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V. Rachakonda et al. / European Journal of Medicinal Chemistry 70 (2013) 536e547
539
Table 1
Primary antimycobacterial and cytotoxicity screening of diverse quinolinyl heterocycles.
Compound
Antimycobacterial activity (against M. smegmatis strain)
Cytotoxicity activity (against A549 cells)
MIC (
m
g/mL)a,b
Std. Dev.c
IC50
(
m
M)d
Std. Dev
5
7
8
9
>50
>50
14.66
>50
e
96.373
94.198
137.510
>200
20.335
18.000
4.534
e
1.25
e
10
12a
14f
>50
e
117.724
144.839
170.745
e
32.516
28.677
48.263
e
34.97
57.87
2.08
4.2
13.18
0.04
0.98
Rifampicin (Control)
Isoniazid (Control)
12.07
e
e
a
Mycobacterium smegmatis ATCC 14468 (MC2).
Concentration of compounds inhibiting growth by 50%.
b
c
GI50 values are indicated as mean ꢂ SD (standard deviation) of three independent experiments.
d
IC50 (mM) against A549 cells.
45 ꢀC. Melting points were recorded by open capillary method and
were uncorrected. IR spectra were recorded on PerkineElmer 683,
Nicolet Nezus 670 spectrometer. 1H NMR and 13C NMR were
recorded in CDCl3 or DMSO-d6 solvents on Bruker AV-300 MHz and
Varian, Innova 500 MHz NMR. Chemical shifts were reported in
parts per million (ppm) with respect to internal standard TMS.
Coupling constants (J) are quoted in hertz (Hz). Mass spectra were
obtained on Finnigan MAT1020B, micromass VG70-70H or Agilent
technologies LC/MSD trapSL spectrometer operating at 70ev using
direct inlet system.
acid. The reaction mixture was maintained at 100 ꢀC with vigorous
stirring for 3 h. At the end of the period, the reaction mixture was
cooled to room temperature and the separated solid was filtered,
washed with ice cold water, ethyl acetate and dried to obtain
desired compound 4.
4.4. Synthesis of 2-methylquinoline-3-carbohydrazide (5)
To a clear solution of 3b (1 mmol) in EtOH, hydrazine hydrate
(3 mmol) was added and the reaction mixture was refluxed over
night. After completion of the reaction (TLC control), the reaction
mixture was cooled to r.t, and the precipitate was filtered. Recrys-
talization from ethanol followed by filtration and washing with
cold ethanol gave pure compound 5 as a white crystalline Solid, mp
4.2. Synthesis of C-4 unsubstituted 2-methyl quinolinyl derivatives
(3aec)
190e193 ꢀC; 1H NMR (300 MHz, CDCl3)
d (ppm): 9.62 (brs, D2O
To a clear solution of 2-amino benzyl alcohol or 6-chloro benzyl
alcohol 1 (1 mmol) in EtOH containing MnO2 (3 mmol), compound
2(aec) (1 mmol) was added and the reaction mixture was refluxed
for appropriate time (TLC control). The reaction mixture was
filtered through celite bed. From the filtrate, ethanol was removed
under reduced pressure and residue was subjected to column
chromatography to obtain pure product 3(aec).
exchangeable,1H, NH), 8.19 (s,1H, ArH), 7.93 (d, J ¼ 8.3 Hz,1H, ArH),
7.84 (d, J ¼ 8.1 Hz 1H, ArH), 7.70 (t, J ¼ 7.0 Hz, 1H, ArH), 7.5 (t,
J ¼ 7.7 Hz, 1H, ArH), 3.27 (brs, 2H, NH2), 2.75 (s, 3H, CH3); MS (ESI)
m/z: 202 [M þ H]þ; FTIR (KBr)
n
(cmꢁ1): 3258 (NH2), 1620 (C]O).
4.5. Synthesis of 3-(dimethylamino)-1-(2-methylquinolin-3-yl)
prop-2-en-1-one (6)
4.2.1. 1-(2-Methylquinolin-3-yl)ethanone (3a)
Yield 92% as a white solid, mp 63e65 ꢀC; 1H NMR (300 MHz,
To a solution of 3a (1 mmol) in xylene, DMF-DMA (3 mmol) was
added and the reaction mixture refluxed for 10 h (TLC control). The
xylene was removed under reduced pressure and the product was
triturated with hexane. The resulting solid was filtered and washed
with cold hexane to obtain pure product 6 as pale yellow solid. The
product was taken up for further steps without purification.
