Synthesis, characterization and in vitro antibacterial evaluation of 1-(7,7-dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4-yl)piperidine-4-carboxamide derivatives

Article abstract of DOI:10.1007/s11164-017-2945-0

A series of six novel 1-(7,7-dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4-yl)piperidine-4-carboxamide derivatives has been synthesized and characterized using various spectral techniques (¹H and ¹³C NMR, LCMS, IR). The antiba

Full text of DOI:10.1007/s11164-017-2945-0

Res Chem Intermed
DOI 10.1007/s11164-017-2945-0
Synthesis, characterization and in vitro antibacterial
evaluation of 1-(7,7-dimethyl-2-morpholino-5,6,7,8-
tetrahydroquinazolin-4-yl)piperidine-4-carboxamide
derivatives
Balaraman Selvakumar1,2 Kuppanagounder P. Elango2
•
Received: 24 January 2017 / Accepted: 20 March 2017
Ó Springer Science+Business Media Dordrecht 2017
Abstract A series of six novel 1-(7,7-dimethyl-2-morpholino-5,6,7,8-tetrahydro-
quinazolin-4-yl)piperidine-4-carboxamide derivatives has been synthesized and
characterized using various spectral techniques (1H and 13C NMR, LCMS, IR). The
antibacterial activities of these compounds have been screened against nine different
Gram-positive and Gram-negative bacterial strains. The results show that quina-
zoline derivatives containing thiazole ring 2a and 2b exhibit good antibacterial
activity amongst the compounds under investigation.
Keywords Synthesis Á Characterization Á Tetrahydroquinazoline Á Piperazine Á
Morpholine Á Antibacterial
Introduction
Heterocyclic chemistry is playing an important role in medicinal chemistry and
serving as key templates for numerous therapeutic agents [1–3]. The majority of the
biologically active substances contain heterocyclic rings. Among them, the
pyrimidine scaffold is found in many natural products and the chemistry of
pyrimidine derivatives play an important role in the field of drugs, agricultural
chemicals, and many biological processes [4–6]. The pyrimidine derivatives show
various biological activities including antitubercular, anti-inflammatory,
Electronic supplementary material The online version of this article (doi:10.1007/s11164-017-2945-0)
contains supplementary material, which is available to authorized users.
&
Kuppanagounder P. Elango
drkpelango@rediffmail.com
1
2
Anthem Biosciences Private Limited, Bangalore 560 099, India
Department of Chemistry, Gandhigram Rural Institute (Deemed University),
Gandhigram 624 302, India
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B. Selvakumar, K. P. Elango
anticonvulsant, antimicrobial, antibacterial, antifungal, anticancer and analgesic
[7–12]. 2-Morphilino-substituted pyrimidine derivatives have been used to treat
diseases and disorders arising from abnormal cell growth, particularly those
associated with PI3 kinase such as cancer, immune disorders, viral infection and
neurological disorders [13–15]. A review of literature revealed that 2-(morpholin-4-
yl)-5,6,7,8-tetrahydroquinazolin-4-amine derivatives were proved to show potent
hypoglycemic activity [16]. Structure–Activity Relationship Study of 2-(morpholin-
4-yl)-5,6,7,8-tetrahydroquinazolin-4-amine derivatives revealed its selective and
potent inhibition of p97 ATPase [17] and GATA modulator [18]. Tricyclic ring
containing morpholine, piperazine and pyrimidine were reported as fast-acting
antimalarial agents [19] and histamine H4 receptor modulators [20]. Likewise,
isonipecotic acid is one of the most important heterocyclic compounds found in
many of the notable drugs, which act as antihelmintic, antidepressant and
antihistamine [21].
