Library design, synthesis and biological exploration of novel 3,4′-bicarbostyril derivatives as potent antimicrobial, antitubercular and antimalarial agents

Article abstract of DOI:10.1007/s00044-017-1797-x

Abstract: A library comprises diversely substituted novel 3,4′-bicarbostyril derivatives have been designed by molecular hybridization technique and synthesized via multi-component reaction. Compounds G22 (MIC = 12.5 μg/mL) and G38 (MIC = 25 μg/mL) exhibited 99% inhibition against Mycobacterium tuberculosis, while compounds G40 (IC₅₀ = 0.019 μg/mL) and G20 (IC₅₀ = 0.028 μg/mL) found to have excellent activity against Plasmodium falciparum. Compounds G37 (MIC = 25 μg/mL) and G8, G18, and G38 (MIC = 50 μg/mL) elicited excellent antimicrobial activity compared to standard drugs. Biological results revealed that the potency of the title compounds strongly depends on the length and flexibility of various spacers at N?1, the electronic influence of substituent at R₁ and lipophilicity of CH₃ group at R₂ position on bicarbostyril system. Graphical Abstract: [InlineMediaObject not available: see fulltext.]

Full text of DOI:10.1007/s00044-017-1797-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-1797-x
ORIGINAL RESEARCH
Library design, synthesis and biological exploration of novel
3,4′-bicarbostyril derivatives as potent antimicrobial,
antitubercular and antimalarial agents
Hardik H. Jardosh1 Nileshkumar D. Vala1 Manish P. Patel1
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Received: 20 June 2015 / Accepted: 3 February 2017
© Springer Science+Business Media New York 2017
Abstract A library comprises diversely substituted novel
3,4′-bicarbostyril derivatives have been designed by mole-
cular hybridization technique and synthesized via multi-
component reaction . Compounds G22 (MIC = 12.5 µg/mL)
and G38 (MIC = 25 µg/mL) exhibited 99% inhibition
against Mycobacterium tuberculosis, while compounds G40
(IC50 = 0.019 µg/mL) and G20 (IC50 = 0.028 µg/mL) found
to have excellent activity against Plasmodium falciparum.
Compounds G37 (MIC = 25 µg/mL) and G8, G18, and G38
(MIC = 50 µg/mL) elicited excellent antimicrobial activity
compared to standard drugs. Biological results revealed that
the potency of the title compounds strongly depends on the
length and flexibility of various spacers at N−1, the elec-
tronic influence of substituent at R1 and lipophilicity of CH3
group at R2 position on bicarbostyril system.
Graphical Abstract
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Keywords Carbostyril
Quinoline
Multi-component
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Electronic supplementary material The online version of this article
(doi:10.1007/s00044-017-1797-x) contains supplementary material,
which is available to authorized users.
reaction Antimicrobial activity Antitubercular activity
Antimalarial activity
* Manish P. Patel
patelmanish1069@yahoo.com
1
Department of Chemistry, Sardar Patel University, Vallabh
Vidyanagar 388120 Gujarat, India

Med Chem Res
Introduction
Jardosh et al. 2013e; Kanani and Patel 2014; Srivastava et al.
2015; Narhe et al. 2014), which allows a combination of two
or more bio-potent moieties and pharmacophoric groups in a
single scaffold could lead to the creation of successful drugs.
Moreover, the diversity oriented synthesis (DOS) has
exhibited considerable importance and proved to explore the
library of complex and diverse biologically important het-
erocyclic compounds in less time (Srivastava et al. 2015;
Narhe et al. 2014; Kumar et al. 2011). In the context of our
goal to discover biologically potent bicarbostyril system and
our incessant efforts towards the development of quinoline
based heterocyclic compounds (Kathrotiya and Patel 2013;
Jardosh and Patel 2012, 2013a, b, c, d, e, 2014; Sangani
et al. 2014; Kanani and Patel 2014), we have designed and
synthesized small library of hitherto novel 3,4′-bicarbostyril
derivatives by incorporating:
Malaria is a vicious and endemic infectious disease across
Asia, Africa, Europe, and America (Cures et al. 2013).
Also, the treatment and control of malaria became more
difficult because of the spread of drug resistance to most
antimalarial drugs including chloroquine, mefloquine, ato-
vaquone, primaquine and sulphadoxine (Jagoe 2014).
Consequently, the World Health Organization suggested
developing efficient vaccines for the elimination of malaria
(WHO 2014a). On the other hand, tuberculosis is one of the
world’s deadliest diseases, caused by Mycobacterium
tuberculosis bacteria (MTB) (WHO 2014b). The prevalence
of multidrug-resistant TB and extensively drug-resistant TB
substantiates the urgent need for the development of new
antitubercular drugs (Mdluli et al. 2015). Moreover, the
treatment of infectious diseases caused by bacteria and
fungi remains an important and challenging problem due to
multi-drug resistant microbial pathogens. Hence, Infectious
Diseases Society of America gives a proposal for a “10 × 20
initiative” in which they noted ‘Time has came for a global
commitment to develop new antibacterial drugs” and sug-
gested that minimum ten new drugs should be developed by
2020 (Infectious Diseases Society of America 2010). In
order to defeat these issues, there is an urgent need to dis-
cover competent antimicrobial, antitubercular and anti-
malarial drugs for the effective chemotherapy.
The carbostyril (2-quinolone) is a biologically vital
scaffold and found in number of alkaloids such as, Bucha-
pine (McCormick et al. 1996), Semecarpifoline (Chen et al.
2001), Peniprequinolone (Hayashi et al. 1997) and Penige-
quinolone B (Kimura et al. 1996) (Fig. 1). In recent years,
medicinal chemists have gained special attention towards the
development of a new class of antimicrobial, antitubercular
and antimalarial agents based on quinolone moiety (Plech
et al. 2013; Cui et al. 2013; Asif et al. 2013; Kathrotiya and
Patel 2013). As a result, Delafloxacin (Butler et al. 2013),
Bedaquiline (TMC 207) (Butler et al. 2013) and SJ733
(Jiménez-Díaz et al. 2014) were derived as potential drug
candidates for the antibacterial, anti-TB and antimalarial
activities, respectively (Fig. 1). On the other hand, spacers
like amine –NH– and amide –CONH– (specifically iso-
niazid) were incorporated in the molecules by adopting
molecular hybridization approach to boost the activities of
resultant compounds, e.g., SJ733 (Jiménez-Díaz et al. 2014),
DSM265 (Coteron et al. 2011), Sudoterb (LL3858) (Arora
et al. 2010) (Fig. 1). Also, the allyl group at the heterocyclic
N-atom has been found to enhance antimicrobial activity and
plays an imperative role in the development of new anti-
microbial agents (Jardosh and Patel 2012, 2013a, b, c, d,
2014). Over the last few years, molecular hybridization
technique proved to be a very successful technique (Jardosh
and Patel 2012, 2013a, b, c, d, 2014; Sangani et al. 2014;
i) Spacers having different length at the N-1 position of
carbostyril: phenyl (Ph), benzyl, phenyl hydrazine
(PHZ), benzohydrazide (BHZ) and isoniazid (INH)
ii) Electron donating and withdrawing groups at the C-4
position of N-allyl carbostyril: H, CH3, OCH3, and Cl
iii) Lipophilic methyl group at C-7 position of carbostyril
ring
In the light of aforesaid findings and mentioned
hypothesis, we report herein the library design and synthesis
of novel 3,4′-bicarbostyril derivatives via three component
cyclo-condensation reaction between 1-allyl-2-oxo-1,2-
dihydroquinoline-3-carbaldehydes, Meldrum’s acid and
various β-enaminones. The structures of title derivatives
were elucidated on the basis of FT-IR, 1H NMR, 13C NMR
(APT), mass spectra and elemental analysis. All these
derivatives were evaluated for their in vitro antimicrobial
activity against a representative panel of bacteria and fungi,
antitubercular activity against M. tuberculosis bacteria and
antimalarial activity against P. falciparum (Fig. 2).
Experimental
Materials and methods
All the reagents were procured from Sigma-Aldrich and
were used without further purification. Organic solvents
were purchased from Merck and purified by standard
methods and stored over molecular sieves. All reactions
were monitored by thin-layer chromatography (TLC, on
aluminum plates coated with silica gel 60F254, 0.25 mm
thickness, Merck) carried on fluorescent coated plates and
detection of the components was made by exposure to
iodine vapors or ultra-violet light. The course of the reaction
was followed by TLC using solvent system chloroform:
methanol::9:1. Melting points of all the title compounds

Med Chem Res
Fig. 1 Quinoline based alkaloids and repurposed drugs
were determined by the open tube capillary method (using
silicon oil 350 cst) and are uncorrected. The IR spectra were
recorded on a Perkin-Elmer Spectrum GX FT-IR Spectro-
photometer (Perkin-Elmer, USA) using potassium bromide
pellets in the range 4000–400 cm−1 and frequencies of only
Perkin-Elmer 2400 series-II elemental analyzer (Perkin-
Elmer, USA) and all compounds are within 0.4% of the
theoretical compositions. Standard drugs ampicillin, cipro-
floxacin, chloramphenicol, griseofulvin, nystatin, isoniazid,
rifampicin, quinine and chloroquine were commercial.
1
characteristic peaks are expressed in cm−1. H NMR and
13C NMR (APT) spectra were recorded in DMSO-d6 on a
Bruker Avance 400F (MHz) spectrometer (Bruker Scientific
Corporation Ltd., Switzerland) using TMS as an internal
standard at 400 and 100 MHz, respectively. Chemical shifts
are reported in parts per million (ppm). Splitting patterns are
designated as s, for singlet; d, for doublet; m, for multiplet.
The mass spectra were scanned on a Shimadzu LCMS 8030
mass spectrometer (Shimadzu, Tokyo, Japan). ESI source
and triple quardrupole mass analyzer were used for analysis.
Elemental analysis (% C, H, N) was carried out using a
General procedure for the synthesis of β-enaminones
E(1–10)
In a round-bottom flask, equimolar (3 mmol) mixture of 1,3-
cyclohexanedione/dimedone C(1–2) and aniline D1/benzyl
amine D2/BHZ D3/INH D4 heated at 120 °C till the com-
pletion of the reaction as confirmed by the TLC (30 min.).
The crude products obtained were purified by recrystalization
with ethanol: water (1:4) mixture and dried. The products
were obtained quantitatively with an excellent purity.

Med Chem Res
Fig. 2 Design of 3,4′-bicarbostyril derivatives
General procedure for the synthesis of 3,4′-
bicarbostyrilderivatives G(1–40)
121.70, 126.66, 127.55, 128.21, 128.87, 129.87, 132.10,
132.62, 133.24, 133.62, 137.00, 137.45, and 157.65 (16C,
Ar–C+allylic C=C), 160.52 (C=O), 169.49 (C=O),
195.48 (C=O); MS (ESI) m/z 424.6 [M]+; anal. calcd. for
C27H24N2O3 (424.49 g/mol): C, 76.39; H, 5.70; N, 6.60;
Found: C, 76.63; H, 5.54; N, 6.58.
A 100 mL round bottomed flask, fitted with a reflux con-
denser, was charged with a mixture of 1-allyl-2-oxo-1,2-
dihydroquinoline-3-carbaldehydes B(1–4) (1 mmol), Mel-
drum’s acid F (1 mmol), various β-enaminones E(1–10)
(1 mmol) and a catalytic amount of piperidine (0.2 mmol) in
ethanol (10 mL). The reaction mixture was heated under
reflux for 3–4 h and the progress of the reaction was mon-
itored by TLC. After completion of the reaction (as evi-
denced by TLC), the reaction mixture was cooled to room
temperature and stirred magnetically for further 20 min, the
solid mass separated was collected by filtration, washed
well with ethanol (15 mL) and purified by recrystalization
from equal volume ratio of chloroform and methanol
(20 mL) to obtain a pure solid sample.