CDCl3)
d
(ppm): 8.42 (s, 1H, ArH), 8.01 (d, J ¼ 9.1 Hz, 1H, ArH), 7.84e
7.71 (m, 2H, ArH), 7.52 (t, J ¼ 6.0 Hz, 1H, ArH), 2.90 (s, 3H, COCH3),
2.71 (s, 3H, CH3): MS (ESI) m/z: 186 [M þ H]þ; FTIR (KBr)
2967 (Ar Stretch), 1676 (C]O).
n
(cmꢁ1):
4.2.2. Ethyl 2-methylquinoline-3-carboxylate (3b)
Yield 91% as a white solid, mp 58e60 ꢀC; 1H NMR (300 MHz,
CDCl3)
d
(ppm): 8.68 (s, 1H, ArH), 8.01 (d, J ¼ 8.3 Hz, 1H, ArH), 7.82
4.6. Synthesis of 4-(2-methylquinolin-3-yl)pyrimidin-2-amine (7)
(d, J ¼ 8.1 Hz, 1H, ArH), 7.76 (t, J ¼ 7.0 Hz, 1H, ArH), 7.50 (t, J ¼ 7.9 Hz,
1H, ArH), 4.47e4.37 (q, 2H, OCH2), 2.97 (s, 3H, ArCH3), 1.46 (t,
J ¼ 7.2 Hz, 3H, CH3); MS (ESI) m/z: 216 [M þ H]þ, 217 [M þ 2]þ; FTIR
To a clear solution of NaOH (3 mmol) in methanol containing
guanidine hydrochloride (1 mmol), compound 6 (1 mmol) was
added and the reaction mixture was refluxed for 8 h. After
completion of the reaction (TLC control), the separated solid was
filtered off, washed with water and cold methanol. Recrystallization
from hot methanol gave the pure product 7 (70%) as white solid, mp
(KBr)
n
(cmꢁ1): 2969 (Ar Stretch), 1714 (C]O).
4.2.3. Methyl 2-methylquinoline-3-carboxylate (3c)
Yield 85% as a white solid, mp 62e65 ꢀC; 1H NMR (300 MHz,
207e210 ꢀC; 1H NMR (300 MHz, CDCl3)
d
(ppm): 8.43 (d, J ¼ 5.3 Hz,
CDCl3)
d
(ppm): 8.70 (s, 1H, ArH), 8.01 (d, J ¼ 8.3 Hz, 1H, ArH), 7.82
(d, J ¼ 8.3 Hz,1H, ArH), 7.75 (t, J ¼ 6.8 Hz,1H, ArH), 7.51 (t, J ¼ 8.3 Hz,
1H, ArH), 3.97 (s, 3H, OCH3), 2.97 (s, 3H, ArCH3); MS (ESI) m/z: 202
1H, ArH), 8.19 (s, 1H, ArH), 8.06 (d, J ¼ 8.3 Hz, 1H, ArH), 7.84 (d,
J ¼ 8.3 Hz, 1H, ArH), 7.71e7.77 (m, 1H, ArH), 7.53 (t, J ¼ 6.8 Hz, 1H,
ArH), 6.86 (d, J ¼ 5.3 Hz, 1H, ArH), 5.20 (brs, 2H, NH2), 2.82 (s, 3H,
[M þ H]þ; FTIR (KBr)
n
(cmꢁ1): 2950 (Ar Stretch), 1724 (C]O).
CH3); 13C NMR (75 MHz, CDCl3 þ DMSO-d6)
d (ppm): 165.5, 163.1,
4.3. Synthesis of 2-bromo-1-(2-methylquinoln-3-yl)ethanone (4)
158.3, 156.1, 146.7, 135.9, 132.1, 129.6, 127.7, 127.6, 125.8, 109.7, 24.0;
MS (ESI) m/z: 266 [M þ H]þ, 288 [M þ Na]þ; HRMS (ESI) calcd for
To the hot solution of 3a (1 mmol) in glacial acetic acid (AcOH) at
C
16H16ON3 [M þ H]þ: 266.12811. Found: 266.12879; FTIR (KBr)
n
100 ꢀC was added a solution of bromine (1 mmol) in glacial acetic
(cmꢁ1): 3319 (NH2), 3170.