2-a)-pyrimidine-6- carboxamide derivatives were synthesized and evaluated for their anti-inflammatory potential by protein denaturation method. The structures of title compounds were characterized by IR and NMR spectral data. The SAR studies reveal that compounds containing electron withdrawing polar group at para position of 5-phenyl ring and electron withdrawing non-polar group at para position of 2-benzylidene moiety of thiazolo pyrimidine nucleus have better anti-inflammatory potential. The 2D-QSAR studies were performed on VLife MDS software which reveals that anti-inflammatory potential of benzylidene-3-oxo-5H- oxazolo/thiazolo (3,2-a)-pyrimidine-6-carboxamides is dependent on estate contribution, alignment independent, individual and path count descriptors.

Full text of DOI:10.1007/s00044-012-0189-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0189-5
ORIGINAL RESEARCH
In vitro anti-inflammatory potential and QSAR analysis
of oxazolo/thiazolo pyrimidine derivatives
•
Ramesh L. Sawant Charusheela A. Bansode
•
Jyoti B. Wadekar
Received: 24 January 2012 / Accepted: 4 August 2012
Ó Springer Science+Business Media, LLC 2012
Abstract Twenty-six different benzylidene oxazolo/
thiazolo (3,2-a)-pyrimidine-6-carboxamide derivatives were
synthesized and evaluated for their anti-inflammatory
potential by protein denaturation method. The structures of
title compounds were characterized by IR and NMR spectral
data. The SAR studies reveal that compounds containing
electron withdrawing polar group at para position of 5-phe-
nyl ring and electron withdrawing non-polar group at para
position of 2-benzylidene moiety of thiazolo pyrimidine
nucleus have better anti-inflammatory potential. The 2D-
QSAR studies were performed on VLife MDS software
which reveals that anti-inflammatory potential of benzyli-
(Kappe, 2000a, b), blood platelet aggregation inhibitor
(Tozkoparan et al., 1995), drug for the treatment of benign
prostatic hyperplasia (Nagarathnam et al., 1998), anti-
inflammatory (Tozkoparan et al., 2000), muscarinic (Jung
et al., 2001), antifungal, and antibacterial drugs (Kappe,
2000a, b; Sawant and Bhatia, 2009). Thiazolidinone deriv-
atives are associated with diverse biological activities like
antibacterial, antifungal, and antitubercular (Sharma et al.,
2009). It is well known that pyrimidine and fused hetero-
cyclic pyrimidine derivatives are of great biological interest,
especially as antiviral, antitumor, antimicrobial, and anti-
inflammatory agents (Mishra and Tomar, 2011; Wilson
et al., 2008; Rensloet al., 2006; Ashok et al., 2007; Zaher and
Elassar, 2002; Shah and Vaghasia, 2007).
dene-3-oxo-5H-oxazolo/thiazolo
boxamides is dependent on estate contribution, alignment
independent, individual and path count descriptors.
(3,2-a)-pyrimidine-6-car-
Inflammation is the response of living tissues to injury. It
involves a complex array of enzyme activation, mediator
release, and extravasations of fluid, cell migration, tissue
breakdown and repair (Chinnasamy et al., 2010; Mwangi
et al., 2011). Many in vitro assays, each based on a specific
biochemical or cellular mechanism have been developed for
the initial screening of the anti-inflammatory compounds. A
number of anti-inflammatory drugs are known to inhibit the
denaturation of proteins as an in vitro screening model for
anti-inflammatory compounds (Naik and Sheth, 1976).
The QSAR analysis infers the biological activity of new
or untested chemical from the molecular structure, or
properties of similar compounds whose activities have
already been assessed (Schultz et al., 2003). QSAR models
are highly effective in describing the structural basis of
biological activity. It is now widely used for the prediction
of physicochemical properties and biological activities in
chemical, environmental, and pharmaceutical areas. The
success of QSAR approach can be explained by the insight
offered into the structural determination of chemical
properties and the possibility to estimate the properties of
Keywords Anti-inflammatory potential ꢀ
Oxazolopyrimidine ꢀ Thiazolopyrimidine ꢀ Carboxamide ꢀ
2D QSAR
Introduction
Pyrimidines possess versatile biological activities such as
calcium channel modulator (Kappe, 1998; Sawant et al.,
2011), selective 1-adrenoreceptor antagonist (Barrow et al.,
2000), HIV gpl20-CD4 inhibitior (Patil et al., 1995), anti-
viral (Hurst and Hull, 1961), anticancer drug with mitotic
kinesin inhibition (Kappe et al., 2000), oral antihypertensive
R. L. Sawant (&) ꢀ C. A. Bansode ꢀ J. B. Wadekar
Department of Pharmaceutical Chemistry and PG Studies, Pd.
Dr. Vithalrao Vikhe Patil Foundation’s College of Pharmacy,
Post MIDC, Vilad Ghat, Ahmednagar 414111, MS, India
e-mail: sawantrl@yahoo.com
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Med Chem Res
new chemical compounds without the need to synthesize
and test them (Sawant and Bhatia, 2008).
7–8 h. The resulting solution was cooled to room tempera-
ture and poured into crushed ice with vigorous stirring. The
resulting solid was filtered and washed with cold methanol.
In the present work, we propose to synthesize a series of
benzylidene-3-oxo-5H-oxazolo/thiazolo (3,2-a)-pyrimidine-
6-carboxamides, confirm their structures by spectral analysis,
and evaluate the title compounds for their anti-inflammatory
potential by protein denaturation method and 2D-QSAR
analysis to deduce a correlation between structure and anti-
inflammatory potential.
