894
Chem. Pharm. Bull. 56(7) 894—896 (2008)
Vol. 56, No. 7
Synthesis and Evaluation of Novel N-Substituted-6-methoxynaphthalene-
2-Carboxamides as Potential Chemosensitizing Agents for Cancer
Tushar Narendra LOKHANDE, ,a Chelakara Lakshmann VISWANATHAN,*,a and
*
b
Aarti Shashikant JUVEKAR
a Department of Pharmaceutical Chemistry, Bombay College of Pharmacy; Kalina, Santacruz (E), Mumbai-400 098,
India: and b Department of Chemotherapy, Tata Memorial Centre, Advanced Center for Treatment, Research and
Education in Cancer (ACTREC); Kharghar, New Mumbai-410 208, India.
Received November 27, 2007; accepted April 15, 2008; published online April 28, 2008
A novel class of molecules with structure N-[3-(heteroaryl)propyl]-6-methoxynaphthalene-2-carboxamides
8—13 were synthesized by condensing 6-methoxy-2-naphthoyl chloride 1 with 3-(heteroaryl)propyl amines 2—7.
Compounds 8—12 were evaluated in vitro, in P388 murine lymphocytic leukemia cell line (P388) using SRB
assay for cytotoxicity and in adriamycin resistant P388 murine lymphocytic leukemia cell line (P388/ADR) using
MTT assay for resistant reversal activity. Compounds 8—12 were non-toxic at lower dose of 20 mg/ml, and effec-
tively reversed adriamycin resistance. However, at higher doses (40, 80 mg/ml) they showed significant cytotxicity
and hence reversal potency was not determined at these concentrations.
Key words 6-methoxynaphthalene-2-carboxamide; multidrug resistance reversal agent; chemosensitizer
2—7 (12 mmol) in turn at room temperature in chloroform for 3—4 h to get
compounds 8—13. Chloroform was removed under vacuum and the residue
obtained was washed with water and then purified by column chromatogra-
phy using, chloroform : ethyl acetate, 80 : 20 as eluent and then recrystallized
from alcohol.
N-[3-(Pyrrolidin-2-one-1-yl)propyl]-6-methoxynaphthalene-2-carboxam-
ide (8): Yield 74.4%. mp 113—115 °C. 1H-NMR (300 MHz, CDCl3) d:
1.3—1.6 (2H, m, –CH2), 1.8—2.1 (2H, m, –CH2), 2.3 (2H, t, –CH2,
Jꢁ7.45 Hz), 2.6—2.8 (4H, m, 2 –CH2), 3.3 (2H, t, –CH2, Jꢁ7.95 Hz) 3.6
(3H, s, –OCH3), 6.2 (1H, s, –NH), 7.1—7.2 (2H, m, Ar-H), 7.6 (1H, s, Ar-
H), 7.72—7.86 (2H, m, Ar-H), 7.88 (1H, s, Ar-H). IR (KBr) cmꢂ1: 3431,
1641. Anal. Calcd for C19H22N2O3: C, 69.85; H, 6.74; N, 8.57. Found: C,
70.08; H, 6.75; N, 8.75.
Effective cancer chemotherapy can be severely impaired
by drug resistance, wherein P-glycoprotein (Pgp), a mem-
brane protein is invovlved in effluxing cytotoxic agents from
cell.1) The agents used to combat drug resistance are called
chemosensitizers or resistant reversal agents. Reversal agents
like verapamil, cyclosporine, propafenone and quinidine
were non-specific in their action and produced toxicity when
used in vivo.2) Non-toxic chemosensitizing agents were then
developed and among them Elacridar (GF-120918) showed
good promise.3)
In our laboratory a pharmacophore for chemosensitizing
activity was developed using Elacridar as a query molecule
and based on this pharmacophore, a series of substituted 6-
methoxynaphthalene-2-carboxamides were synthesized and
they exhibited good Chemosensitizing activity.4) These
agents contained substituted piperazinopropyl as substituents
on amide nitrogen.
N-[3-(Benzimidazol-1-yl)propyl]-6-methoxynaphthalene-2-carboxamide
1
(9): Yield 72.5%. mp 95—96 °C. H-NMR (300 MHz, CDCl3) d: 1.5—1.7
(2H, m, –CH2), 2.8—2.9 (4H, m, 2-CH2), 3.98 (3H, s, –OCH3), 6.2 (1H, s,
–NH), 7.12—7.22 (2H, m, Ar-H), 7.30—7.38 (2H, m, Ar-H), 7.6 (1H, s, Ar-
H), 7.74—7.88 (2H, m, Ar-H), 7.98 (1H, s, Ar-H), 8.26 (2H, d, Ar-H,
Jꢁ8.19 Hz), 8.52 (1H, s, Ar-H), IR (KBr) cmꢂ1: 3435, 1705. Anal. Calcd for
C22H21N3O2: C, 73.45; H, 5.84; N, 11.68. Found: C, 73.55; H, 5.86; N,
11.74.