1-Allyl-6-methyl-1′-phenyl-3′,4′,7′,8′-tetrahydro-3,4′-biqui-
noline-2,2′,5′(1H,1′H,6′H)-trione (G2) Yield: 75%; mp:
226–228 °C; IR (KBr, νmax, cm−1): 3020 (Ar C–H str.),
1
1705, 1642, and 1628 (C=O str.); H NMR (400 MHz,
DMSO-d6) δ ppm: 1.92–2.69 (m, 9H, 3 × CH2 of cyclo-
hexenone ring+CH3), 2.80 (dd, 1H, J1 = 15.6 Hz, J2 =
16.0 Hz, H-3), 3.03 (dd, 1H, J1 = 8.0 Hz, J2 = 8.0 Hz, H-3),
4.43 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-4), 4.89 (d, 2H, J
= 6.4 Hz, N–CH2), 4.92 (d, 1H, J = 16.8 Hz, N–
СН2СН=СН-trans), 5.11 (d, 1H, J = 10.4 Hz, N–
СН2СН=СН-cis), 5.90 (m, 1H, CH=CH2), 7.26–8.07 (m,
9H, Ar–H); 13C NMR (APT) (100 MHz, DMSO-d6) δ ppm:
20.42 (CH3), 21.32 (CH2), 27.02 (CH2), 29.72 (quinolone
C-4), 35.44 (quinolone C-3), 36.47 (CH2–CO), 44.72
(allylic N–CH2–CH), 116.10, 117.04, 117.30, 121.68,
126.61, 127.50, 128.19, 128.79, 129.81, 132.12, 132.66,
133.21, 133.63, 137.05, 137.44, and 157.67 (16C, Ar–C
+allylic C=C), 160.53 (C=O), 169.50 (C=O), 195.46
(C=O); MS (ESI) m/z 438.7 [M]+; anal. calcd. for
C28H26N2O3 (438.52 g/mol): C, 76.69; H, 5.98; N, 6.39;
found: C, 76.62; H, 5.99; N, 6.50.
1-Allyl-1′-phenyl-3′,4′,7′,8′-tetrahydro-3,4′-biquinoline-
2,2′,5′(1H,1′H,6′H)-trione (G1) Yield: 72%; mp: 224–226
°C; IR (KBr, νmax, cm−1): 3020 (Ar C–H str.), 1702, 1642,
1
and 1620 (C=O str.); H NMR (400 MHz, DMSO-d6) δ
ppm: 1.94–2.41 (m, 6H, 3 × CH2 of cyclohexenone ring),
2.74 (dd, 1H, J1 = 15.6 Hz, J2 = 16.0 Hz, H-3), 3.10 (dd,
1H, J1 = 8.0 Hz, J2 = 8.0 Hz, H-3), 4.42 (t, 1H, J1 = 7.2, J2
= 7.6 Hz, CH, H-4), 4.85 (d, 2H, J = 6.4 Hz, N-CH2), 4.90
(d, 1H, J = 16.8 Hz, N-СН2СН=СН-trans), 5.10 (d, 1H, J
= 10.4 Hz, N-СН2СН=СН-cis), 5.90 (m, 1H, CH=CH2),
7.23–8.05 (m, 10H, Ar–H); 13C NMR (APT) (100 MHz,
DMSO-d6) δ ppm: 21.27 (CH2), 26.95 (CH2), 29.67 (qui-
nolone C-4), 35.54 (quinolone C-3), 36.44 (CH2–CO),
44.74 (allylic N–CH2–CH), 116.12, 117.10, 117.36,
1-Allyl-6-methoxy-1′-phenyl-3′,4′,7′,8′-tetrahydro-3,4′-
biquinoline-2,2′,5′(1H,1′H,6′H)-trione (G3) Yield: 68%;
mp: 237–239 °C; IR (KBr, νmax, cm−1): 3070 (Ar C–H str.),

Med Chem Res
1
1702, 1641, and 1620 (C=O str.); H NMR (400 MHz,
DMSO-d6) δ ppm: 1.94–2.42 (m, 6H, 3 × CH2 of cyclo-
hexenone ring), 2.78 (dd, 1H, J1 = 15.6 Hz, J2 = 16.0 Hz,
H-3), 3.08 (dd, 1H, J1 = 8.0 Hz, J2 = 8.0 Hz, H-3), 3.80 (s,
3H, OCH3), 4.49 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-4),
4.84 (d, 2H, J = 6.4 Hz, N–CH2), 4.91 (d, 1H, J = 16.8 Hz,
N–СН2СН=СН-trans), 5.09 (d, 1H, J = 10.4 Hz, N–
СН2СН=СН-cis), 5.89 (m, 1H, CH=CH2), 7.21–8.06 (m,
9H, Ar–H); 13C NMR (APT) (100 MHz, DMSO-d6) δ ppm:
21.18 (CH2), 26.52 (CH2), 29.60 (quinolone C-4), 35.55
(quinolone C-3), 36.47 (CH2–CO), 44.75 (allylic N–
CH2–CH), 55.90 (OCH3), 115.36, 117.07, 117.32, 121.62,
126.64, 127.52, 128.23, 129.90, 132.02, 132.41, 133.26,
133.68, 137.12, 137.84, 154.24, and 157.62 (16C, Ar–C
+allylic C=C), 160.48 (C=O), 169.52 (C=O), 195.46
(C=O); MS (ESI) m/z 454.6 [M]+; anal. calcd. for
C28H26N2O4 (454.52 g/mol): C, 73.99; H, 5.77; N, 6.16;
found: C, 74.13; H, 5.56; N, 6.31.
CH3 of dimedone ring), 29.60 (quinolone C-4), 32.97
(CH2), 35.67 (quinolone C-3), 38.82 (C(CH3)2), 44.57
(CH2–CO), 49.61 (allylic N–CH2–CH), 114.65, 115.85,
117.18, 119.82, 122.52, 126.71, 127.62, 128.82, 129.00,
130.66, 130.87, 132.55, 134.45, 138.19, 138.46, and 155.82
(16C, Ar–C+allylic C=C), 160.67 (C=O), 170.25 (C=O),
195.21 (C=O); MS (ESI) m/z 452.7 [M]+; anal. calcd. for
C29H28N2O3 (452.54 g/mol): C, 76.97; H, 6.24; N, 6.19;
found: C, 76.89; H, 6.55; N, 5.83.
1-Allyl-6,7′,7′-trimethyl-1′-phenyl-3′,4′,7′,8′-tetrahydro-
3,4′-biquinoline-2,2′,5′(1H,1′H,6′H)-trione
(G6) Yield:
74%; mp: 235–237 °C; IR (KBr, νmax, cm−1): 3070 (Ar
C–H str.), 1704, 1641, and 1620 (C=O str.); 1H NMR (400
MHz, DMSO-d6) δ ppm: 0.98 (s, 3H, CH3 of dimedone
ring), 1.02 (s, 3H, CH3 of dimedone ring), 1.71–2.69 (m,
7H, 2 × CH2 of dimedone ring+CH3), 2.80 (dd, 1H, J1 =
15.2 Hz, J2 = 15.6 Hz, H-3), 3.10 (dd, 1H, J1 = 8.4 Hz, J2
= 8.4 Hz, H-3), 4.48 (t, 1H, J1 = 7.6, J2 = 8.0 Hz, CH, H-
4), 4.92 (d, 2H, J = 5.2 Hz, N–CH2), 4.99 (d, 1H, J = 17.2
Hz, N–СН2СН=СН-trans), 5.14 (d, 1H, J = 10.4 Hz, N–
СН2СН=СН-cis), 5.92 (m, 1H, CH=CH2), 7.23–8.07 (m,
9H, Ar–H); 13C NMR (APT) (100 MHz, DMSO-d6) δ ppm:
24.58, 25.67 (2 × CH3 of dimedone ring), 29.51 (CH3),
29.62 (quinolone C-4), 32.98 (CH2), 35.65 (quinolone C-3),
38.78 (C(CH3)2), 44.56 (CH2–CO), 49.64 (allylic N–
CH2–CH), 114.66, 115.82, 117.15, 119.81, 116.41, 126.80,
127.57, 128.83, 129.12, 130.57, 130.93, 132.54, 134.47,
138.20, 138.51, and 155.77 (16C, Ar–C+allylic C=C),
160.68 (C=O), 170.22 (C=O), 195.19 (C=O); MS (ESI)
m/z 466.6 [M]+; anal. calcd. for C30H30N2O3 (466.57 g/
mol): C, 77.23; H, 6.48; N, 6.00; found: C, 77.40; H, 6.47;
N, 6.04.
1-Allyl-6-chloro-1′-phenyl-3′,4′,7′,8′-tetrahydro-3,4′-biqui-
noline-2,2′,5′(1H,1′H,6′H)-trione (G4) Yield: 80%; mp:
243–245 °C; IR (KBr, νmax, cm−1): 3070 (Ar C–H str.),
1
1705, 1643, and 1620 (C=O str.); H NMR (400 MHz,
DMSO-d6) δ ppm: 1.96–2.42 (m, 6H, 3 × CH2 of cyclo-
hexenone ring), 2.76 (dd, 1H, J1 = 15.6 Hz, J2 = 16.0 Hz,
H-3), 3.11 (dd, 1H, J1 = 8.0 Hz, J2 = 8.0 Hz, H-3), 4.40 (t,
1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-4), 4.88 (d, 2H, J = 6.4
Hz, N–CH2), 4.93 (d, 1H, J = 16.8 Hz, N–СН2СН=СН-
trans), 5.14 (d, 1H, J = 10.4 Hz, N–СН2СН=СН-cis), 5.91
(m, 1H, CH=CH2), 7.31–8.10 (m, 9H, Ar–H); 13C NMR
(APT) (100 MHz, DMSO-d6) δ ppm: 21.84 (CH2), 28.49
(CH2), 30.02 (quinolone C-4), 36.16 (quinolone C-3), 36.42
(CH2–CO), 44.81 (allylic N–CH2–CH), 115.05, 117.07,
117.34, 121.68, 126.70, 128.15, 128.34, 128.95, 130.03,
132.23, 132.74, 133.57, 133.77, 137.24, 137.55, and 158.02
(16C, Ar–C+allylic C=C), 160.57 (C=O), 169.56 (C=O),
195.52 (C=O); MS (ESI) m/z 458.7 [M]+, 460.5 [M+2]+;
anal. calcd. for C27H23ClN2O3 (458.94 g/mol): C, 70.66; H,
5.05; N, 6.10; Found: C, 70.63; H, 5.30; N, 6.34.