Hence, it is presumed that molecules containing the 2-morphilino-substituted
pyrimidine ring linked to isonipecotic acid along with extended amide would exhibit
promising biological activity. Owing to the known biological properties of thiazole
[22, 23], pyrimidine [4–6], hydrazine [24] and isoxazole [25] moieties, the amine
group containing respective hetero molecules are used for preparing novel amide
compounds which are expected to show enhanced biological activity. The main
objective, therefore, of the present endeavor is the synthesis of 1-(7,7-dimethyl-2-
morpholino-5,6,7,8-tetrahydroquinazolin-4-yl)piperidine-4-carboxylic acid (1) and
1-(7,7-dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4-yl)piperidine-4-car-
boxamide derivatives (2) and screening the antibacterial activity of these compounds
against Gram-positive and Gram-negative bacteria strains.
Experimental
All the chemicals used in the study are ofcommercially available high-purity
grade (Aldrich or Merck, India). The solvents were of commercially available
reagent grade and used as supplied. TLC experiments were performed on
alumina-backed silica gel 40F254 plates (Merck, Germany). The plates were
illuminated under UV (254 nm) and KMnO4. Melting points were determined
using a melting point apparatus (B-540; Buchi, Germany) without corrections.
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Synthesis, characterization and in vitro antibacterial…
All 1H and 13C NMR spectra were recorded on a Bruker (Germany) 300 or
400 MHz NMR. Molecular masses of unknown compounds were checked by
LCMS (6200 series; Agilent, India). Chemical shifts are reported in ppm (d)
with reference to internal standard TMS. The signals are designated as follows:
singlet (s), doublet (d), triplet (t), doublet of doublet (dd), doublet of triplet (dt),
multiplet (m), and broad singlet (bs). IR spectra were recorded using a Bruker
Alpha FT-IR spectrometer (Bruker) using a diamond attenuated total reflectance
(ATR) single reflectance module (24 scans). All reactions were carried out under
a nitrogen/argon atmosphere unless otherwise stated. Elemental analysis was
carried out with a Thermo Scientific, model Flash 1112EA apparatus and Eagar
xperience software.
Methyl 4,4-dimethyl-2-oxocyclohexane-1-carboxylate (4) Dimethyl carbonate
(3.3 mL, 0.039 mol) and NaH (1.24 g, 0.052 mol) in THF (24 mL) were heated
to about 80 °C for 30 min. Then, 3,3-dimethyl cyclohexanone (2.0 g, 0.016 mol)
was added and stirred for 2.5 h under nitrogen atmosphere. After reaction
completion by TLC (10% methanol in chloroform), the reaction mass was cooled
to about 0 °C and methanol followed by water was added. Then, the resultant
reaction mixture was acidified to pH 1 using 3 M HCl and the product was extracted
with dichloromethane, dried over sodium sulfate and concentrated under reduced
1
pressure to afford 4. Yield: 85%, pale yellow liquid. H NMR (400 MHz, DMSO-
d6, d ppm): 0.91 (s, 6H), 1.32–1.36 (t, 2H, J1 = 6.3 Hz, J2 = 6 Hz), 2.03 (s, 2H),
2.17–2.19 (t, 2H, J1 = 6.3 Hz, J2 = 6 Hz), 3.71 (s, 3H), 12.09 (s, 1H, enol-OH); IR
(ATR, t cm-1): 821, 1065, 1231, 1441,1617, 1657, 1712, 1746, 2922, 2952; LCMS
(ESI) m/z for C10H16O3 [M ? H]?: 184.9 Da.
7,7-Dimethyl-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (5) To a stir-
red solution of potassium hydroxide (17 g, 0.298 mol) and S-methyl isothiourea
hemisulfate (24.5 g, 0.176 mol) in water (125 mL), compound 4 (25 g, 0.135 mol)
was added dropwise over 15 min at ambient temperature, stirred for 5 h and heated
to about 100 °C for 3 h. After reaction completion by TLC (10% methanol in
chloroform), the reaction mass was cooled to about 0 °C then acidified with acetic
acid (about pH 5) to produce a precipitate. The solid was collected by filtration and
dried under vacuum to give the desired compound 5. Yield: 82%, pale yellow solid,
m.p: 249–253 °C; 1H NMR (400 MHz, DMSO-d6, d ppm): 0.95 (s, 6H), 1.37–1.41
(t, 3H, J = 6 Hz), 2.17 (m, 4H), 3.33 (s, 2H), 7.59 (bs, NH); IR (ATR, t cm-1):
1400, 1538, 1628, 1657, 1692, 2916, 3289; LCMS (ESI) m/z [M ? H]?: 225.0 Da;
123

B. Selvakumar, K. P. Elango
Anal. Calcd for C11H16N2OS: C, 58.90; H, 7.19; N, 12.49; S, 14.29, Found: C,
58.91; H, 7.21; N, 12.48; S, 14.28%.