General procedure for the synthesis (Alam et al., 2010)
of benzylidene-3-oxo-5H-oxazolo/thiazolo (3,2-a)-
pyrimidine-6-carboxamide (5a–5z)
A mixture of tetrahydropyrimidine carboxamide derivative
(10 mmol), monochloroacetic acid (15 mmol), anhydrous
sodium acetate (2 g), glacial acetic acid (20 ml), acetic
anhydride (15 ml), and aromatic aldehyde (10 mmol) were
heated to reflux, and temperature was maintained at
140–142 °C for 4–5 h. The resulting solution was cooled to
room temperature and poured the reaction mixture in ice
water (150 ml) to yield solid product. Compound obtained
was filtered and recrystallized from ethanol.
Experimental section
Twenty-six different benzylidene oxazolo/thiazolo (3,2-a)-
pyrimidine-6-carboxamide derivatives (5a–5z) were synthe-
sized according to Scheme 1. Melting points were determined
using precision digital melting point apparatus VEEGO
(Model-VMP-D) and are uncorrected. Completion of reaction
was routinely checked by TLC using mobile phase as toluene:
chloroform: ethyl acetate. The IR spectra were recorded on
2-(4-Methoxybenzylidene)-7-methyl-3-oxo-N,5-diphenyl-
2,3-dihydro-5H (1,3) thiazolo (3,2-a)-pyrimidine-6-
carboxamide (5a)
1
Jasco FT/IR 4100 spectrophotometer. H NMR spectra were
recorded on Varian Mercury YH-300 spectrometer using
CDCl3 as a solvent and TMS as internal standard. Chemical
shifts are reported in ppm. Multiplicities are abbreviated as: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet.
Yield: 89.11 %. m.p. 196–197 °C. IR (KBr), v, cm-1
:
3371.93 (NH), 3055 (=C–H), 1712.94 (C=O), 1643.32
(C=O), 1593.42 (C=N), 1261.78 (Asy Ar–OCH3), 1029.04
(Sym Ar–OCH3), 701.56 (C–S). 1H NMR (300 MHz,
CDCl3, TMS):d 1.56 (s, 3H, CH3), 3.86 (s, 3H, OCH3),
6.13 (s, 1H, Ar–CH), 7.19–7.69 (m, 14H, Ar–CH), 7.42 (s,
1H, exocyclic CH), 7.92 (s, 1H, NH-amide).
General procedure for the synthesis (Pansuriya et al.,
2009) of tetrahydropyrimidine-5-carboxamide (4a–4h)
A mixture of appropriate aromatic aldehyde (10 mmol);
acetoacetanilide (10 mmol); and urea or thiourea (15 mmol)
in methanol (25 ml) and concentrated hydrochloric acid(two
drops); and aluminum chloride (3 mmol) was placed in
round bottom flask. The mixture was heated to reflux for
2-(4-Chlorobenzylidene)-7-methyl-3-oxo-N,5-diphenyl-
2,3-dihydro-5H (1,3) thiazolo (3,2-a)-pyrimidine-6-
carboxamide (5b)
Yield: 73.87 %. m.p. 200–201 °C. IR (KBr), v, cm-1
3371.34 (NH), 3109.04 (=C–H), 1720.39 (C=O), 1643.24
:
1
(C=O), 1515.94 (C=N), 756.04 (C–Cl), 686.61 (C–S). H
NMR (300 MHz, CDCl3, TMS):d 1.64 (s, 3H, CH3), 5.41
(s, 1H, Ar–CH), 6.93–7.66 (m, 14H, Ar–CH), 7.41 (s, 1H,
exocyclic CH), 8.18 (s, 1H, NH-amide).
2-(4-Nitrobenzylidene)-7-methyl-3-oxo-N,5-diphenyl-
2,3-dihydro-5H (1,3) thiazolo (3,2-a)-pyrimidine-6-
carboxamide (5c)
Yield: 68.44 %. m.p. 206–208 °C. IR (KBr), v, cm-1
:
3348.72 (NH), 3025.33 (=C–H), 1718.46 (C=O), 1658.32
(C=O), 1523.42 (C=N), 1499.43 (Asy Ar–NO2), 1312.49
(Sym Ar–NO2), 704.36 (C–S). 1H NMR (300 MHz,
CDCl3, TMS):d 1.60 (s, 3H, CH3), 5.84 (s, 1H, Ar–CH),
6.99–7.58 (m, 14H, Ar–CH), 7.44 (s, 1H, exocyclic CH),
7.96 (s, 1H, NH-amide).
Scheme 1 Synthesis of benzylidene oxazolo/thiazolo (3,2-a)-pyrimi-
dine-6-carboxamide
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Med Chem Res
(C=O), 1609.22 (C=N), 1197.82 (C–N), 1065.35 (C–O). 1H
NMR (300 MHz, CDCl3, TMS):d 1.63 (s, 3H, CH3), 3.04
(s, 6H, (CH3)2), 5.84 (s, 1H, Ar–CH), 7.02–7.65 (m, 14H,
Ar–CH), 7.38 (s, 1H, exocyclic CH), 7.98 (s, 1H, NH-
amide).