1-Allyl-6-methoxy-7′,7′-dimethyl-1′-phenyl-3′,4′,7′,8′-tetra-
hydro-3,4′-biquinoline-2,2′,5′(1H,1′H,6′H)-trione
(G7)
Yield: 67%; mp: 241–243 °C; IR (KBr, νmax, cm−1): 3020
1
(Ar C–H str.), 1702, 1642, and 1628 (C=O str.); H NMR
(400 MHz, DMSO-d6) δ ppm: 0.97 (s, 3H, CH3 of dime-
done ring), 1.02 (s, 3H, CH3 of dimedone ring), 1.72–2.70
(m, 4H, 2 × CH2 of dimedone ring), 2.80 (dd, 1H, J1 =
15.2 Hz, J2 = 15.6 Hz, H-3), 3.07 (dd, 1H, J1 = 8.0 Hz, J2
= 8.0 Hz, H-3), 3.82 (s, 3H, OCH3), 4.46 (t, 1H, J1 = 8.0,
J2 = 8.4 Hz, CH, H-4), 4.93 (d, 2H, J = 6.4 Hz, N–CH2),
4.97 (d, 1H, J = 16.4 Hz, N–СН2СН=СН-trans), 5.13 (d,
1H, J = 10.0 Hz, N–СН2СН=СН-cis), 5.91 (m, 1H,
CH=CH2), 7.22–8.08 (m, 9H, Ar–H); 13C NMR (APT)
(100 MHz, DMSO-d6) δ ppm: 24.62, 26.30 (2 × CH3 of
dimedone ring), 29.64 (quinolone C-4), 33.01 (CH2), 35.62
(quinolone C-3), 38.80 (C(CH3)2), 44.57 (CH2–CO), 49.74
(allylic N–CH2–CH), 55.86 (OCH3), 115.71, 117.16,
119.78, 122.39, 126.85, 127.58, 128.87, 129.09, 130.51,
130.88, 132.58, 134.46, 138.20, 138.46, 154.89, and 156.18
1-Allyl-7′,7′-dimethyl-1′-phenyl-3′,4′,7′,8′-tetrahydro-3,4′-
biquinoline-2,2′,5′(1H,1′H,6′H)-trione (G5) Yield: 72%;
mp: 228–230 °C; IR (KBr, νmax, cm−1): 3070 (Ar C–H str.),
1
1702, 1643, and 1628 (C=O str.); H NMR (400 MHz,
DMSO-d6) δ ppm: 0.96 (s, 3H, CH3 of dimedone ring), 1.01
(s, 3H, CH3 of dimedone ring), 1.73–2.69 (m, 4H, 2 × CH2
of dimedone ring), 2.76 (dd, 1H, J1 = 15.2 Hz, J2 = 15.6
Hz, H-3), 3.08 (dd, 1H, J1 = 8.4 Hz, J2 = 8.4 Hz, H-3), 4.45
(t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-4), 4.90 (d, 2H, J = 5.2
Hz, N–CH2), 4.95 (d, 1H, J = 17.2 Hz, N–СН2СН=СН-
trans), 5.15 (d, 1H, J = 10.4 Hz, N–СН2СН=СН-cis), 5.90
(m, 1H, CH=CH2), 7.25–8.07 (m, 10H, Ar–H); 13C NMR
(APT) (100 MHz, DMSO-d6) δ ppm: 24.62, 25.69 (2 ×

Med Chem Res
(16C, Ar–C+allylic C=C), 160.68 (C=O), 169.98 (C=O),
195.20 (C=O); MS (ESI) m/z 482.7 [M]+; anal. calcd. for
C30H30N2O4 (482.57 g/mol): C, 74.67; H, 6.27; N, 5.81;
found: C, 74.83; H, 6.02; N, 5.64.
229–231 °C; IR (KBr, νmax, cm−1): 2955 (Ar C–H str.),
1690, 1643, and 1612 (C=O str.); H NMR (400 MHz,
1
DMSO-d6) δ ppm: 2.01–2.73 (m, 9H, 3 × CH2 of cyclo-
hexenone ring+CH3), 2.81 (dd, 1H, J1 = 15.2 Hz, J2 =
15.6 Hz, H-3), 3.05 (dd, 1H, J1 = 8.4 Hz, J2 = 8.4 Hz, H-3),
4.37 (t, 1H, J1 = 7.6, J2 = 8.0 Hz, CH, H-4), 4.87 (d, 2H, J
= 16.4 Hz, BnCH2), 4.98 (d, 2H, J = 6.4 Hz, N–CH2–CH),
5.04 (d, 1H, J = 16.4 Hz, N–СН2СН=СН-trans), 5.14 (d,
1H, J = 10.4 Hz, N–СН2СН=СН-cis), 5.90 (m, 1H,
CH=CH2), 7.17–7.58 (m, 9H, Ar–H); 13C NMR (APT)
(100 MHz, DMSO-d6) δ ppm: 20.53 (CH3), 21.82 (CH2),
26.67 (CH2), 29.61 (quinolone C-4), 35.71 (quinolone C-3),
36.15 (CH2–CO), 44.62 (BnCH2), 44.94 (allylic N–
CH2–CH), 115.29, 115.54, 117.07, 119.94, 126.50, 126.82,
127.17, 127.62, 129.20, 130.54, 130.65, 132.98, 134.70,
138.15, 138.52, and 157.94 (16C, Ar–C+allylic C=C),
160.79 (C=O), 170.15 (C=O), 195.35 (C=O); MS (ESI) m/
z 452.7 [M]+; anal. calcd. for C29H28N2O3 (452.54 g/mol):
C, 76.97; H, 6.24; N, 6.19; found: C, 76.79; H, 6.29; N,
6.11.
1-Allyl-6-chloro-7′,7′-dimethyl-1′-phenyl-3′,4′,7′,8′-tetrahy-
dro-3,4′-biquinoline-2,2′,5′(1H,1′H,6′H)-trione
(G8)
Yield: 81%; mp: 254–256 °C; IR (KBr, νmax, cm−1): 3070
1
(Ar C–H str.), 1705, 1643, and 1628 (C=O str.); H NMR
(400 MHz, DMSO-d6) δ ppm: 0.96 (s, 3H, CH3 of dime-
done ring), 1.01 (s, 3H, CH3 of dimedone ring), 1.73–2.69
(m, 4H, 2 × CH2 of dimedone ring), 2.78 (dd, 1H, J1 =
15.6 Hz, J2 = 16.0 Hz, H-3), 3.10 (dd, 1H, J1 = 8.0 Hz, J2
= 8.0 Hz, H-3), 4.47 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-
4), 4.89 (d, 2H, J = 6.4 Hz, N–CH2), 4.96 (d, 1H, J = 17.2
Hz, N–СН2СН=СН-trans), 5.13 (d, 1H, J = 10.8 Hz, N–
СН2СН=СН-cis), 5.87 (m, 1H, CH=CH2), 7.31–8.11 (m,
9H, Ar–H); 13C NMR (APT) (100 MHz, DMSO-d6) δ ppm:
24.51, 25.53 (2 × CH3 of dimedone ring), 29.58 (quinolone
C-4), 32.96 (CH2), 35.61 (quinolone C-3), 38.77 (C(CH3)2),
44.58 (CH2–CO), 49.63 (allylic N–CH2–CH), 114.68,
115.87, 117.20, 119.77, 122.51, 126.74, 127.58, 128.81,
129.18, 130.52, 130.69, 132.54, 134.36, 138.22, 138.52,
and 157.27 (16C, Ar–C+allylic C=C), 160.58 (C=O),
169.59 (C=O), 195.25 (C=O); MS (ESI) m/z 487.0 [M]+,
488.9 [M+2]+; anal. calcd. for C29H27ClN2O3 (486.99 g/
mol): C, 71.52; H, 5.59; N, 5.75; found: C, 71.21; H, 5.38;
N, 5.66.
1-Allyl-1′-benzyl-6-methoxy-3′,4′,7′,8′-tetrahydro-3,4′-
biquinoline-2,2′,5′(1H,1′H,6′H)-trione (G11) Yield: 63%;
mp: 235–237 °C; IR (KBr, νmax, cm−1): 2955 (Ar C–H str.),
1
1697, 1643, and 1605 (C=O str.); H NMR (400 MHz,
DMSO-d6) δ ppm: 2.06–2.72 (m, 6H, 3 × CH2 of cyclo-
hexenone ring), 2.80 (dd, 1H, J1 = 15.6 Hz, J2 = 16.0 Hz,
H-3), 3.00 (dd, 1H, J1 = 8.0 Hz, J2 = 8.0 Hz, H-3), 3.82 (s,
3H, OCH3), 4.33 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-4),
4.88 (d, 2H, J = 16.4 Hz, BnCH2), 4.95 (d, 2H, J = 7.2 Hz,
N–CH2–CH), 5.04 (d, 1H, J = 16.8 Hz, N–СН2СН=СН-
trans), 5.14 (d, 1H, J = 10.8 Hz, N–СН2СН=СН-cis), 5.89
(m, 1H, CH=CH2), 7.07–7.39 (m, 9H, Ar–H); 13C NMR
(APT) (100 MHz, DMSO-d6) δ ppm: 21.81 (CH2), 26.75
(CH2), 29.81 (quinolone C-4), 35.76 (quinolone C-3), 36.22
(CH2–CO), 44.74 (BnCH2), 44.97 (allylic N–CH2–CH),
56.16 (OCH3), 110.11, 110.93, 115.67, 116.69, 117.08,
120.74, 126.87, 127.23, 127.72, 129.25, 131.05, 132.96,
133.18, 138.14, 154.58, and 157.89 (16C, Ar–C+allylic
C=C), 160.31 (C=O), 170.17 (C=O), 195.36 (C=O); MS
(ESI) m/z 468.3 (M+.); anal. calcd. for C29H28N2O4
(468.54 g/mol): C, 74.34; H, 6.02; N, 5.98; found: C, 74.35;
H, 6.06; N, 6.14.
1-Allyl-1′-benzyl-3′,4′,7′,8′-tetrahydro-3,4′-biquinoline-
2,2′,5′(1H,1′H,6′H)-trione (G9) Yield: 62%; mp: 220–222
°C; IR (KBr, νmax, cm−1): 2955 (Ar C–H str.), 1690, 1643,
1
and 1605 (C=O str.); H NMR (400 MHz, DMSO-d6) δ
ppm: 2.04–2.71 (m, 6H, 3 × CH2 of cyclohexenone ring),
2.80 (dd, 1H, J1 = 15.2 Hz, J2 = 15.6 Hz, H3), 3.01 (dd, 1H,
J1 = 8.4 Hz, J2 = 8.4 Hz, H-3), 4.34 (t, 1H, J1 = 7.6, J2 =
8.0 Hz, CH, H-4), 4.87 (d, 2H, J = 16.4 Hz, BnCH2), 4.98
(d, 2H, J = 6.4 Hz, N–CH2), 5.05 (d, 1H, J = 16.4 Hz, N–
СН2СН=СН-trans), 5.15 (d, 1H, J = 10.4 Hz, N–
СН2СН=СН-cis), 5.91 (m, 1H, CH=CH2), 7.18–7.58 (m,
10H, Ar–H); 13C NMR (APT) (100 MHz, DMSO-d6) δ
ppm: 21.80 (CH2), 26.69 (CH2), 29.59 (quinolone C-4),
35.70 (quinolone C-3), 36.16 (CH2-CO), 44.64 (BnCH2),
44.95 (allylic N–CH2–CH), 115.31, 115.57, 117.12,
119.93, 126.52, 126.84, 127.15, 127.61, 129.17, 130.55,
130.67, 133.01, 134.73, 138.12, 138.48, and 157.93 (16C,
Ar–C+allylic C=C), 160.78 (C=O), 170.14 (C=O),
195.37 (C=O); MS (ESI) m/z 438.6 [M]+; anal. calcd. for
C28H26N2O3 (438.52 g/mol): C, 76.69; H, 5.98; N, 6.39;
found: C, 76.90; H, 5.80; N, 6.29.