7,7-Dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4(3H)-one (6) In
a
round-bottom flask, compound 5 (5 g, 0.022 mol) was dissolved in morpholine
(20 mL) and heated to about 120 °C for 2 h. After reaction completion by TLC
(10% methanol in chloroform), morpholine was removed completely under reduced
pressure to give a crude mass which was stirred for 60 min in methyl-t-butyl ether
(25 mL), and the solid obtained was collected by filtration and dried to afford
compound 6. Yield: 86%, white solid, m.p: 244–248 °C; 1H NMR (400 MHz,
DMSO-d6, d ppm): 0.92 (s, 6H), 1.38–1.43 (t, 3H, J1 = 6.3 Hz, J2 = 6.8 Hz), 2.17
(s, 2H), 2.25–2.29 (t, 3H, J1 = 6.3 Hz, J2 = 6.8 Hz), 3.47–3.5 (t, 4H, J1 = 6 Hz,
J2 = 6.8 Hz), 3.6–3.63 (t, 4H, J1 = 6 Hz, J2 = 6.8 Hz), 11 (bs, NH); IR (ATR,
t cm-1): 1254, 1380, 1569, 1633, 2851, 3301; LCMS (ESI) m/z [M ? H]?: 264.3,
found: 264.2 Da; Anal. Calcd for C14H21N3O2: C, 63.85; H, 8.04; N, 15.96, Found:
C, 63.84; H, 8.09; N, 15.95%.
4-(4-Chloro-7,7-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)morpholine
(7) To
compound 6 (10 g, 0.035 mol), phosphorous oxychloride (45 mL, 0.029 mol) was
added and heated to about 90 °C and stirred for 2 h. After reaction completion by
TLC (10% methanol in chloroform), POCl3 was removed completely under vacuum
to give a brown crude material. The resultant mixture was co-distilled with toluene
and diluted with ethyl acetate, then slowly quenched with sodium bicarbonate under
stirring by maintaining the temperature at about 10 °C. Layers were separated and
the organic layer was dried over sodium sulfate and concentrated to obtain
1
compound 7. Yield: 74%, off-white solid. m.p: 69–73 °C; H NMR (400 MHz,
DMSO-d6, d ppm): 0.94 (s, 6H), 1.53–1.59 (m, 3H, J1 = 8.8 Hz, J2 = 8.8 Hz), 2.44
(m, 4H), 3.62 (s, 8H); IR (ATR, t cm-1): 1257, 1316, 1440, 1513, 1578, 2846,
2949; LCMS (ESI) m/z for C14H20ClN3O [M ? H]?: 282.1 Da.