Our continued interest in this area led to the development
of another novel series of chemosensitizing agents. In the
present work we replaced the piperazine ring by other hetero-
cyclic systems in order to study their potential for contribut-
ing to chemosensitizing activity on evaluation. The hetero-
cyclic systems chosen were based on their lipophilicity and
their ability to act as an hydrogen bond acceptor/donor
group. It is proposed to synthesise these novel molecules and
evaluate them for cytotoxicity and for chemosensitizing ac-
tivity in resistant cancer cell lines.
N-[3-(2-Methylbenzimidazol-1-yl)propyl]-6-methoxynaphthalene-2-car-
boxamide (10): Yield 70.6%. mp 72—74 °C. 1H-NMR (300 MHz, CDCl3) d:
1.5—1.7 (2H, m, –CH2), 2.24 (3H, s, –CH3), 2.8—2.9 (4H, m, 2-CH2), 3.98
(3H, s, –OCH3), 6.2 (1H, s, –NH), 7.12—7.20 (2H, m, Ar-H), 7.30—7.50
(2H, m, Ar-H), 7.6 (1H, s, Ar-H), 7.74—7.88 (2H, m, Ar-H), 8.0 (1H, s, Ar-
H), 8.2 (2H, d, Ar-H, Jꢁ8.08 Hz), IR (KBr) cmꢂ1: 3447, 1684. Anal. Calcd
for C23H23N3O2: C, 73.90; H, 6.15; N, 11.24. Found: C, 74.01; H, 6.16; N,
11.34.
N-[3-(Benzotriazol-1-yl)propyl]-6-methoxynaphthalene-2-carboxamide
(11): Yield 74.5%. mp 188—190 °C. 1H-NMR (300 MHz, DMSO-d6) d:
1.5—1.6 (2H, m, –CH2), 2.8—2.9 (4H, m, 2-CH2), 3.98 (3H, s, –OCH3), 6.2
(1H, s, –NH), 7.18—7.26 (2H, m, Ar-H), 7.42—7.48 (2H, dd, Ar-H,
Jꢁ6.86 Hz), 7.6 (1H, s, Ar-H), 7.84 (2H, d, Ar-H, Jꢁ8.55 Hz), 8.20 (2H, d,
Ar-H, Jꢁ8.27 Hz), 8.32 (1H, s, Ar-H), IR (KBr) cmꢂ1: 3315, 1620. Anal.
Calcd for C21H20N4O2: C, 69.92; H, 5.54; N, 15.53. Found: C, 70.02; H,
5.55; N, 15.62.
N-[3-(1,2,3,4-Tetrahydroisoquinolin-2-yl)propyl]-6-methoxynaphthalene-
2-carboxamide (12): Yield 75%. mp 148—150 °C. 1H-NMR (300 MHz,
CDCl3) d: 1.4—1.6 (2H, m, –CH2), 2.2—2.4 (4H, m, 2-CH2 ), 2.8 (4H, t, 2-
CH2, Jꢁ6.30 Hz), 3.4 (2H, d, –CH2) 3.98 (3H, s, –OCH3), 6.2 (1H, s, –NH),
7.14—7.24 (6H, m, Ar-H), 7.6 (1H, s, Ar-H), 7.74—7.82 (2H, dd, Ar-H,
Jꢁ8.53 Hz), 8.0 (1H, s, Ar-H). IR (KBr) cmꢂ1: 3433, 1618. Anal. Calcd for
C24H26N2O2: C, 76.90; H, 6.94; N, 7.47. Found: C, 76.92; H, 6.95; N, 7.54.
N-[3-(4-Amino-3-methylthio-5-phenyl-1,2,4-triazol-4-yl)-propyl]-6-
methoxynaphthalene-2-carboxamide (13): Yield 76%. mp 194—195 °C. 1H-
NMR (300 MHz, DMSO-d6) d: 1.4—1.5 (2H, m, –CH2), 2.6 (3H, s,
Experimental
Chemistry All melting points were recorded on Thermonik melting
point apparatus and are uncorrected; fourier-transform infrared (FT-IR)
spectra (KBr discs) were recorded in Jasco FT-IR 5300 instrument. Proton-
NMR spectra were recorded on Varian VX-300 NMR spectrophotometer
(300 MHz) using CDCl3 and DMSO-d6 as solvents. The chemical shift val-
ues are reported in d units (ppm) relative to internal standard tetramethylsi-
lane (TMS). Column Chromatography was performed using Silica gel, 60—
120 mesh, from Qualigens fine chemicals, India. Elemental analysis values
for final compounds were within ꢀ0.4% of theoretical value.
General Method for Preparation of N-[3-(Heteroaryl)propyl]-6-
methoxynaphthalene-2-carboxamides (8—13) 6-Methoxy-2-naphthoyl
chloride 1 (10 mmol) was condensed with different heteroaryl propylamines
∗
To whom correspondence should be addressed. e-mail: tusharlokhande@hotmail.com; chelakara_viswanathan@yahoo.com © 2008 Pharmaceutical Society of Japan