1-Allyl-1′-benzyl-6-chloro-3′,4′,7′,8′-tetrahydro-3,4′-biqui-
noline-2,2′,5′(1H,1′H,6′H)-trione (G12) Yield: 70%; mp:
241–243 °C; IR (KBr, νmax, cm−1): 2955 (Ar C–H str.),
1
1690, 1643, and 1605 (C=O str.); H NMR (400 MHz,
DMSO-d6) δ ppm: 2.05–2.70 (m, 6H, 3 × CH2 of cyclo-
hexenone ring), 2.81 (dd, 1H, J1 = 15.6 Hz, J2 = 16.0 Hz,
H-3), 3.09 (dd, 1H, J1 = 8.0 Hz, J2 = 8.0 Hz, H-3), 4.36 (t,
1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-4), 4.90 (d, 2H, J = 16.0
Hz, BnCH2), 4.99 (d, 2H, J = 6.4 Hz, N–CH2–CH),
1-Allyl-1′-benzyl-6-methyl-3′,4′,7′,8′-tetrahydro-3,4′-biqui-
noline-2,2′,5′(1H,1′H,6′H)-trione (G10) Yield: 61%; mp:

Med Chem Res
5.07 (d, 1H, J = 16.4 Hz, N–СН2СН=СН-trans), 5.18 (d,
1H, J = 10.4 Hz, N–СН2СН=СН-cis), 5.93 (m, 1H,
CH=CH2), 7.20–7.61 (m, 9H, Ar–H); 13C NMR (APT)
(100 MHz, DMSO-d6) δ ppm: 21.85 (CH2), 26.72 (CH2),
29.64 (quinolone C-4), 35.72 (quinolone C-3), 36.15
(CH2–CO), 44.61 (BnCH2), 44.96 (allylic N–CH2–CH),
115.30, 115.60, 117.16, 119.90, 126.50, 126.86, 127.19,
127.68, 129.22, 130.58, 130.70, 133.12, 134.70, 138.21,
138.56, and 157.96 (16C, Ar–C+allylic C=C), 160.75
(C=O), 170.18 (C=O), 195.35 (C=O); MS (ESI) m/z 473.0
[M]+, 474.9 [M+2]+; anal. calcd. for C28H25ClN2O3
(472.96 g/mol): C, 71.10; H, 5.33; N, 5.92; found: C, 71.02;
H, 5.17; N, 5.73.
29.60 (quinolone C-4), 33.05 (CH2), 35.74 (quinolone C-3),
39.83 (C(CH3)2), 44.64 (CH2–CO), 44.83 (BnCH2), 49.65
(allylic N–CH2–CH), 114.56, 115.32, 117.16, 119.87,
122.50, 127.11, 127.66, 128.92, 129.05, 130.71, 130.84,
132.94, 134.66, 138.22, 138.45, and 155.76 (16C, Ar–C
+allylic C=C), 160.74 (C=O), 170.27 (C=O), 195.18
(C=O); MS (ESI) m/z 480.8 [M]+; anal. calcd. for
C31H32N2O3 (480.60 g/mol): C, 77.47; H, 6.71; N, 5.83;
found: C, 77.22; H, 6.41; N, 5.61.
1-Allyl-1′-benzyl-6-methoxy-7′,7′-dimethyl-3′,4′,7′,8′-tetra-
hydro-3,4′-biquinoline-2,2′,5′(1H,1′H,6′H)-trione (G15)
Yield: 69%; mp: 244–246 °C; IR (KBr, νmax, cm−1): 2955
1
(Ar C–H str.), 1690, 1643, and 1612 (C=O str.); H NMR
1-Allyl-1′-benzyl-7′,7′-dimethyl-3′,4′,7′,8′-tetrahydro-3,4′-
biquinoline-2,2′,5′(1H,1′H,6′H)-trione (G13) Yield: 65%;
mp: 228–230 °C; IR (KBr, νmax, cm−1): 2955 (Ar C–H str.),
(400 MHz, DMSO-d6) δ ppm: 0.99 (s, 3H, CH3 of dime-
done ring), 1.03 (s, 3H, CH3 of dimedone ring), 2.15–2.78
(m, 4H, 2 × CH2 of dimedone ring), 2.82 (dd, 1H, J1 =
15.2 Hz, J2 = 15.6 Hz, H-3), 3.07 (dd, 1H, J1 = 8.4 Hz, J2
= 8.4 Hz, H-3), 3.81 (s, 3H, OCH3), 4.35 (t, 1H, J1 = 7.2,
J2 = 7.6 Hz, CH, H-4), 4.82 (d, 2H, J = 16.4 Hz, BnCH2),
4.89 (d, 2H, J = 6.4 Hz, N–CH2–CH), 4.95 (d, 1H, J =
17.2 Hz, N–СН2СН=СН-trans), 5.10 (d, 1H, J = 10.4 Hz,
N–СН2СН=СН-cis), 5.89 (m, 1H, CH=CH2), 7.16–7.54
(m, 9H, Ar–H); 13C NMR (APT) (100 MHz, DMSO-d6) δ
ppm: 27.42, 29.18 (2 × CH3 of dimedone ring), 29.54
(quinolone C-4), 33.04 (CH2), 35.75 (quinolone C-3), 39.82
(C(CH3)2), 44.65 (CH2–CO), 44.84 (BnCH2), 49.62 (allylic
N–CH2–CH), 55.92 (OCH3), 114.55, 115.36, 117.11,
119.85, 122.47, 127.10, 127.61, 128.87, 129.07, 130.75,
132.91, 134.65, 138.25, 138.48, 154.36, and 156.23 (16C,
Ar–C+allylic C=C), 160.76 (C=O), 170.24 (C=O),
195.19 (C=O); MS (ESI) m/z 496.8 [M]+; anal. calcd. for
C31H32N2O4 (496.60 g/mol): C, 74.98; H, 6.50; N, 5.64;
found: C, 75.10; H, 6.78; N, 5.79.
1
1697, 1643, and 1612 (C=O str.); H NMR (400 MHz,
DMSO-d6) δ ppm: 0.99 (s, 3H, CH3 of dimedone ring), 1.05
(s, 3H, CH3 of dimedone ring), 2.16–2.80 (m, 4H, 2 × CH2
of dimedone ring), 2.83 (dd, 1H, J1 = 15.2 Hz, J2 = 15.6
Hz, H-3), 3.06 (dd, 1H, J1 = 8.4 Hz, J2 = 8.4 Hz, H-3), 4.37
(t, 1H, J1 = 8.0, J2 = 8.4 Hz, CH, H-4), 4.84 (d, 2H, J =
16.0 Hz, BnCH2), 4.91 (d, 2H, J = 4.4 Hz, N–CH2–CH),
4.98 (d, 1H, J = 19.2 Hz, N–СН2СН=СН-trans), 5.14 (d,
1H, J = 11.9 Hz, N–СН2СН=СН-cis), 5.90 (m, 1H,
CH=CH2), 7.19–7.57 (m, 10H, Ar–H); 13C NMR (APT)
(100 MHz, DMSO-d6) δ ppm: 27.60, 29.25 (2 × CH3 of
dimedone ring), 29.58 (quinolone C-4), 33.06 (CH2), 35.76
(quinolone C-3), 39.88 (C(CH3)2), 44.65 (CH2–CO), 44.81
(BnCH2), 49.64 (allylic N–CH2–CH), 114.54, 115.35,
117.14, 119.84, 122.48, 127.07, 127.65, 128.99, 129.08,
130.70, 130.87, 132.99, 134.68, 138.21, 138.49, and 155.78
(16C, Ar–C+allylic C=C), 160.76 (C=O), 170.29 (C=O),
195.19 (C=O); MS (ESI) m/z 467.0 [M]+; anal. calcd. for
C30H30N2O3 (466.57 g/mol): C, 77.23; H, 6.48; N, 6.00;
found: C, 77.42; H, 6.77; N, 5.91.
1-Allyl-1′-benzyl-6-chloro-7′,7′-dimethyl-3′,4′,7′,8′-tetrahy-
dro-3,4′-biquinoline-2,2′,5′(1H,1′H,6′H)-trione
(G16)
Yield: 73%; mp: 254–256 °C; IR (KBr, νmax, cm−1): 2955
1
1-Allyl-1′-benzyl-6,7′,7′-trimethyl-3′,4′,7′,8′-tetrahydro-
3,4′-biquinoline-2,2′,5′(1H,1′H,6′H)-trione (G14) Yield:
64%; mp: 236–238 °C; IR (KBr, νmax, cm−1): 2955 (Ar
C–H str.), 1697, 1643, and 1605 (C=O str.); 1H NMR (400
MHz, DMSO-d6) δ ppm: 0.98 (s, 3H, CH3 of dimedone
ring), 1.01 (s, 3H, CH3 of dimedone ring), 2.14–2.81 (m,
7H, 2 × CH2 of dimedone ring+CH3), 2.85 (dd, 1H, J1 =
15.2 Hz, J2 = 15.6 Hz, H-3), 3.10 (dd, 1H, J1 = 8.0 Hz, J2
= 8.0 Hz, H-3), 4.38 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-
4), 4.86 (d, 2H, J = 16.4 Hz, BnCH2), 4.92 (d, 2H, J = 5.2
Hz, N–CH2–CH), 4.97 (d, 1H, J = 17.2 Hz, N–
СН2СН=СН-trans), 5.13 (d, 1H, J = 10.8 Hz, N–
СН2СН=СН-cis), 5.90 (m, 1H, CH=CH2), 7.18–7.55 (m,
9H, Ar–H); 13C NMR (APT) (100 MHz, DMSO-d6) δ ppm:
27.58, 28.22 (2 × CH3 of dimedone ring), 28.97 (CH3),
(Ar C–H str.), 1697, 1643, and 1612 (C=O str.); H NMR
(400 MHz, DMSO-d6) δ ppm: 1.01 (s, 3H, CH3 of dime-
done ring), 1.04 (s, 3H, CH3 of dimedone ring), 2.13–2.79
(m, 4H, 2 × CH2 of dimedone ring), 2.84 (dd, 1H, J1 =
17.2 Hz, J2 = 17.6 Hz, H-3), 3.06 (dd, 1H, J1 = 8.0 Hz, J2
= 8.4 Hz, H-3), 4.33 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-
4), 4.85 (d, 2H, J = 10.8 Hz, BnCH2), 4.92 (d, 2H, J = 7.6
Hz, N–CH2–CH), 5.00 (d, 1H, J = 16.4 Hz, N–
СН2СН=СН-trans), 5.14 (d, 1H, J = 10.4 Hz, N–
СН2СН=СН-cis), 5.90 (m, 1H, CH=CH2), 7.20–7.59 (m,
9H, Ar–H); 13C NMR (APT) (100 MHz, DMSO-d6) δ ppm:
21.16, 22.06 (2 × CH3 of dimedone ring), 29.64 (quinolone
C-4), 33.14 (CH2), 35.55 (quinolone C-3), 38.78 (C(CH3)2),
44.32 (CH2–CO), 44.81 (BnCH2), 49.58 (allylic N–
CH2–CH), 111.39, 114.57, 116.95, 117.45, 121.16, 126.47,

Med Chem Res
127.04, 127.34, 128.01, 128.89, 130.23, 132.13, 132.75,
137.23, 138.20, and 155.88 (16C, Ar–C+allylic C=C),
160.76 (C=O), 170.29 (C=O), 195.19 (C=O); MS (ESI) m/
79%; mp: 246–248 °C; IR (KBr, νmax, cm−1): 3248 (NH
str.), 2924 (Ar C–H str.), 1697, 1643 and 1612 (C=O str.);
1H NMR (400 MHz, DMSO-d6) δ ppm: 2.18–2.70 (m, 6H,
3 × CH2 of cyclohexenone ring), 2.79 (dd, 1H, J1 = 14.8
Hz, J2 = 15.2 Hz, H-3), 3.09 (dd, 1H, J1 = 8.4 Hz, J2 = 8.4
Hz, H-3), 3.79 (s, 3H, OCH3), 4.37 (t, 1H, J1 = 8.0, J2 =
8.4 Hz, CH, H-4), 4.88 (d, 2H, J = 6.4 Hz, N–CH2–CH),
4.93 (d, 1H, J = 17.2 Hz, N–СН2СН=СН-trans), 5.10 (d,
1H, J = 10.4 Hz, N–СН2СН=СН-cis), 5.88 (m, 1H,
CH=CH2), 6.69–7.70 (m, 9H, Ar–H), 8.34 (s, 1H, NH);
13C NMR (APT) (100 MHz, DMSO-d6) δ ppm: 21.64
(CH2), 25.37 (CH2), 29.68 (quinolone C-4), 35.29 (quino-
lone C-3), 36.28 (CH2–CO), 44.52 (allylic N–CH2–CH),
55.81 (OCH3), 112.36, 113.34, 113.71, 114.38, 115.25,
117.06, 120.18, 120.46, 130.18, 130.53, 131.72, 133.05,
134.65, 136.51, 148.13, and 151.62 (16C, Ar–C+allylic
C=C), 160.35 (C=O), 168.54 (C=O), 195.42 (C=O); MS
(ESI) m/z 469.5 [M]+; anal. calcd. for C28H27N3O4 (469.53
g/mol): C, 71.62; H, 5.80; N, 8.95; found: C, 71.94; H,
5.95; N, 9.12.
z
501.1 [M]+, 503.0 [M+2]+; anal. calcd. for
C30H29ClN2O3 (501.02 g/mol): C, 71.92; H, 5.83; N, 5.59;
found: C, 72.08; H, 5.86; N, 5.85.