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Synthesis, characterization and in vitro antibacterial…
Ethyl 1-(7,7-Dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4-yl) piperidine-
4-carboxylate (8) To a solution of compound 7 (25 g, 0.088 mol) in ethanol
(125 mL), triethylamine (0.177 mol) and ethyl isonipecotate (0.088 mol) were
added at about 25 °C. The resultant reaction mixture was heated to about 120 °C for
5 h. After reaction completion, the reaction mixture was concentrated under reduced
pressure to dryness and the concentrate was dissolved in dichloromethane and
washed with 1 N HCl. The organic layer was concentrated under reduced pressure
to afford compound 8. Yield: 80%, off-white solid, m.p: 73–77 °C. 1H NMR
(300 MHz, DMSO-d6, d ppm): 0.98 (s, 6H), 1.18–1.22 (t, 3H, J1 = 6.3 Hz,
J2 = 6 Hz), 1.39–1.48 (m, 2H), 1.65–1.68 (m, 2H), 1.86–1.89 (m, 2H), 2.27 (s, 2H),
2.32–2.45 (m, 2H), 2.79–2.87 (m, 2H), 3.56–3.59 (m, 8H), 3.68–3.72 (m, 2H),
4.04–4.1 (q, 2H, J = 7.2 Hz); IR (ATR, t cm-1):994, 1113, 1167, 1366, 1417,
1542, 1565, 1724, 2920, 2954; LCMS (ESI) m/z [M ? H]?: 403.5 Da; Anal. Calcd
for C22H34N4O3: C, 65.64; H, 8.51; N, 13.92, Found: C, 65.65; H, 8.53; N, 13.90%.
1-(7,7-Dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4-yl)piperidine-4-car-
boxylic acid (1) To a solution of compound 8 (25 g, 0.062 mol) in THF (200 mL),
lithium hydroxide (0.124 mol) in water (75 mL) was added and heated to 45–50 °C
for 4 h. After reaction completion, THF was removed completely under reduced
pressure to afford a thick syrup which was diluted with water (150 mL) and ethyl
acetate (150 mL). The organic layer was removed and the resultant aqueous layer
was acidified to pH about 3 using 1 N HCl. The product was extracted using
dichloromethane (2 9 100 mL) and concentrated under reduced pressure to afford
1
compound 1. Yield: 90%, off-white solid, m.p: 189–193 °C. H NMR (300 MHz,
DMSO-d6, d ppm): 0.99 (s, 6H), 1.38–1.45 (m, 2H), 1.6–1.67 (m, 2H), 1.85–1.89
(m, 2H), 2.32 (s, 2H), 2.43–2.5 (m, 5H), 2.78–2.86 (m, 2H), 3.57–3.71 (m, 10H),
12.1 (bs, 1H, OH-acid); 13C NMR (75 MHz, DMSO-d6) d: 21.9, 27.9, 28.8, 35.4,
43.9, 46.1, 47.1, 66.0, 105.8, 159.0, 164.2, 165.6, 175.8; IR (ATR, t cm-1): 991,
1110, 1413, 1537, 1612, 1709, 2846, 2919; LCMS (ESI) m/z [M ? H]?: 375.3 Da;
123

B. Selvakumar, K. P. Elango
Anal. Calcd for C20H30N4O3: C, 64.15; H, 8.07; N, 14.96, Found: C, 64.14; H, 8.10;
N, 14.95%.
General procedure for synthesis of compounds 2a–f
To the solution of compound 1 (1 eqv.) in DMF (10 vol.), EDC.HCl (1.5 eqv.) and
HOBT (0.4 eqv.) were added under nitrogen atmosphere at 25–30 °C. This mixture
was stirred for 15 min and then the corresponding amine (a–f, 1 eqv.) followed by
triethyl amine (2 eqv.) were added and the resultant reaction mixture was stirred for
4 h at 25–30 °C. After reaction completion, the reaction was quenched with 10%
sodium bicarbonate (5 vol.) and the solid precipitated was collected by filtration, the
wet cake was washed with water and dried to afford the desired product 2a–f.