2-(4-Dimethylaminobenzylidene)-7-methyl-3-oxo-N,5-
diphenyl-2,3-dihydro-5H (1,3) thiazolo (3,2-a)-pyrimidine-
6-carboxamide (5d)
Yield: 75.55 %. m.p. 186–188 °C. IR (KBr), v, cm-1
3328.53 (NH), 3043.67 (=C–H), 1708.23 (C=O), 1665.18
:
1
(C=O), 1606.22 (C=N), 1192.98 (C–N), 693.20 (C–S). H
5-(4-Methoxyphenyl)-N-phenyl-2-(4-chlorobenzylidene)-
7-methyl-3-oxo-2,3dihydro-5H (1,3) thiazolo
(3,2-a)-pyrimidine-6-carboxamide (5i)
NMR (300 MHz, CDCl3, TMS):d 1.59 (s, 3H, CH3), 3.062
(s, 6H, (CH3)2), 5.64 (s, 1H, Ar–CH), 7.01–7.54 (m, 14H,
Ar–CH), 7.47 (s, 1H, exocyclic CH), 7.94 (s, 1H, NH-
amide).
Yield: 78.63 %. m.p. 206–207 °C. IR (KBr), v, cm-1
:
3321.19 (NH), 3001.03 (=C–H), 1712.67 (C=O), 1647.10
(C=O),1512.09 (C=N), 1245.93 (Asy Ar–OCH3), 1076.28
2-(4-Methoxybenzylidene)-7-methyl-3-oxo-N,5-diphenyl-
2,3-dihydro-5H (1,3) oxazolo (3,2-a)-pyrimidine-6-
carboxamide (5e)
1
(Sym Ar–OCH3), 756.04 (C–Cl), 694.33 (C–S). H NMR
(300 MHz, CDCl3, TMS):d 1.68 (s, 3H, CH3), 3.78 (s, 3H,
OCH3), 5.65 (s, 1H, Ar–CH), 6.96–7.56 (m, 13H, Ar–CH),
7.40 (s, 1H, exocyclic CH), 8.02 (s, 1H, NH-amide).
Yield: 80.68 %. m.p. 203–205 °C. IR (KBr), v, cm-1
:
3370.93 (NH), 3054 (=C–H), 1713.94 (C=O), 1665.32
(C=O),1596.42 (C=N), 1262.78 (Asy Ar–OCH3), 1030.04
(Sym Ar–OCH3), 1028.66 (C–O). 1H NMR (300 MHz,
CDCl3, TMS):d 1.55 (s, 3H, CH3), 3.83 (s, 3H, OCH3),
6.09 (s, 1H, Ar–CH), 7.04–7.18 (m, 14H, Ar–CH), 7.45 (s,
1H, exocyclic CH), 8.02 (s, 1H, NH-amide).
5-(4-Methoxyphenyl)-N-phenyl-2-(4-nitrobenzylidene)-
7-methyl-3-oxo-2,3dihydro-5H (1,3) thiazolo
(3,2-a)-pyrimidine-6-carboxamide (5j)
Yield: 80.78 %. m.p. 215–217 °C. IR (KBr), v, cm-1
:
3367.57 (NH), 3086.65 (=C–H), 1716.23 (C=O), 1675.23
(C=O),1576.52 (C=N), 1494.43 (Asy Ar–NO2), 1370.49
(Sym Ar–NO2), 1246.93 (Asy Ar–OCH3), 1054.28 (Sym
Ar–OCH3), 690.23 (C–S). 1H NMR (300 MHz, CDCl3,
TMS):d 1.66 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 5.63 (s, 1H,
Ar–CH), 6.94–7.58 (m, 13H, Ar–CH), 7.36 (s, 1H, exocyclic
CH), 7.98 (s, 1H, NH-amide).
2-(4-Chlorobenzylidene)-7-methyl-3-oxo-N,5-diphenyl-
2,3-dihydro-5H (1,3) oxazolo (3,2-a)-pyrimidine-6-
carboxamide (5f)
Yield: 86.30 %. m.p. 207–208 °C. IR (KBr), v, cm-1
:
3368.34 (NH), 3107.04 (=C–H), 1716.39 (C=O), 1659.24
(C=O), 1518.94 (C=N), 1018.44 (C–O), 758.04 (C–Cl). 1H
NMR (300 MHz, CDCl3, TMS):d 1.62 (s, 3H, CH3), 5.98
(s, 1H, Ar–CH), 6.99–7.33 (m, 14H, Ar–CH), 7.46 (s, 1H,
exocyclic CH), 8.11 (s, 1H, NH-amide).
5-(4-Methoxyphenyl)-N-phenyl-2-(4-dimethylamino-
benzylidene)-7-methyl-3-oxo-2,3 dihydro-5H
(1,3) thiazolo (3,2-a)-pyrimidine-6-carboxamide (5k)
Yield: 72.28 %. m.p. 198–200 °C. IR (KBr), v, cm-1
3332.59 (NH), 3090.42 (=C–H), 1707.84 (C=O), 1686.28
:
2-(4-Nitrobenzylidene)-7-methyl-3-oxo-N,5-
diphenyl-2,3-dihydro-5H (1,3) oxazolo (3,2-a)-
pyrimidine-6-carboxamide (5g)
(C=O),1572.53 (C=N), 1244.93 (Asy Ar–OCH3), 1046.28
1
(Sym Ar–OCH3), 1189.78 (C–N), 692.66 (C–S). H NMR
Yield: 88.83 %. m.p. 210–211 °C. IR (KBr), v, cm-1
:
(300 MHz, CDCl3, TMS):d 1.56 (s, 3H, CH3), 3.06 (s, 6H,
(CH3)2), 3.69 (s, 3H, OCH3), 5.69 (s, 1H, Ar–CH),
6.92–7.52 (m, 13H, Ar–CH), 7.39 (s, 1H, exocyclic CH),
8.00 (s, 1H, NH-amide).