1-Allyl-1′-(phenylamino)-3′,4′,7′,8′-tetrahydro-3,4′-biquino-
line-2,2′,5′(1H,1′H,6′H)-trione (G17) Yield: 76%; mp:
235–237 °C; IR (KBr, νmax, cm−1): 3248 (NH str.), 2924
1
(Ar C–H str.), 1697, 1642, and 1605 (C=O str.); H NMR
(400 MHz, DMSO-d6) δ ppm: 2.18–2.71 (m, 6H, 3 × CH2
of cyclohexenone ring), 2.80 (dd, 1H, J1 = 15.2 Hz, J2 =
15.6 Hz, H-3), 3.12 (dd, 1H, J1 = 8.0 Hz, J2 = 8.0 Hz, H-3),
4.36 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-4), 4.87 (d, 2H, J
= 5.6 Hz, N–CH2–CH), 4.94 (d, 1H, J = 17.6 Hz, N–
СН2СН=СН-trans), 5.10 (d, 1H, J = 10.4 Hz, N–
СН2СН=СН-cis), 5.90 (m, 1H, CH=CH2), 6.71–7.72 (m,
10H, Ar–H), 8.37 (s, 1H, NH); 13C NMR (APT) (100 MHz,
DMSO-d6) δ ppm: 21.62 (CH2), 25.37 (CH2), 29.75 (qui-
nolone C-4), 35.30 (quinolone C-3), 36.26 (CH2–CO),
44.55 (allylic N–CH2–CH), 112.40, 113.32, 113.71,
114.38, 115.25, 117.05, 120.15, 120.38, 130.12, 130.51,
131.46, 131.72, 133.06, 134.66, 136.51, and 148.12 (16C,
Ar–C+allylic C=C), 160.36 (C=O), 168.55 (C=O),
195.45 (C=O); MS (ESI) m/z 439.6 [M]+; anal. calcd. for
C27H25N3O3 (439.51 g/mol): C, 73.78; H, 5.73; N, 9.56;
found: C, 73.80; H, 5.71; N, 9.59.
1-Allyl-6-chloro-1′-(phenylamino)-3′,4′,7′,8′-tetrahydro-
3,4′-biquinoline-2,2′,5′(1H,1′H,6′H)-trione (G20) Yield:
84%; mp: 259–261; IR (KBr, νmax, cm−1): 3256 (NH str.),
1
3040 (Ar C–H str.), 1697, 1642 and 1605 (C=O str.); H
NMR (400 MHz, DMSO-d6) δ ppm: 2.19–2.70 (m, 6H, 3 ×
CH2 of cyclohexenone ring), 2.80 (dd, 1H, J1 = 15.2 Hz, J2
= 15.6 Hz, H-3), 3.11 (dd, 1H, J1 = 8.0 Hz, J2 = 8.0 Hz, H-
3), 4.36 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-4), 4.86 (d, 2H,
J = 5.6 Hz, N–CH2–CH), 4.96 (d, 1H, J = 17.6 Hz,
N–СН2СН=СН-trans), 5.12 (d, 1H, J = 10.4 Hz,
N–СН2СН=СН-cis), 5.91 (m, 1H, CH=CH2), 6.72–7.72
(m, 9H, Ar–H), 8.37 (s, 1H, NH); 13C NMR (APT) (100
MHz, DMSO-d6) δ ppm: 21.64 (CH2), 25.38 (CH2), 29.77
(quinolone C-4), 35.32 (quinolone C-3), 36.26 (CH2–CO),
44.57 (allylic N–CH2–CH), 112.43, 113.33, 113.75,
114.40, 115.24, 117.07, 120.14, 120.37, 130.16, 130.55,
131.50, 131.78, 133.10, 134.64, 136.50, and 148.18 (16C,
Ar–C+allylic C=C), 160.39 (C=O), 168.56 (C=O),
195.47 (C=O); MS(ESI) m/z 474.0 [M]+, 476.1 [M+2]+;
anal. calcd. for C27H24ClN3O3 (473.95 g/mol): C, 68.42; H,
5.10; N, 8.87; found: C, 68.33; H, 4.86; N, 9.03.
1-Allyl-6-methyl-1′-(phenylamino)-3′,4′,7′,8′-tetrahydro-
3,4′-biquinoline-2,2′,5′(1H,1′H,6′H)-trione (G18) Yield:
75%; mp: 240–242 °C; IR (KBr, νmax, cm−1): 3256 (NH
str.), 3040 (Ar C–H str.), 1697, 1643, and 1605 (C=O str.);
1H NMR (400 MHz, DMSO-d6) δ ppm: 2.17–2.75 (m, 9H,
3 × CH2 of cyclohexenone ring+CH3), 2.81 (dd, 1H, J1 =
13.2 Hz, J2 = 13.6 Hz, H-3), 3.16 (dd, 1H, J1 = 8.0 Hz, J2
= 8.0 Hz, H-3), 4.38 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-
4), 4.89 (d, 2H, J = 5.6 Hz, N–CH2–CH), 4.95 (d, 1H, J =
17.6 Hz, N–СН2СН=СН-trans), 5.12 (d, 1H, J = 10.4 Hz,
N–СН2СН=СН-cis), 5.91 (m, 1H, CH=CH2), 6.70–7.70
(m, 9H, Ar–H), 8.35 (s, 1H, NH); 13C NMR (APT) (100
MHz, DMSO-d6) δ ppm: 20.49 (CH3), 21.67 (CH2), 25.40
(CH2), 29.74 (quinolone C-4), 35.31 (quinolone C-3), 36.29
(CH2–CO), 44.54 (allylic N–CH2–CH), 112.38, 113.35,
113.73, 114.37, 115.24, 117.04, 120.14, 120.40, 130.14,
130.52, 131.44, 131.70, 133.07, 134.68, 136.52, and 148.11
(16C, Ar–C+allylic C=C), 160.38 (C=O), 168.56 (C=O),
195.45 (C=O); MS (ESI) m/z 453.6 [M]+; anal. calcd. for
C28H27N3O3 (453.53 g/mol): C, 74.15; H, 6.00; N, 9.27;
found: C, 74.09; H, 5.89; N, 9.35.
1-Allyl-7′,7′-dimethyl-1′-(phenylamino)-3′,4′,7′,8′-tetrahy-
dro-3,4′-biquinoline-2,2′,5′(1H,1′H,6′H)-trione
(G21)
Yield: 79%; mp: 234–236 °C; IR (KBr, νmax, cm−1): 3256
(NH str.), 3040 (Ar C–H str.), 1697, 1643 and 1612 (C=O
1
str.); H NMR (400 MHz, DMSO-d6) δ ppm: 0.96 (s, 3H,
CH3 of dimedone ring), 1.02 (s, 3H, CH3 of dimedone ring),
1.94–2.81 (m, 4H, 2 × CH2 of dimedone ring), 3.04 (dd,
1H, J1 = 16.0 Hz, J2 = 16.4 Hz, H-3), 3.47 (dd, 1H, J1 =
8.0 Hz, J2 = 8.0 Hz, H-3), 4.72 (t, 1H, J1 = 7.2, J2 = 7.6 Hz,
CH, H-4), 4.86 (d, 2H, J = 6.4 Hz, N–CH2–CH),
1-Allyl-6-methoxy-1′-(phenylamino)-3′,4′,7′,8′-tetrahydro-
3,4′-biquinoline-2,2′,5′(1H,1′H,6′H)-trione (G19) Yield:

Med Chem Res
5.18 (d, 1H, J = 17.2 Hz, N–СН2СН=СН-trans), 5.40 (d,
1H, J = 10.4 Hz, N–СН2СН=СН-cis), 6.02 (m, 1H,
CH=CH2), 7.17–7.89 (m, 10H, Ar–H), 8.81 (s, 1H, NH);
13C NMR (APT) (100 MHz, DMSO-d6) δ ppm: 27.87,
28.61 (2 × CH3 of dimedone ring), 31.64 (quinolone C-4),
33.47 (CH2), 35.81 (quinolone C-3), 39.89 (C(CH3)2),
45.21 (CH2–CO), 49.92 (allylic N–CH2–CH), 112.02,
113.32, 117.09, 123.71, 125.45, 126.21, 127.94, 128.50,
129.87, 132.96, 134.40, 136.05, 139.42, 144.78, 155.94,
and 158.54 (16C, Ar–C+allylic C=C), 159.89 (C=O),
169.94 (C=O), 194.95 (C=O); MS (ESI) m/z 467.4 [M]+;
anal. calcd. for C29H29N3O3 (467.56 g/mol): C, 74.50; H,
6.25; N, 8.99; found: C, 74.40; H, 5.89; N, 9.30.
ring), 31.81 (quinolone C-4), 33.52 (CH2), 35.86 (quino-
lone C-3), 39.95 (C(CH3)2), 45.24 (CH2–CO), 49.96 (allylic
N–CH2–CH), 57.18 (OCH3), 111.93, 113.46, 117.13,
123.69, 125.49, 126.24, 127.90, 128.55, 129.91, 133.00,
134.46, 136.03, 139.46, 144.80, 156.01, and 158.60 (16C,
Ar–C+allylic C=C), 159.85 (C=O), 169.88 (C=O),
194.87 (C=O); MS (ESI) m/z 497.4 [M]+; anal. calcd. for
C30H31N3O4 (497.58 g/mol): C, 72.41; H, 6.28; N, 8.44;
found: C, 72.35; H, 6.45; N, 8.26.
1-Allyl-6-chloro-7′,7′-dimethyl-1′-(phenylamino)-3′,4′,7′,8′-
tetrahydro-3,4′-biquinoline-2,2′,5′(1H,1′H,6′H)-trione
(G24) Yield: 86%; mp: 258–260 °C; IR (KBr, νmax
,
cm−1): 3256 (NH str.), 3040 (Ar C–H str.), 1697, 1643, and
1
1-Allyl-6,7′,7′-trimethyl-1′-(phenylamino)-3′,4′,7′,8′-tetra-
hydro-3,4′-biquinoline-2,2′,5′(1H,1′H,6′H)-trione (G22)
Yield: 77%; mp: 245–247 °C; IR (KBr, νmax, cm−1): 3248
(NH str.), 2924 (Ar C–H str.), 1697, 1642, and 1605 (C=O
1605 (C=O str.); H NMR (400 MHz, DMSO-d6) δ ppm:
0.97 (s, 3H, CH3 of dimedone ring), 1.02 (s, 3H, CH3 of
dimedone ring), 1.95–2.82 (m, 4H, 2 × CH2 of dimedone
ring), 3.05 (dd, 1H, J1 = 14.8 Hz, J2 = 15.2 Hz, H-3), 3.45
(dd, 1H, J1 = 8.4 Hz, J2 = 8.4 Hz, H-3), 4.75 (t, 1H, J1 =
7.6, J2 = 8.0 Hz, CH, H-4), 4.89 (d, 2H, J = 5.2 Hz,
N–CH2–CH), 5.20 (d, 1H, J = 17.2 Hz, N–СН2СН=СН-
trans), 5.46 (d, 1H, J = 10.8 Hz, N–СН2СН=СН-cis), 6.08
(m, 1H, CH=CH2), 7.20–7.91 (m, 9H, Ar–H), 8.86 (s, 1H,
NH); 13C NMR (APT) (100 MHz, DMSO-d6) δ ppm: 27.81,
28.57 (2 × CH3 of dimedone ring), 31.65 (quinolone C-4),
33.45 (CH2), 35.72 (quinolone C-3), 39.82 (C(CH3)2),
45.26 (CH2–CO), 49.95 (allylic N–CH2–CH), 112.14,
113.44, 117.23, 123.65, 125.48, 126.26, 127.95, 128.54,
129.81, 132.95, 134.48, 136.11, 139.40, 144.82, 155.96,
and 158.58 (16C, Ar–C+allylic C=C), 160.01 (C=O),
170.04 (C=O), 195.03 (C=O); MS (ESI) m/z 502.1 [M]+,
503.9 [M+2]+; anal. calcd. for C29H28ClN3O3 (502.00 g/
mol): C, 69.38; H, 5.62; N, 8.37; found: C, 69.59; H, 5.71;
N, 8.38.