1-(7,7-Dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4-yl)-N-(4-methoxy-
benzo[d]thiazol-2-yl)piperidine-4-carboxamide (2a) Compound 2a is an off-
1
white solid. Yield: 72%, H NMR (300 MHz, DMSO-d6, d ppm): 0.82–0.84 (m,
2H), 0.98 (s, 6H), 1.42–1.45 (m, 2H), 1.62–1.72 (m, 2H), 1.89–1.93 (m, 2H), 2.32
(s, 2H), 2.72–2.85 (m, 2H), 3.57–3.59 (m, 8H), 3.8–3.84 (m, 2H), 3.9 (s, 3H),
6.96–6.99 (d, 2H, J = 8.1 Hz), 7.21–7.26 (t, 1H, J1 = 7.5 Hz, J2 = 8.4 Hz),
7.49–7.52 (d, 1H, J = 7.8 Hz), 12.5 (s, 1H, NH-amide); 13C NMR (100 MHz,
DMSO-d6) d: 22.5, 28.5, 29.1, 31.7, 35.9, 42.2, 44.4, 46.6, 47.7, 56.2, 66.5, 106.4,
108.0, 113.9, 124.8, 133.2, 138.8, 152.2, 156.9, 159.5, 164.8, 166.0, 174.4; IR
(ATR, t cm-1): 970, 1048, 1109, 1258, 1543, 1654, 1691, 2848, 2915; LCMS (ESI)
m/z [M ? H]?: 537.5 Da; Anal. Calcd. for C28H36N6O3S: C, 62.66; H, 6.76; N,
15.66; S, 5.97, Found: C, 62.65; H, 6.77; N, 15.65; S, 5.95%.
1-(7,7-Dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4-yl)-N-(thiazol-2-yl)pi-
1
peridine-4-carboxamide (2b) Compound 2b is an off-white solid. Yield: 82%, H
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Synthesis, characterization and in vitro antibacterial…
NMR (300 MHz, DMSO-d6, d ppm): 0.95 (s, 6H), 1.42 (m, 2H), 1.7–1.73 (m, 2H),
1.88–1.91 (m, 2H), 2.32 (s, 2H), 2.72–2.88 (m, 2H), 3.56–3.59 (m, 8H), 3.79–3.84
(m, 2H), 9.15 (s, 2H); 13C NMR (100 MHz, DMSO-d6) d:23.2, 28.0, 28.4, 31.2,
35.2, 36.2, 41.2, 45.1, 47.3, 65.9, 105.6, 111.9, 114.8, 117.7, 120.6, 149.1, 151.1,
158.2–159.2, 162.7, 163.5, 173.3; IR (ATR, t cm-1): 955, 1114, 1318, 1428, 1545,
1692, 2947; LCMS (ESI) m/z [M ? H]?: 458.5 Da; Anal. Calcd for C23H32N6O2S:
C, 60.50; H, 7.06; N, 18.41; S, 7.02, Found: C, 60.49; H, 7.09; N, 18.40; S, 7.01%.
1-(7,7-Dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4-yl)-N-(2-oxo-1,2-di-
hydropyrimidin-4-yl)piperidine-4-carboxamide (2c) Compound 2c is an off-white
solid. Yield: 65%; 1H NMR (300 MHz, DMSO-d6, d ppm): 0.99 (s, 6H), 1.36–1.51
(m, 2H), 1.62–1.69 (m, 2H), 1.81–1.85 (m, 2H), 2.26 (s, 2H), 2.43–2.65 (m, 3H),
2.69–2.77 (m, 3H), 3.56–3.58 (m, 8H), 3.77–3.81 (m, 2H), 7.10–7.13 (d, 2H,
J = 7.2 Hz), 7.79–7.81 (d, 2H, J = 6.9 Hz), 10.79 (bs, 1H, amide), 11.5 (bs, 1H,
keto-enol); 13C NMR (75 MHz, DMSO-d6) d: 22.7, 27.5, 27.9, 34.7, 41.9, 44.6,
46.8, 65.3, 94.5, 105.1, 109.4–120.9, 148.2, 150.4, 152.2, 154.6, 157.5–159.0,
162.6, 163.0, 175.1; IR (ATR, t cm-1): 810, 1112, 1306, 1456, 1555, 1688, 1726,
2951; LCMS (ESI) m/z [M ? H]?: 468.7 Da; Anal. Calcd for C24H33N7O3: C,
61.65; H, 7.11; N, 20.97; Found: C, 61.65; H, 7.15; N, 20.99%.