3346.72 (NH), 3045.33 (=C–H), 1716.46 (C=O), 1690.32
(C=O), 1574.42 (C=N), 1509.88 (Asy Ar–NO2), 1322.49
(Sym Ar–NO2), 1035.87 (C–O). 1H NMR (300 MHz,
CDCl3, TMS):d 1.57 (s, 3H, CH3), 6.08 (s, 1H, Ar–CH),
6.94–7.21 (m, 14H, Ar–CH), 7.42 (s, 1H, exocyclic CH),
7.89 (s, 1H, NH-amide).
5-(4-Methoxyphenyl)-N-phenyl2-(4-chlorobenzylidene)-
7-methyl-3-oxo-2,3 dihydro-5H (1,3) oxazolo
(3,2-a)-pyrimidine-6-carboxamide (5l)
2-(4-Dimethylaminobenzylidene)-7-methyl-3-oxo-N,
5-diphenyl-2,3-dihydro-5H (1,3) oxazolo
(3,2-a)-pyrimidine-6-carboxamide (5h)
Yield: 83.44 %. m.p. 213–214 °C. IR (KBr), v, cm-1
:
3368.57 (NH), 3088.65 (=C–H), 1716.23 (C=O), 1675.23
(C=O), 1596.52 (C=N), 1244.93 (Asy Ar–OCH3), 1078.28
(Sym Ar–OCH3), 1022.23 (C–O), 760.04 (C–Cl). 1H NMR
(300 MHz, CDCl3, TMS):d 1.66 (s, 3H, CH3), 3.79 (s, 3H,
Yield: 63.90 %. m.p. 189–191 °C. IR (KBr), v, cm-1
3330.53 (NH), 3043.67 (=C–H), 1703.25 (C=O), 1685.18
:
123

Med Chem Res
5-(4-Chlorophenyl)-N-phenyl-2-(4-dimethyl-
aminobenzylidene)-7-methyl-3-oxo-2,3 dihydro-5H
(1,3) thiazolo (3,2-a)-pyrimidine-6-carboxamide (5q)
OCH3), 5.63 (s, 1H, Ar–CH), 6.95–7.57 (m, 13H, Ar–CH),
7.38 (s, 1H, exocyclic CH), 7.96 (s, 1H, NH-amide).
5-(4-Methoxyphenyl)-N-phenyl-2-(4-nitrobenzylidene)-
7-methyl-3-oxo-2,3dihydro-5H (1,3) oxazolo(3,2-a)
pyrimidine-6-carboxamide (5m)
Yield: 76.22 %. m.p. 216–218 °C. IR (KBr), v, cm-1: 3326.53
(NH), 3016.52 (=C–H), 1695.32 (C=O), 1665.23 (C=O),
1573.52 (C=N), 1190.78 (C–N), 751.06 (C–Cl), 702.65 (C–S).
1H NMR (300 MHz, CDCl3, TMS):d1.63 (s, 3H, CH3), 3.34 (s,
6H, (CH3)2), 5.37 (s, 1H, Ar–CH), 6.91–7.76 (m, 13H, Ar–CH),
7.35 (s, 1H, exocyclic CH), 8.12 (s, 1H, NH-amide).
Yield: 76.45 %. m.p. 220–222 °C. IR (KBr), v, cm-1
:
3330.59 (NH), 3059.42 (=C–H), 1705.84 (C=O), 1689.28
(C=O),1579.53 (C=N), 1493.88 (Asy Ar–NO2), 1345.11
(Sym Ar–NO2), 1251.93 (Asy Ar–OCH3), 1072.28 (Sym
1
5-(4-Chlorophenyl)-N-phenyl-2-(4-dimethyl-
aminobenzylidene)-7-methyl-3-oxo-2,3 dihydro-5H
(1,3) oxazolo (3,2-a)-pyrimidine-6-carboxamide (5r)
Ar–OCH3), 1023.18 (C–O). H NMR (300 MHz, CDCl3,
TMS):d 1.61 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 5.66 (s, 1H,
Ar–CH), 6.93–7.51 (m, 13H, Ar–CH), 7.40 (s, 1H, exo-
cyclic CH), 7.99 (s, 1H, NH-amide).
Yield: 87.37 %. m.p. 220–222 °C. IR (KBr), v, cm-1
:
3328.25 (NH), 3057.03 (=C–H), 1709.67 (C=O), 1658.10
(C=O),1514.09 (C=N), 1245.93 (Asy Ar–OCH3), 1056.28
(Sym Ar–OCH3), 1016.23 (C–O), 756.04 (C–Cl). 1H NMR
(300 MHz, CDCl3, TMS):d 1.65 (s, 3H, CH3), 3.81 (s, 3H,
OCH3), 5.35 (s, 1H, Ar–CH), 6.93–7.32 (m, 13H, Ar–CH),
7.45 (s, 1H, exocyclic CH), 7.92 (s, 1H, NH-amide).