1
str.); H NMR (400 MHz, DMSO-d6) δ ppm: 0.98 (s, 3H,
CH3 of dimedone ring), 1.03 (s, 3H, CH3 of dimedone ring),
1.93–2.85 (m, 7H, 2 × CH2 of dimedone ring+CH3), 3.03
(dd, 1H, J1 = 14.8 Hz, J2 = 15.2 Hz, H-3), 3.45 (dd, 1H, J1
= 7.6 Hz, J2 = 8.0 Hz, H-3), 4.73 (t, 1H, J1 = 7.2, J2 = 7.6
Hz, CH, H-4), 4.85 (d, 2H, J = 6.4 Hz, N–CH2–CH), 5.17
(d, 1H, J = 16.4 Hz, N–СН2СН=СН-trans), 5.41 (d, 1H, J
= 10.4 Hz, N–СН2СН=СН-cis), 5.99 (m, 1H, CH=CH2),
7.16–7.89 (m, 9H, Ar–H), 8.82 (s, 1H, NH); 13C NMR
(APT) (100 MHz, DMSO-d6) δ ppm: 27.81, 28.57 (2 ×
CH3 of dimedone ring), 29.14 (CH3), 31.62 (quinolone C-
4), 33.45 (CH2), 35.78 (quinolone C-3), 39.84 (C(CH3)2),
45.26 (CH2–CO), 49.91 (allylic N–CH2–CH), 112.07,
113.36, 117.15, 123.74, 125.49, 126.26, 127.92, 128.51,
129.85, 132.94, 134.41, 136.08, 139.43, 144.75, 155.91,
and 158.52 (16C, Ar–C+allylic C=C), 159.94 (C=O),
169.98 (C=O), 194.97 (C=O); MS (ESI) m/z 481.7 [M]+;
anal. calcd. for C30H31N3O3 (481.59 g/mol): C, 74.82; H,
6.49; N, 8.73; found: C, 74.93; H, 6.53; N, 8.52.
N-(1-allyl-2,2′,5′-trioxo-1,2,3′,4′,5′,6′,7′,8′-octahydro-3,4′-
biquinolin-1′(2′H)-yl)benzamide (G25) Yield: 81%; mp:
242–244 °C; IR (KBr, νmax, cm−1): 3271 (NH str.), 2962
1
1-Allyl-6-methoxy-7′,7′-dimethyl-1′-(phenylamino)-
(Ar C–H str.), 1720, 1636, and 1589 (C=O str.); H NMR
3′,4′,7′,8′-tetrahydro-3,4′-biquinoline-2,2′,5′(1H,1′H,6′H)-
(400 MHz, DMSO-d6) δ ppm: 2.08–2.70 (m, 6H, 3 × CH2
of cyclohexenone ring), 2.84 (dd, 1H, J1 = 16.0 Hz, J2 =
16.4 Hz, H-3), 3.16 (dd, 1H, J1 = 7.6 Hz, J2 = 8.0 Hz, H-3),
4.43 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-4), 4.92 (d, 2H, J
= 6.4 Hz, N–CH2–CH), 5.02 (d, 1H, J = 17.2 Hz, N–
СН2СН=СН-trans), 5.15 (d, 1H, J = 9.6 Hz, N–
СН2СН=СН-cis), 5.93 (m, 1H, CH=CH2), 7.25–8.08 (m,
10H, Ar–H), 11.07 (s, 1H, NH); 13C NMR (APT) (100
MHz, DMSO-d6) δ ppm: 21.64 (CH2), 25.14 (CH2), 29.58
(quinolone C-4), 35.71 (quinolone C-3), 36.33 (CH2–CO),
44.64 (allylic N–CH2–CH), 114.34, 115.35, 115.86,
120.10, 120.39, 128.17, 129.17, 130.26, 130.57, 130.75,
131.79, 131.89, 133.02, 136.00, 138.51, and 158.10 (16C,
Ar–C+allylic C=C), 160.79 (C=O), 167.00 (C=O),
trione (G23) Yield: 72%; mp: 252–254 °C; IR (KBr, νmax
,
cm−1): 3248 (NH str.), 2924 (Ar C–H str.), 1697, 1642, and
1
1612 (C=O str.); H NMR (400 MHz, DMSO-d6) δ ppm:
0.94 (s, 3H, CH3 of dimedone ring), 1.01 (s, 3H, CH3 of
dimedone ring), 1.96–2.84 (m, 4H, 2 × CH2 of dimedone
ring), 3.05 (dd, 1H, J1 = 15.6 Hz, J2 = 16.0 Hz, H-3), 3.48
(dd, 1H, J1 = 8.4 Hz, J2 = 8.4 Hz, H-3), 3.83 (s, 3H,
OCH3), 4.74 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-4), 4.88
(d, 2H, J = 5.6 Hz, N–CH2–CH), 5.21 (d, 1H, J = 17.2 Hz,
N–СН2СН=СН-trans), 5.44 (d, 1H, J = 10.8 Hz, N–
СН2СН=СН-cis), 6.09 (m, 1H, CH=CH2), 7.18–7.90 (m,
9H, Ar–H), 8.83 (s, 1H, NH); 13C NMR (APT) (100 MHz,
DMSO-d6) δ ppm: 28.21, 30.83 (2 × CH3 of dimedone

Med Chem Res
167.50 (C=O), 195.31 (C=O); MS (ESI) m/z 467.4 [M]+;
anal. calcd. for C28H25N3O4 (467.52 g/mol): C, 71.93; H,
5.39; N, 8.99; found: C, 72.20; H, 5.49; N, 8.91.
1H NMR (400 MHz, DMSO-d6) δ ppm: 2.07–2.71 (m, 6H,
3 × CH2 of cyclohexenone ring), 2.83 (dd, 1H, J1 = 16.0
Hz, J2 = 16.4 Hz, H-3), 3.15 (dd, 1H, J1 = 7.6 Hz, J2 = 8.0
Hz, H-3), 4.45 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-4), 4.93
(d, 2H, J = 6.4 Hz, N–CH2–CH), 5.03 (d, 1H, J = 17.2 Hz,
N–СН2СН=СН-trans), 5.14 (d, 1H, J = 9.6 Hz, N–
СН2СН=СН-cis), 5.92 (m, 1H, CH=CH2), 7.24–8.07 (m,
9H, Ar–H), 11.08 (s, 1H, NH); 13C NMR (APT) (100 MHz,
DMSO-d6) δ ppm: 21.65 (CH2), 25.16 (CH2), 29.57 (qui-
nolone C-4), 35.72 (quinolone C-3), 36.35 (CH2–CO),
44.65 (allylic N–CH2–CH), 114.35, 115.38, 115.85,
120.11, 120.42, 128.18, 129.25, 130.28, 130.55, 130.72,
131.80, 131.84, 133.06, 136.08, 140.52, and 158.16 (16C,
Ar–C+allylic C=C), 160.82 (C=O), 167.09 (C=O),
167.54 (C=O), 195.35 (C=O); MS (ESI) m/z 502.0 [M]+,
504.1 [M+2]+; anal. calcd. for C28H24ClN3O4 (501.96 g/
mol): C, 67.00; H, 4.82; N, 8.37; found: C, 66.96; H, 4.63;
N, 8.25.
N-(1-allyl-6-methyl-2,2′,5′-trioxo-1,2,3′,4′,5′,6′,7′,8′-octa-
hydro-3,4′-biquinolin-1′(2′H)-yl)benzamide (G26) Yield:
80%; mp: 247–249 °C; IR (KBr, νmax, cm−1): 3256 (NH
str.), 2955 (Ar C–H str.), 1720, 1620 and 1582 (C=O str.);
1H NMR (400 MHz, DMSO-d6) δ ppm: 2.07–2.73 (m, 9H,
3 × CH2 of cyclohexenone ring+CH3), 2.82 (dd, 1H, J1 =
16.0 Hz, J2 = 16.4 Hz, H-3), 3.15 (dd, 1H, J1 = 8.0 Hz, J2
= 8.0 Hz, H-3), 4.41 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-
4), 4.93 (d, 2H, J = 6.4 Hz, N–CH2–CH), 5.05 (d, 1H, J =
16.4 Hz, N–СН2СН=СН-trans), 5.12 (d, 1H, J = 9.6 Hz,
N–СН2СН=СН-cis), 5.91 (m, 1H, CH=CH2), 7.23–8.07
(m, 9H, Ar–H), 11.05 (s, 1H, NH); 13C NMR (APT) (100
MHz, DMSO-d6) δ ppm: 21.65 (CH2), 25.18 (CH2), 27.14
(CH3), 29.57 (quinolone C-4), 35.72 (quinolone C-3), 36.35
(CH2–CO), 44.62 (allylic N–CH2–CH), 114.32, 115.37,
115.85, 120.11, 120.42, 128.18, 129.20, 130.28, 130.54,
130.74, 131.81, 131.92, 133.06, 136.07, 138.54, and 158.15
(16C, Ar–C+allylic C=C), 160.74 (C=O), 167.03 (C=O),
167.48 (C=O), 195.34 (C=O); MS (ESI) m/z 481.5 (M+.);
anal. calcd. for C29H27N3O4 (481.54 g/mol): C, 72.33; H,
5.65; N, 8.73; found: C, 72.17; H, 5.57; N, 8.92.
N-(1-allyl-7′,7′-dimethyl-2,2′,5′-trioxo-1,2,3′,4′,5′,6′,7′,8′-
octahydro-3,4′-biquinolin-1′(2′H)-yl)benzamide
(G29)
Yield: 83%; mp: 245–247 °C; IR (KBr, νmax, cm−1): 3232
(NH str.), 2962 (Ar C–H str.), 1720, 1636, and 1582 (C=O
1
str.); H NMR (400 MHz, DMSO-d6) δ ppm: 1.08 (s, 3H,
CH3 of dimedone ring), 1.10 (s, 3H, CH3 of dimedone ring),
2.21–2.75 (m, 4H, 2 × CH2 of dimedone ring), 2.81 (dd,
1H, J1 = 16.0 Hz, J2 = 16.4 Hz, H-3), 3.14 (dd, 1H, J1 =
8.0 Hz, J2 = 8.0 Hz, H-3), 4.47 (t, 1H, J1 = 8.0, J2 = 8.4 Hz,
CH, H-4), 4.92 (d, 2H, J = 6.4 Hz, N–CH2–CH), 4.97 (d,
1H, J = 17.2 Hz, N–СН2СН=СН-trans), 5.12 (d, 1H, J =
10.4 Hz, N–СН2СН=СН-cis), 5.89 (m, 1H, CH=CH2),
7.31–8.02 (m, 10H, Ar–H), 10.75 (s, 1H, NH); 13C NMR
(APT) (100 MHz, DMSO-d6) δ ppm: 20.47, 20.68 (2 ×
CH3 of dimedone ring), 29.32 (quinolone C-4), 32.94
(CH2), 36.31 (quinolone C-3), 38.40 (C(CH3)2), 44.57
(CH2–CO), 49.85 (allylic N–CH2–CH), 113.41, 114.79,
115.26, 116.91, 120.35, 128.20, 128.75, 128.86, 129.24,
130.45, 131.54, 133.08, 134.81, 135.83, 136.54, and 156.06
(16C, Ar–C+allylic C=C), 160.56 (C=O), 167.05 (C=O),
167.52 (C=O), 195.24 (C=O); MS (ESI) m/z 495.4 [M]+;
anal. calcd. for C30H29N3O4 (495.57 g/mol): C, 72.71; H,
5.90; N, 8.48; found: C, 72.58; H, 5.81; N, 8.32.