1-(7,7-Dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4-yl)piperidine-4-car-
1
bohydrazide (2d) Compound 2d is a pale yellow solid. Yield: 77%; H NMR
(300 MHz, DMSO-d6, d ppm): 0.94 (s, 6H), 1.40 (m, 2H), 1.65 (m, 4H), 2.3 (s, 2H),
2.4 (m, 2H), 2.71 (m, 2H), 3.55–3.58 (m, 8H), 3.76–3.80 (m, 2H),7.4 (bs, 2H, NH2),
9.0 (bs, 1H, amide); IR (ATR, t cm-1): 975, 1112, 1420, 1540, 1566, 1636, 2818,
123

B. Selvakumar, K. P. Elango
3316; LCMS (ESI) m/z [M ? H]?: 489.3 Da; Anal. Calcd for C20H32N6O2: C,
61.83; H, 8.30; N, 21.63; Found: C, 61.82; H, 8.34; N, 21.62%.
1-(7,7-Dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4-yl)-N-(3,5-dimethylisox-
azol-4-yl)piperidine-4-carboxamide (2e) Compound 2e is an off-white solid. Yield:
68%. 1H NMR (300 MHz, CDCl3, d ppm): 1.02 (s, 6H), 1.50–1.59 (m, 2H), 2.46 (S,
2H), 2.17 (s, 3H), 2.31 (s, 23H), 2.44 (s, 2H), 2.47–2.51 (m, 2H), 2.82–2.9 (m, 2H),
3.71–3.74 (m, 8H), 3.87–3.92 (m, 2H), 6.48 (s, 1H, amide); 13C NMR (75 MHz,
DMSO-d6) d: 9.4, 10.7, 21.9, 24.3, 28.0, 28.4, 28.6, 28.8, 31.2, 35.5, 41.8, 44.0,
46.1, 47.2, 66.0, 105.8, 114.2, 157.4, 159.0, 162.0, 164.3, 165.6, 173.9; IR (ATR, t
cm-1): 875, 1005, 1113, 1228, 1365, 1418, 1544, 1664, 1742, 2850, 2921, 3294;
LCMS (ESI) m/z [M ? H]?: 469.3 Da; Anal. Calcd for C25H36N6O3: C, 64.08; H,
7.74; N, 17.93; Found: C, 64.10; H, 7.75; N, 17.91%.
1-(7,7-Dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4-yl)-N-(4-fluo-
rophenethyl)piperidine-4-carboxamide (2f) Compound 3f is an off-white
1
solid. Yield: 86%; H NMR (300 MHz, CDCl3, d ppm): 1.02 (s, 6H), 1.48 (m,
2H), 1.82–1.84 (m, 4H), 2.18–2.23 (m, 1H), 2.44–2.48 (m, 4H), 2.80–2.82 (m, 4H),
3.52–3.54 (m, 2H), 3.71–3.75 (m, 10H), 7.02–7.04 (m, 2H), 7.14–7.16 (m, 2H); 13
C
NMR (100 MHz, DMSO-d6) d: 22.4, 28.4, 28.8, 29.3, 34.6, 35.9, 42.5, 44.4, 46.6,
47.8, 66.5, 106.3, 115.2–115.4, 130.8–130.9, 136.0–136.1, 159.5, 160.0, 162.4,
164.7, 166.0, 174.5; IR (ATR, t cm-1): 824, 1000, 1110, 1223, 1527, 1566, 1646,
123

Synthesis, characterization and in vitro antibacterial…
1742, 2921, 3359; LCMS (ESI) m/z [M ? H]?: 496.8 Da; Anal. Calcd for
C28H38FN5O2: C, 67.85; H, 7.73; N, 14.13; Found: C, 67.84; H, 7.74; N, 14.12%.