5-(4-Methoxyphenyl)-N-phenyl-2-(4-dimethyl-
aminobenzylidene)-7-methyl-3-oxo-2,3 dihydro-5H
(1,3) oxazolo (3,2-a)-pyrimidine-6-carboxamide (5n)
Yield: 85.32 %. m.p. 201–203 °C. IR (KBr), v, cm-1
:
3328.23 (NH), 3018.03 (=C–H), 1710.67 (C=O), 1661.10
(C=O), 1520.09 (C=N), 1255.39 (Asy Ar–OCH3), 1076.28
(Sym Ar–OCH3), 1190.75 (C–N), 1021.54 (C–O). 1H
NMR (300 MHz, CDCl3, TMS):d 1.62 (s, 3H, CH3), 3.05
(s, 6H, (CH3)2), 3.86 (s, 3H, OCH3), 5.70 (s, 1H, Ar–CH),
6.92–7.56 (m, 13H, Ar–CH), 7.36 (s, 1H, exocyclic CH),
7.86 (s, 1H, NH-amide).
5-(4-Chlorophenyl)-N-phenyl-2-(4-nitrobenzylidene)-
7-methyl-3-oxo-2,3dihydro-5H (1,3) oxazolo (3,2-a)-
pyrimidine-6-carboxamide (5s)
Yield: 80.65 %. m.p. 226–228 °C. IR (KBr), v, cm-1
:
3322.26 (NH), 3011.03 (=C–H), 1706.67 (C=O), 1662.10
(C=O),1510.09 (C=N), 1532.28 (Asy Ar–NO2), 1313.45
1
(Sym Ar–NO2), 757.06 (C–Cl), 1022.98 (C–O). H NMR
5-(4-Chlorophenyl)-N-phenyl-2-(4-methoxybenzylidene)-
7-methyl-3-oxo-2,3dihydro-5H (1,3) thiazolo (3,2-a)-
pyrimidine-6-carboxamide (5o)
(300 MHz, CDCl3, TMS):d 1.64 (s, 3H, CH3), 6.12 (s, 1H,
Ar–CH), 6.95–7.84 (m, 13H, Ar–CH), 7.44 (s, 1H, exo-
cyclic CH), 8.16 (s, 1H, NH-amide).
Yield: 77.33 %. m.p. 221–223 °C. IR (KBr), v, cm-1
:
5-(4-Chlorophenyl)-N-phenyl-2-(4-
dimethylaminobenzylidene)-7-methyl-3-oxo-2,3 dihydro-
5H (1,3) oxazolo (3,2-a)-pyrimidine-6-carboxamide (5t)
3328.19 (NH), 3031.03 (=C–H), 1709.67 (C=O), 1679.10
(C=O), 1514.09 (C=N), 1245.93 (Asy Ar–OCH3), 1076.28
1
(Sym Ar–OCH3), 765.04 (C–Cl), 691.33 (C–S). H NMR
(300 MHz, CDCl3, TMS):d 1.68 (s, 3H, CH3), 3.84 (s, 3H,
OCH3), 5.41 (s, 1H, Ar–CH), 6.82–7.23 (m, 13H, Ar–CH),
7.41 (s, 1H, exocyclic CH), 8.05 (s, 1H, NH-amide).
Yield: 75.29 %. m.p. 219–220 °C. IR (KBr), v, cm-1
:
3278.76 (NH), 3035.75 (=C–H), 1701.10 (C=O), 1643.24
(C=O),1585.38 (C=N), 1195.78 (C–N), 744.47 (C–Cl),
1014.22 (C–O). 1H NMR (300 MHz, CDCl3, TMS):d 1.58
(s, 3H, CH3), 3.06 (s, 6H, (CH3)2), 5.34 (s, 1H, Ar–CH),
6.93–7.68 (m, 13H, Ar–CH), 7.38 (s, 1H, exocyclic CH),
8.22 (s, 1H, NH-amide).
5-(4-Chlorophenyl)-N-phenyl-2-(4-nitrobenzylidene)-7-
methyl-3-oxo-2,3dihydro-5H (1,3) thiazolo (3,2-a)-
pyrimidine-6-carboxamide (5p)
Yield: 84.49 %. m.p. 225–226 °C. IR (KBr), v, cm-1
:
5-(4-Nitrophenyl)-N-phenyl-2-(4-methoxybenzylidene)-
7-methyl-3-oxo-2,3dihydro-5H (1,3) thiazolo (3,2-a)-
pyrimidine-6-carboxamide (5u)
3322.19 (NH), 3011.03 (=C–H), 1703.67 (C=O), 1682.10
(C=O),1510.09 (C=N), 1496.43 (Asy Ar–NO2), 1343.49
1
(Sym Ar–NO2), 757.06 (C–Cl), 697.23 (C–S). H NMR
(300 MHz, CDCl3, TMS):d 1.67 (s, 3H, CH3), 5.39 (s, 1H,
Ar–CH), 6.86–7.51 (m, 13H, Ar–CH), 7.43 (s, 1H, exo-
cyclic CH), 7.86 (s, 1H, NH-amide).
Yield: 81.60 %. m.p. 227–228 °C. IR (KBr), v, cm-1
3324.53 (NH), 3076.52 (=C–H), 1718.23 (C=O), 1669.23
:
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Med Chem Res
(C=O), 1570.52 (C=N), 1494.76 (Asy Ar–NO2), 1345.11
(Sym Ar–NO2), 1248.54 (Asy Ar–OCH3), 1042.11 (Sym
Ar–OCH3), 700.86 (C–S). 1H NMR (300 MHz, CDCl3,
TMS):d 1.68 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 5.96 (s, 1H,
Ar–CH), 6.96–7.25 (m, 13H, Ar–CH), 7.46 (s, 1H, exo-
cyclic CH), 8.01 (s, 1H, NH-amide).
(s, 1H, Ar–CH), 6.23–7.26 (m, 13H, Ar–CH), 7.40 (s, 1H,
exocyclic CH), 8.04 (s, 1H, NH-amide).