N-(1-allyl-6-methoxy-2,2′,5′-trioxo-1,2,3′,4′,5′,6′,7′,8′-octa-
hydro-3,4′-biquinolin-1′(2′H)-yl)benzamide (G27) Yield:
78%; mp: 257–259 °C; IR (KBr, νmax, cm−1): 3217 (NH
str.), 2955 (Ar C–H str.), 1720, 1628, and 1597 (C=O str.);
1H NMR (400 MHz, DMSO-d6) δ ppm: 2.06–2.71 (m, 6H,
3 × CH2of cyclohexenone ring), 2.80 (dd, 1H, J1 = 16.0
Hz, J2 = 16.4 Hz, H-3), 3.12 (dd, 1H, J1 = 8.0 Hz, J2 = 8.0
Hz, H-3), 3.82 (s, 3H, OCH3), 4.42 (t, 1H, J1 = 7.2, J2 =
7.6 Hz, CH, H-4), 4.91 (d, 2H, J = 6.4 Hz, N–CH2–CH),
5.04 (d, 1H, J = 16.4 Hz, N–СН2СН=СН-trans), 5.10 (d,
1H, J = 9.6 Hz, N–СН2СН=СН-cis), 5.92 (m, 1H,
CH=CH2), 7.21–8.05 (m, 9H, Ar–H), 11.06 (s, 1H, NH);
13C NMR (APT) (100 MHz, DMSO-d6) δ ppm: 21.64
(CH2), 25.16 (CH2), 29.56 (quinolone C-4), 35.71 (quino-
lone C-3), 36.34 (CH2–CO), 44.63 (allylic N–CH2–CH),
55.90 (OCH3), 114.30, 115.35, 115.86, 120.14, 120.40,
128.19, 129.25, 130.30, 130.51, 131.88, 132.02, 133.10,
136.08, 138.56, 154.24, and 158.17 (16C, Ar–C+allylic
C=C), 160.72 (C=O), 167.02 (C=O), 167.47 (C=O),
195.32 (C=O); MS (ESI) m/z 497.6 (M+.); anal. calcd. for
C29H27N3O5 (497.54 g/mol): C, 70.01; H, 5.47; N, 8.45;
found: C, 70.03; H, 5.63; N, 8.70.
N-(1-allyl-6,7′,7′-trimethyl-2,2′,5′-trioxo-1,2,3′,4′,5′,6′,7′,8′-
octahydro-3,4′-biquinolin-1′(2′H)-yl)benzamide
(G30)
Yield: 84%; mp: 250–252 °C; IR (KBr, νmax, cm−1): 3217
(NH str.), 2955 (Ar C–H str.), 1728, 1628, and 1597 (C=O
1
str.); H NMR (400 MHz, DMSO-d6) δ ppm: 1.09 (s, 3H,
CH3 of dimedone ring), 1.11 (s, 3H, CH3 of dimedone ring),
2.22–2.78 (m, 7H, 2 × CH2 of dimedone ring+CH3), 2.82
(dd, 1H, J1 = 12.4 Hz, J2 = 12.8 Hz, H-3), 3.19 (dd, 1H, J1
= 8.4 Hz, J2 = 8.4 Hz, H-3), 4.49 (t, 1H, J1 = 8.0, J2 = 8.4
Hz, CH, H-4), 4.90 (d, 2H, J = 6.4 Hz, N–CH2–CH), 4.95
N-(1-allyl-6-chloro-2,2′,5′-trioxo-1,2,3′,4′,5′,6′,7′,8′-octahy-
dro-3,4′-biquinolin-1′(2′H)-yl)benzamide
(G28) Yield:
87%; mp: 264–266 °C; IR (KBr, νmax, cm−1): 3256 (NH
str.), 2962 (Ar C–H str.), 1728, 1620, and 1589 (C=O str.);

Med Chem Res
(d, 1H, J = 17.6 Hz, N–СН2СН=СН-trans), 5.14 (d, 1H, J
= 10.8 Hz, N–СН2СН=СН-cis), 5.90 (m, 1H, CH=CH2),
7.32–8.02 (m, 9H, Ar–H), 10.73 (s, 1H, NH); 13C NMR
(APT) (100 MHz, DMSO-d6) δ ppm: 20.45, 20.66 (2 ×
CH3 of dimedone ring), 27.75 (CH3), 29.29 (quinolone C-
4), 32.92 (CH2), 36.36 (quinolone C-3), 38.41 (C(CH3)2),
44.55 (CH2–CO), 49.86 (allylic N–CH2–CH), 113.43,
114.78, 115.25, 116.92, 120.31, 128.18, 128.74, 128.84,
129.22, 130.42, 131.53, 133.05, 134.79, 135.80, 136.56,
and 156.02 (16C, Ar–C+allylic C=C), 160.58 (C=O),
167.02 (C=O), 167.50 (C=O), 195.20 (C=O); MS (ESI)
m/z 509.5 [M]+; anal. calcd. for C31H31N3O4 (509.60 g/
mol): C, 73.06; H, 6.13; N, 8.25; found: C, 73.34; H, 6.35;
N, 8.23.
9H, Ar–H), 10.78 (s, 1H, NH); 13C NMR (APT) (100 MHz,
DMSO-d6) δ ppm: 20.49, 20.72 (2 × CH3 of dimedone
ring), 29.38 (quinolone C-4), 32.96 (CH2), 36.33 (quino-
lone C-3), 38.42 (C(CH3)2), 44.59 (CH2–CO), 49.88 (allylic
N–CH2–CH), 113.42, 114.81, 115.28, 117.02, 120.38,
128.21, 128.73, 128.85, 129.29, 130.48, 131.51, 133.12,
134.87, 135.86, 136.50, and 156.10 (16C, Ar–C+allylic
C=C), 160.58 (C=O), 167.07 (C=O), 167.54 (C=O),
195.26 (C=O); MS (ESI) m/z 529.9 [M]+, 532.1 [M+2]+;
anal. calcd. for C30H28ClN3O4 (530.01 g/mol): C, 67.98; H,
5.32; N, 7.93; found: C, 68.24; H, 5.06; N, 7.61.
N-(1-allyl-2,2′,5′-trioxo-1,2,3′,4′,5′,6′,7′,8′-octahydro-3,4′-
biquinolin-1′(2′H)-yl)isonicotinamide (G33) Yield: 82%;
mp: 251–253 °C; IR (KBr, νmax, cm−1): 3456 (NH str.),
1
N-(1-allyl-6-methoxy-7′,7′-dimethyl-2,2′,5′-trioxo-
2962 (Ar C–H str.), 1728, 1682, and 1620 (C=O str.); H
1,2,3′,4′,5′,6′,7′,8′-octahydro-3,4′-biquinolin-1′(2′H)-yl)ben-
zamide (G31) Yield: 80%; mp: 263–265 °C; IR (KBr,
νmax, cm−1): 3232 (NH str.), 2955 (Ar C–H str.), 1720,
NMR (400 MHz, DMSO-d6) δ ppm: 2.10–2.73 (m, 6H, 3 ×
CH2 of cyclohexenone ring), 2.86 (dd, 1H, J1 = 15.2 Hz, J2
= 15.6 Hz, H-3), 3.14 (dd, 1H, J1 = 8.0 Hz, J2 = 8.0 Hz, H-
3), 4.42 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-4), 4.91 (d, 2H,
J = 5.2 Hz, N-CH2–CH), 5.01 (d, 1H, J = 16.4 Hz, N–
СН2СН=СН-trans), 5.13 (d, 1H, J = 10.4 Hz, N–
СН2СН=СН-cis), 5.90 (m, 1H, CH=CH2), 7.23–8.06 (m,
9H, Ar–H), 11.13 (s, 1H, NH); 13C NMR (APT) (100 MHz,
DMSO-d6) δ ppm: 21.72 (CH2), 25.28 (CH2), 29.62 (qui-
nolone C-4), 35.76 (quinolone C-3), 36.35 (CH2–CO),
44.68 (allylic N–CH2–CH), 114.38, 115.91, 120.23,
120.46, 128.25, 129.29, 130.31, 130.86, 131.81, 131.93,
133.14, 136.46, 138.51, 151.32, and 155.84 (15C, Ar–C
+allylic C=C), 160.64 (C=O), 167.12 (C=O), 167.74
(C=O), 195.37 (C=O); MS (ESI) m/z 468.4 [M]+; anal.
calcd. for C27H24N4O4 (468.50 g/mol): C, 69.22; H, 5.16;
N, 11.96; found: C, 69.11; H, 4.85; N, 12.17.
1
1620, and 1582 (C=O str.); H NMR (400 MHz, DMSO-
d6) δ ppm: 1.08 (s, 3H, CH3 of dimedone ring), 1.11 (s, 3H,
CH3 of dimedone ring), 2.21–2.69 (m, 4H, 2 × CH2 of
dimedone ring), 2.81 (dd, 1H, J1 = 15.6 Hz, J2 = 16.0 Hz,
H-3), 3.20 (dd, 1H, J1 = 7.6 Hz, J2 = 8.0 Hz, H-3), 3.82 (s,
3H, OCH3), 4.52 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-4),
4.89 (d, 2H, J = 6.4 Hz, N–CH2–CH), 4.95 (d, 1H, J =
17.6 Hz, N–СН2СН=СН-trans), 5.14 (d, 1H, J = 10.0 Hz,
N–СН2СН=СН-cis), 5.90 (m, 1H, CH=CH2), 7.16–8.08
(m, 9H, Ar–H), 11.10 (s, 1H, NH); 13C NMR (APT) (100
MHz, DMSO-d6) δ ppm: 27.45, 28.89 (2 × CH3 of dime-
done ring), 29.43 (quinolone C-4), 33.01 (CH2), 36.49
(quinolone C-3), 38.42 (C(CH3)2), 44.70 (CH2–CO), 49.87
(allylic N–CH2–CH), 56.14 (OCH3), 111.16, 114.98,
116.96, 118.69, 121.17, 128.06, 128.28, 129.37, 130.88,
131.22, 131.74, 133.02, 133.20, 135.79, 154.61, and 156.07
(16C, Ar–C+allylic C=C), 160.28 (C=O), 166.92 (C=O),
167.56 (C=O), 195.21 (C=O); MS (ESI) m/z 525.3 [M]+;
anal. calcd. for C31H31N3O5 (525.59 g/mol): C, 70.84; H,
5.94; N, 7.99; found: C, 70.90; H, 6.09; N, 7.93.