Results and discussion
The protocol employed for the synthesis of 1-(7,7-dimethyl-2-morpholino-5,6,7,8-
tetrahydroquinazolin-4-yl)piperidine-4-carboxylic acid (1) and 1-(7,7-dimethyl-2-
morpholino-5,6,7,8-tetrahydroquinazolin-4-yl)piperidine-4-carboxamide
deriva-
tives (2) is shown in Scheme 1. Treatment of 3,3-dimethyl cyclohexanone (3) with
dimethyl carbonate in the presence of sodium hydride in tetrahydrofuran provided
methyl 4,4-dimethyl-2-oxocyclohexane-1-carboxylate (4) [26]. Compound 4 was
coupled with S-methylisothiourea hemi sulfate in water to afford 7,7-dimethyl-2-
(methylthio)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (5) as
a
product. 7,7-
Dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4(3H)-one (6) was synthe-
sized from 5 by replacing the SMe group with morpholine as reported earlier
[20]. The synthesis of ethyl 1-(7,7-dimethyl-2-morpholino-5,6,7,8-tetrahydroquina-
zolin-4-yl) piperidine-4-carboxylate (8) from 6 involves two nucleouphilic
replacement reactions, i.e. initial replacement of the hydroxyl group by chlorine
in the presence of POCl3 to provide (7) and then replacement of the chlorine group
with ethyl isonipecotate. Hydrolysis of the intermediate 8 using lithium hydroxide
yielded compound 1.
Several amide derivatives (2a–f) were synthesized by treating 1 with corre-
sponding amines (RNH2, a–g) using TEA, EDC.HCl and HOBT in DMF. The
structures of compounds 2a–f were confirmed by using elemental analysis, IR
(ATR), NMR and LCMS spectral techniques. The antibacterial activities of these
compounds were screened against five Gram-positive and four Gram-negative
bacterial strains.
All the newly synthesized compounds (2a–f) were evaluated for their in vitro
antibacterial activity against human pathogens by means of a standard two-fold
serial dilution method using agar media. The in vitro antibacterial activity was
performed against five Gram-positive bacterial strains. Staphylococcus aureus,
Enterococcus faecalis, Staphylococcus epidermidis, E. faecalis and Bacillus subtilis
and four Gram-negative strains, Escherichia coli, Pseudomonas aeruginosa,
Enterobactera erogenes and Moraxella catarrhalis. In these studies, commercially
available antibiotics Ciprofloxacin and Linezolid were used as reference standards.
The results obtained are shown in Table 1. The results indicated that compounds 2a,
2b and 2c exhibited good potency in inhibiting the growth of both Gram-positive
bacteria and Gram-negative bacteria when used at a dose of 4–16 lg/mL. In
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B. Selvakumar, K. P. Elango
Scheme 1 Synthesis of 2a–f
general, compounds showing inhibition of at least 18 mm were considered to be
active, and hence these compounds were further evaluated for their minimal
inhibitory concentration (MIC). The in vitro antibacterial activity of the compounds
2a, 2b and 2c against Gram-negative bacteria such as E. coli, P. aeruginosa and
Enterobactera erogenes were found to be superior to the marketed drug Linezolid,
but relatively less active when compared to Ciprofloxacin. It is interesting to note
that the compounds 2a and 2b which contains thiazole ring system showed
relatively higher activity as expected, due to the presence of the bioactive thiazole
moiety [22, 23].
Conclusion
In conclusion, the synthesis and characterization of a series of novel 1-(7,7-
dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4-yl)piperidine-4-carboxamide
derivatives (2a–f) have been reported. The antibacterial activities of these compounds
were tested against good number of Gram-positive and Gram-negative bacterial
strains. The results indicated that the thiazole ring containing quinazoline derivatives
2a and 2b showed good antibacterial activity amongst the compounds prepared, and
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Synthesis, characterization and in vitro antibacterial…
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B. Selvakumar, K. P. Elango
further modification of the quinazoline scaffold or the thiazole ring would definitely
indicate lead molecules toward antibacterial therapeutics.
Acknowledgement One of the authors (BS) is grateful to the Management, Anthem Biosciences,
Bangalore, India, for their invaluable support and allocation of resources for this work. He wishes to
thank the Analytical Chemistry team of Anthem Biosciences for carrying out all the analytical work.
Also, the help of the Discovery Biology team of Anthem Biosciences is greatly acknowledged for
executing anti-bacterial studies.
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