5-(4-Nitrophenyl)-N-phenyl-2-(4-dimethyl-
aminobenzylidene)-7-methyl-3-oxo-2,3dihydro-5H
(1,3) oxazolo (3,2-a)-pyrimidine-6-carboxamide (5z)
5-(4-Nitrophenyl)-N-phenyl-2-(4-chlorobenzylidene)-
7-methyl-3-oxo-2,3 dihydro-5H (1,3) thiazolo
(3,2-a)-pyrimidine-6-carboxamide (5v)
Yield: 65.16 %. m.p. 231–233 °C; IR (KBr), v, cm-1
3349.57 (NH), 3072.88 (=C–H), 1704.23 (C=O), 1676.28
(C=O), 1579.62 (C=N), 1508.43 (Asy Ar–NO2), 1345.11
1
(Sym Ar–NO2), 1191.78 (C–N), 1018.65 (C–O). H NMR
:
Yield: 72.66 %. m.p. 230–231 °C. IR (KBr), v, cm-1
3316.53 (NH), 3065.18 (=C–H), 1693.23 (C=O), 1671.23
:
(300 MHz, CDCl3, TMS):d 1.56 (s, 3H, CH3), 3.16 (s, 6H,
(CH3)2), 6.00 (s, 1H, Ar–CH), 6.36–7.09 (m, 13H, Ar–CH),
7.38 (s, 1H, exocyclic CH), 7.92 (s, 1H, NH-amide).
(C=O), 1579.52 (C=N), 1493.88 (Asy Ar–NO2), 1345.11
1
(Sym Ar–NO2), 755.21 (C–Cl), 695.65 (C–S). H NMR
(300 MHz, CDCl3, TMS):d 1.65 (s, 3H, CH3), 6.03 (s, 1H,
Ar–CH), 6.84–7.14 (m, 13H, Ar–CH), 7.45 (s, 1H, exo-
cyclic CH), 8.04 (s, 1H, NH-amide).
Anti-inflammatory potential
The title compounds were screened for anti-inflammatory
potential by inhibition of albumin denaturation technique
(Singh et al., 2009; Sakat et al., 2010). The standard drug
and test compounds were dissolved in minimum amount of
dimethyl formamide (DMF) and diluted with phosphate
buffer (0.2 M, pH 7.4). Final concentration of DMF in all
solutions was less than 2.0 %. Test solution (1 ml) con-
taining different concentration of compounds were mixed
with 1 ml of 1 % mM albumin solution in phosphate buffer
and incubated at 27 1 °C in BOD incubator for 15 min.
Denaturation was induced by keeping the reaction mixture
at 60 1 °C in water bath for 10 min. After cooling the
turbidity was measured at 660 nm. Percentage inhibition of
denaturation was calculated from control. Each experiment
was performed in triplicate and average was taken. The
diclofenac sodium was used as standard drug. Percentage
inhibition was calculated using formula
5-(4-Nitrophenyl)-N-phenyl-2-(4-dimethyl-
aminobenzylidene)-7-methyl-3-oxo-2,3dihydro-5H (1,3)
thiazolo (3,2-a)-pyrimidine-6-carboxamide (5w)
Yield: 79.25 %. m.p. 223–225 °C. IR (KBr), v, cm-1
3315.53 (NH), 3070.88 (=C–H), 1698.23 (C=O), 1667.23
:
(C=O), 1575.62 (C=N), 1499.93 (Asy Ar–NO2), 1335.11
1
(Sym Ar–NO2), 1197.87 (C–N), 693.73 (C–S). H NMR
(300 MHz, CDCl3, TMS):d 1.63 (s, 3H, CH3), 3.24 (s, 6H,
(CH3)2), 5.94 (s, 1H, Ar–CH), 6.93–7.84 (m, 13H, Ar–CH),
7.42 (s, 1H, exocyclic CH), 7.96 (s, 1H, NH-amide).
5-(4-Nitrophenyl)-N-phenyl-2-(4-methoxybenzylidene)-
7-methyl-3-oxo-2,3dihydro-5H (1,3) oxazolo (3,2-a)-
pyrimidine-6-carboxamide (5x)
% inhibition ¼ 100 ꢁ ð1 ꢂ ðVt=VcÞÞ
Yield: 86.06 %. m.p. 230–232 °C. IR (KBr), v, cm-1
:
where, Vt and Vc are mean absorbance value of test group
and control group, respectively. From percentage inhibi-
tion, the half maximal inhibitory concentration (IC50) was
calculated.
3298.05 (NH), 3016.46 (=C–H), 1708.81 (C=O), 1674.10
(C=O), 1573.81 (Asy Ar–NO2), 1342.36 (Sym Ar–NO2),
1257.50 (Asy Ar–OCH3), 1064.63 (Sym Ar–OCH3),
1515.94 (C=N), 1029.92 (C–O). 1H NMR (300 MHz,
CDCl3, TMS):d 1.58 (s, 3H, CH3), 3.78 (s, 3H, OCH3),
5.99 (s, 1H, Ar–CH), 7.23–7.66 (m, 13H, Ar–CH), 7.41 (s,
1H, exocyclic CH), 7.99 (s, 1H, NH-amide).
QSAR analysis
Dataset
5-(4-Nitrophenyl)-N-phenyl-2-(4-chlorobenzylidene)-
7-methyl-3-oxo-2,3dihydro-5H (1,3) oxazolo (3,2-a)-
pyrimidine-6-carboxamide (5y)
The builder module of the VLife MDS was used to gen-
erate molecular models of series of benzylidene-3-oxo-5H-
oxazolo/thiazolo (3,2-a)-pyrimidine-6-carboxamide deriv-
atives. The structures were then energy minimized using
the Merck molecular force field (MMFF). The biological
activity values for the QSAR equation were obtained using
the negative logarithm of half maximal inhibitory
concentration.
Yield: 78.62 %. m.p. 235–236 °C. IR (KBr), v, cm-1
:
3299.53 (NH), 3045.18 (=C–H), 1698.28 (C=O), 1672.23
(C=O), 1579.59 (C=N), 1566.78 (Asy Ar–NO2), 1344.11
(Sym Ar–NO2), 1028.65 (C–O–C), 753.21 (C–Cl). 1H
NMR (300 MHz, CDCl3, TMS):d 1.54 (s, 3H, CH3), 5.92
123

Med Chem Res
correlation coefficient (r2), cross-validated square correla-
tion coefficient (q2), and sequential Fischer test (F).
Activity prediction
The predictability of the QSAR model would be good if the
values of biological activity predicted by the QSAR model
do not appreciably differ from the observed results of
biological activity for the given dataset.
Results and discussion
The tetrahydropyrimidine-5-carboxamide derivatives (4a–
4h) were synthesized by a three-component reaction
involving acetoacetanilide (1), substituted benzaldehydes
(2), and urea or thiourea (3) in the presence of concentrated
hydrochloric acid and aluminum chloride as catalyst.
Subsequently, tetrahydropyrimidine-5-carboxamides (4a–
4h) were treated with chloroacetic acid, anhydrous sodium
acetate, and substituted benzaldehydes in a mixture of
acetic acid and acetic anhydride to afford the title com-
pounds benzylidene-3-oxo-5H-oxazolo/thiazolo (3,2-a)-
pyrimidine-6-carboxamide (5a–5z) as shown in Scheme 1
and Table 1. The purity of compounds was checked by thin
layer chromatography. Their structures were confirmed by
Computational details
The structures were sketched using 2D Draw App and were
exported to QSAR Plus through MDS path. Three-dimen-
sional structures of all the molecules were generated. For
2D QSAR, we used optimized molecule in 2D sheet and
added pIC50 value. All the 2D calculated descriptors were
considered as independent variables and pIC50 was con-
sidered as dependent variable. The training set and test set
were selected using random selection method. Stepwise
multiple linear regression analysis method and simulated
annealing method were used to perform QSAR analysis to
generate several models. The best model was selected on
the basis of various statistical parameters such as squared
1
elemental analysis, and IR and H NMR spectral studies.
The amount of carbon, hydrogen, and nitrogen found by
Table 1 Chemical structures and physicochemical characteristics of title compounds (5a–5z)
Compound
X
R1
R2
Molecular formula
Melting point (°C)
% yield
Rf value
5a
5b
5c
5d
5e
5f
S
H
4-OCH3
4-Cl
C28H23N3O3S
196–197
200–201
206–208
186–188
203–205
207–208
210–211
189–191
206–207
215–217
198–200
213–214
220–222
201–203
221–223
225–226
216–218
220–222
226–228
219–220
227–229
230–231
223–225
230–232
235–236
231–233
89.11
73.87
68.44
75.55
80.68
86.30
88.83
63.90
78.63
80.78
72.28
83.44
76.45
85.32
77.33
84.49
76.22
87.37
80.65
75.29
81.60
72.66
79.25
86.06
78.62
65.16
0.74
0.69
0.67
0.76
0.72
0.68
0.64
0.75
0.54
0.51
0.65
0.52
0.50
0.65
0.53
0.50
0.57
0.50
0.49
0.56
0.49
0.44
0.59
0.48
0.42
0.59
S
H
C27H20N3O2SCl
S
H
4-NO2
C27H20N4O4S
C29H26N4O2S
C28H23N3O4
S
H
4-N(CH3)2
4-OCH3
4-Cl
O
O
O
O
S
H
H
C27H20N3O3Cl
5g
5h
5i
H
4-NO2
C27H20N4O5
H
4-N(CH3)2
4-Cl
C29H26N4O3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-Cl
C28H22N3O2SCl
C28H22N4O4S
C30H28N4O3S
C28H22N3O3Cl
C28H22N4O5
5j
S
4-NO2
5k
5l
S
4-N(CH3)2
4-Cl
O
O
O
S
5m
5n
5o
5p
5q
5r
5s
4-NO2
4-N(CH3)2
4-OCH3
4-NO2
C30H28N4O4
C28H22ClN3O3S
C27H19ClN4O4S
C29H25ClN4O2S
C28H22ClN3O4
C27H19ClN4O5
C29H25ClN4O3
C28H22N4O5S
C27H19N4O4SCl
C29H25N5O4S
C28H22N4O6
S
4-Cl
S
4-Cl
4-N(CH3)2
4-OCH3
4-NO2
O
O
O
S
4-Cl
4-Cl
5t
4-Cl
4-N(CH3)2
4-OCH3
4-Cl
5u
5v
5w
5x
5y
5z
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
S
S
4-N(CH3)2
4-OCH3
4-Cl
O
O
O
C27H19N4O5
4-N(CH3)2
C29H25N5O5
123

Med Chem Res
Table 2 IC50 values for anti-inflammatory potential of title com-
pounds (5a–5z)
Table 3 Selected molecular descriptors of title compounds (5a–5z)
Comp no.
SaaCHE index
T_T_O_4
slogp
2Path Count
Compound
IC50 (ppm)
Compound
IC50 (ppm)
5a*
5b
5c
26.717163
27.575033
24.821455
27.314477
25.860158
26.718028
23.96445
11
10
14
10
16
15
19
15
11
15
11
16
20
16
11
14
10
16
19
15
15
14
14
20
19
19
5.3107
5.9555
5.2103
5.3681
4.5941
5.2389
4.4937
4.6515
5.9641
5.2189
5.3767
5.2475
4.5023
4.6601
5.9641
5.8637
6.0215
5.2475
5.1471
5.3049
5.2189
5.8637
5.2763
4.5023
5.1471
4.5597
55
54
57
57
55
54
57
57
57
60
60
57
60
60
57
59
59
57
59
59
60
59
62
60
59
62
Diclofenac
188.24
5a
5b
5c
5d
5e
5f
291.257
226.318
253.376
316.686
304.179
261.464
283.525
330.312
210.874
254.99
5n
5o
5p
5q
5r
5s
314.544
232.597
190.42
5d
5e
309.862
242.144
192.486
319.524
250.38
5f*
5g
5h
5i
26.457472
25.283111
22.577315
25.025893
24.470666
21.76487
5g
5h
5i
5t
5u
5v
5w
5x
5y
5z
5j*
5k
5l
194.611
336.75
5j
5k
5l
301.677
236.954
272.584
259.104
196.05
5m
5n
5o
24.213448
25.317953
23.459037
25.907614
24.505509
22.646592
25.095169
22.471516
23.318395
23.061177
21.659071
22.50595
5m
339.35
5p
5q*
5r*
5s
elemental analysis is in good agreement with the calculated
amount.
5t
The anti-inflammatory drugs that are known to inhibit
the heat-induced denaturation of proteins are used as in
vitro screening model for anti-inflammatory compounds.
Denaturation of protein is one of the well-documented
cause of rheumatoid arthritis. Production of auto-antigen in
certain arthritic disease may due to denaturation of protein.
The mechanism of denaturation probably involves alteration
of electrostatic hydrogen, hydrophobic, and disulfide bond-
ing. The anti-inflammatory potential of benzylidene-3-oxo-
5H-oxazolo/thiazolo (3,2-a)-pyrimidine-6-carboxamides
(5a–5z) was estimated as a ability to inhibit albumin dena-
turation and expressed as IC50 values (Table 2). The bio-
logical activity data (IC50) was converted to negative log
dose in moles (pIC50) for QSAR analysis. The selected
molecular descriptors of title compounds (5a–5z) are shown
in Table 3. The best model was selected on the basis of
various statistical parameters such as squared correlation
coefficient (r2), cross-validated square correlation coeffi-
cient (q2), and sequential Fischer test (F).
5u
5v
5w
5x
5y
5z*
22.248732
* Test set
For calculation of AI descriptors, every atom in the
molecule was assigned at least one and at most three
attributes. The first attribute is T attribute to thoroughly
characterize the topology of the molecule. The second
attribute is the atom type. The atom symbol is used here.
The third attribute is assigned to atoms taking part in a
double or triple bond. After all atoms have been assigned
their respective attributes, selective distance count statistics
for all combinations of different attributes were computed.
Model-1 reveals that descriptor T_T_O_4 is a negative
contributor to activity which indicates the count of number
of any atoms (single, double, or triple bonded) separated
from any other oxygen atom (single, double, or triple
bonded) by four bonds in a molecule. SaaCHE index is a
positive contributor to activity which indicates electroto-
pological state indices for number of –CH group connected
with two aromatic bonds. The slogp and 2Path Count will
determine the activity. The slogp is negative contributor to
activity. This descriptor signifies log of the octanol/water
partition coefficient. This property calculates logP from the
2D QSAR
pIC50 = 1.1384 ? 0.0334 ( 0.0500) SaaCHE index-
0.0150
( 0.2329)
T_T_O_4-0.1717
( 0.0043)
slogp ? 0.0271 ( 0.5106) 2Path Count (Model-1)
n ¼ 20; r2 ¼ 0:88; q2 ¼ 0:80; F test ¼ 37:8492:
The anti-inflammatory potential according to QSAR
Model-1 is dependent on alignment independent (AI),
estate contribution, individual and path count descriptors.
123

Med Chem Res
given structure. The 2Path Count is a positive contributor
to activity which indicates total number of fragments of
second order (two bond path). Figure 1 shows contribution
of selected descriptors to activity. The selected model 1 is
predictive as observed and predicted pIC50 values are close
with minimum residuals (Table 4).
Conclusion
A series of benzylidene oxazolo/thiazolo (3,2-a)-pyr-
imidine-6-carboxamides were synthesized in good yields.
The benzylidene thiazolo (3,2-a)-pyrimidine-6-carbox-
amide analogs have better anti-inflammatory potential
than the benzylidene oxazolo (3,2-a)-pyrimidine-6-carbox-
amides. Inhibition of protein denaturation by the title com-
pounds and subsequent QSAR analysis reveals that electron
withdrawing polar group at para position of 5-phenyl ring
and electron withdrawing non-polar group at para position of
2-benzylidene moiety of thiazolo pyrimidine nucleus
improves anti-inflammatory potential in the series. This
study forms the basis for the further design and synthesis of
benzylidene oxazolo/thiazolo (3,2-a)-pyrimidine-6-carbox-
amide analogs as anti-inflammatory agent.
Fig. 1 Contribution chart of descriptors
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