N-(1-allyl-6-methyl-2,2′,5′-trioxo-1,2,3′,4′,5′,6′,7′,8′-octa-
hydro-3,4′-biquinolin-1′(2′H)-yl)isonicotinamide (G34)
Yield: 81%; mp: 257–259 °C; IR (KBr, νmax, cm−1): 3402
(NH str.), 2962 (Ar C–H str.), 1720, 1690, and 1582 (C=O
str.); 1H NMR (400 MHz, DMSO-d6) δ ppm: 2.09–2.74 (m,
9H, 3 × CH2 of cyclohexenone ring+CH3), 2.84 (dd, 1H,
J1 = 15.2 Hz, J2 = 15.6 Hz, H-3), 3.12 (dd, 1H, J1 = 7.6 Hz,
J2 = 7.6 Hz, H-3), 4.46 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH,
H-4), 4.92 (d, 2H, J = 6.4 Hz, N–CH2–CH), 5.05 (d, 1H, J
= 17.4 Hz, N–СН2СН=СН-trans), 5.11 (d, 1H, J = 10.4
Hz, N–СН2СН=СН-cis), 5.91 (m, 1H, CH=CH2),
7.22–8.05 (m, 8H, Ar–H), 11.12 (s, 1H, NH); 13C NMR
(APT) (100 MHz, DMSO-d6) δ ppm: 21.75 (CH2), 25.28
(CH2), 27.45 (CH3), 29.63 (quinolone C-4), 35.75 (quino-
lone C-3), 36.38 (CH2–CO), 44.65 (allylic N–CH2–CH),
114.42, 115.88, 120.26, 120.52, 128.28, 129.31, 130.28,
130.80, 131.76, 131.90, 133.11, 136.48, 138.55, 151.34,
and 155.85 (15C, Ar–C+allylic C=C), 160.63 (C=O),
167.12 (C=O), 167.75 (C=O), 195.36 (C=O); MS (ESI)
N-(1-allyl-6-chloro-7′,7′-dimethyl-2,2′,5′-trioxo-
1,2,3′,4′,5′,6′,7′,8′-octahydro-3,4′-biquinolin-1′(2′H)-yl)ben-
zamide (G32) Yield: 88%; mp: 270–272 °C; IR (KBr,
νmax, cm−1): 3271 (NH str.), 2962 (Ar C–H str.), 1728,
1
1636, and 1597 (C=O str.); H NMR (400 MHz, DMSO-
d6) δ ppm: 1.07 (s, 3H, CH3 of dimedone ring), 1.11 (s, 3H,
CH3 of dimedone ring), 2.22–2.76 (m, 4H, 2 × CH2 of
dimedone ring), 2.83 (dd, 1H, J1 = 15.6 Hz, J2 = 16.0 Hz,
H-3), 3.12 (dd, 1H, J1 = 8.4 Hz, J2 = 8.4 Hz, H-3), 4.48 (t,
1H, J1 = 8.0, J2 = 8.4 Hz, CH, H-4), 4.93 (d, 2H, J = 6.4
Hz, N–CH2–CH), 4.99 (d, 1H, J = 16.4 Hz, N–
СН2СН=СН-trans), 5.11 (d, 1H, J = 10.4 Hz, N–
СН2СН=СН-cis), 5.92 (m, 1H, CH=CH2), 7.32–8.04 (m,

Med Chem Res
m/z 482.4 [M]+; anal. calcd. for C28H26N4O4 (482.53 g/
mol): C, 69.70; H, 5.43; N, 11.61; found: C, 69.90; H, 5.14;
N, 11.32.
(NH str.), 2955 (Ar C–H str.), 1728, 1690, and 1589 (C=O
str.); H NMR (400 MHz, DMSO-d6) δ ppm: 1.08 (s, 3H,
1
CH3 of dimedone ring), 1.11 (s, 3H, CH3 of dimedone ring),
2.23–2.78 (m, 4H, 2 × CH2 of dimedone ring), 2.80 (dd, 1H,
J1 = 16.8 Hz, J2 = 17.2 Hz, H-3), 3.22 (dd, 1H, J1 = 8.0 Hz,
J2 = 8.0 Hz, H-3), 4.51 (t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-
4), 4.91 (d, 2H, J = 7.2 Hz, N–CH2–CH), 4.98 (d, 1H, J =
16.2 Hz, N–СН2СН=СН-trans), 5.15 (d, 1H, J = 10.0 Hz,
N–СН2СН=СН-cis), 5.93 (m, 1H, CH=CH2), 7.25–8.84 (m,
9H, Ar–H), 11.39 (s, 1H, NH); 13C NMR (APT) (100 MHz,
DMSO-d6) δ ppm: 19.77, 20.08 (2 × CH3 of dimedone ring),
28.83 (quinolone C-4), 33.02 (CH2), 36.37 (quinolone C-3),
38.29 (C(CH3)2), 44.68 (CH2–CO), 49.86 (allylic N–
CH2–CH), 113.31, 115.01, 117.12, 120.05, 120.35, 121.81,
122.06, 122.61, 130.36, 133.04, 135.95, 138.54, 138.86,
151.21, and 155.75 (15C, Ar–C+allylic C=C), 160.72
(C=O), 165.74 (C=O), 167.39 (C=O), 195.25 (C=O); MS
(ESI) m/z 496.8 [M]+; anal. calcd. for C29H28N4O4 (496.56 g/
mol): C, 70.15; H, 5.68; N, 11.28; Found: C, 70.30; H, 5.85;
N, 11.41.
N-(1-allyl-6-methoxy-2,2′,5′-trioxo-1,2,3′,4′,5′,6′,7′,8′-octa-
hydro-3,4′-biquinolin-1′(2′H)-yl)isonicotinamide (G35)
Yield: 84%; mp: 263–265 °C; IR (KBr, νmax, cm−1): 3163
(NH str.), 2955 (Ar C–H str.), 1720, 1682, and 1620 (C=O
str.); 1H NMR (400 MHz, DMSO-d6) δ ppm: 2.09–2.71 (m,
6H, 3 × CH2of cyclohexenone ring), 2.85 (dd, 1H, J1 =
15.6 Hz, J2 = 16.0 Hz, H-3), 3.14 (dd, 1H, J1 = 8.0 Hz, J2
= 8.0 Hz, H-3), 3.81 (s, 3H, OCH3), 4.47 (t, 1H, J1 = 7.6,
J2 = 8.0 Hz, CH, H-4), 4.94 (d, 2H, J = 6.4 Hz,
N–CH2–CH), 5.08 (d, 1H, J = 16.4 Hz, N–СН2СН=СН-
trans), 5.15 (d, 1H, J = 10.4 Hz, N–СН2СН=СН-cis), 5.92
(m, 1H, CH=CH2), 7.22–8.06 (m, 8H, Ar–H), 11.12 (s, 1H,
NH); 13C NMR (APT) (100 MHz, DMSO-d6) δ ppm: 21.75
(CH2), 25.27 (CH2), 29.65 (quinolone C-4), 35.78 (quino-
lone C-3), 36.32 (CH2–CO), 44.67 (allylic N–CH2–CH),
55.87 (OCH3), 114.36, 115.87, 120.21, 120.48, 128.26,
129.28, 130.30, 130.84, 131.79, 131.91, 133.17, 136.45,
138.52, 151.34, and 155.86 (15C, Ar–C+allylic C=C),
160.62 (C=O), 167.14 (C=O), 167.73 (C=O), 195.36
(C=O); MS (ESI) m/z 498.6 [M]+; anal. calcd. for
C28H26N4O5 (498.53 g/mol): C, 67.46; H, 5.26; N, 11.24;
found: C, 67.18; H, 5.50; N, 11.15.
N-(1-allyl-6,7′,7′-trimethyl-2,2′,5′-trioxo-1,2,3′,4′,5′,6′,7′,8′-
octahydro-3,4′-biquinolin-1′(2′H)-yl)isonicotinamide
(G38) Yield: 83%; mp: 258–260 °C; IR (KBr, νmax
,
cm−1): 3456 (NH str.), 2955 (Ar C–H str.), 1720, 1690, and
1
1589 (C=O str.); H NMR (400 MHz, DMSO-d6) δ ppm:
1.06 (s, 3H, CH3 of dimedone ring), 1.09 (s, 3H, CH3 of
dimedone ring), 2.21–2.78 (m, 7H, 2 × CH2 of dimedone
ring+CH3), 2.81 (dd, 1H, J1 = 16.8 Hz, J2 = 17.2 Hz, H-3),
3.21 (dd, 1H, J1 = 8.0 Hz, J2 = 8.0 Hz, H-3), 4.52 (t, 1H, J1
= 7.2, J2 = 7.6 Hz, CH, H-4), 4.93 (d, 2H, J = 7.2 Hz,
N–CH2–CH), 4.99 (d, 1H, J = 16.2 Hz, N–СН2СН=СН-
trans), 5.16 (d, 1H, J = 10.0 Hz, N–СН2СН=СН-cis), 5.92
(m, 1H, CH=CH2), 7.24–8.83 (m, 8H, Ar–H), 11.40 (s, 1H,
NH); 13C NMR (APT) (100 MHz, DMSO-d6) δ ppm: 19.78,
20.10 (2 × CH3 of dimedone ring), 27.12 (CH3), 28.84
(quinolone C-4), 33.05 (CH2), 36.38 (quinolone C-3), 38.31
(C(CH3)2), 44.67 (CH2–CO), 49.85 (allylic N–CH2–CH),
113.32, 115.04, 117.15, 120.07, 120.36, 121.86, 122.09,
122.62, 130.38, 133.02, 135.91, 138.55, 138.83, 151.25,
and 155.77 (15C, Ar–C+allylic C=C), 160.76 (C=O),
165.78 (C=O), 167.45 (C=O), 195.28 (C=O); MS (ESI) m/
z 510.8 [M]+; anal. calcd. for C30H30N4O4 (510.58 g/mol):
C, 70.57; H, 5.92; N, 10.97; found: C, 70.47; H, 5.89; N,
10.83.
N-(1-allyl-6-chloro-2,2′,5′-trioxo-1,2,3′,4′,5′,6′,7′,8′-octahy-
dro-3,4′-biquinolin-1′(2′H)-yl)isonicotinamide
(G36)
Yield: 87%; mp: 270–272 °C; IR (KBr, νmax, cm−1): 3456
(NH str.), 2962 (Ar C–H str.), 1720, 1690, and 1582 (C=O
str.); 1H NMR (400 MHz, DMSO-d6) δ ppm: 2.10–2.72 (m,
6H, 3 × CH2 of cyclohexenone ring), 2.84 (dd, 1H, J1 =
16.0 Hz, J2 = 16.4 Hz, H-3), 3.10 (dd, 1H, J1 = 8.4 Hz, J2
= 8.4 Hz, H-3), 4.46 (t, 1H, J1 = 7.6, J2 = 8.0 Hz, CH, H-
4), 4.92 (d, 2H, J = 6.4 Hz, N–CH2–CH), 5.07 (d, 1H, J =
16.4 Hz, N–СН2СН=СН-trans), 5.12 (d, 1H, J = 10.4 Hz,
N–СН2СН=СН-cis), 5.93 (m, 1H, CH=CH2), 7.25–8.08
(m, 8H, Ar–H), 11.15 (s, 1H, NH); 13C NMR (APT) (100
MHz, DMSO-d6) δ ppm: 21.81 (CH2), 25.32 (CH2), 29.68
(quinolone C-4), 35.80 (quinolone C-3), 36.41 (CH2–CO),
44.70 (allylic N–CH2–CH), 115.01, 115.98, 120.21,
120.45, 128.20, 129.34, 130.38, 130.90, 131.95, 133.12,
136.45, 138.58, 150.14, 151.30, and 155.81 (15C, Ar–C
+allylic C=C), 160.67 (C=O), 167.15 (C=O), 167.73
(C=O), 195.38 (C=O); MS (ESI) m/z 503.1 [M]+, 504.9
[M+2]+; anal. calcd. for C27H23ClN4O4 (502.95 g/mol): C,
64.48; H, 4.61; N, 11.14; found: C, 64.57; H, 4.69; N,
11.08.
N-(1-allyl-6-methoxy-7′,7′-dimethyl-2,2′,5′-trioxo-
1,2,3′,4′,5′,6′,7′,8′-octahydro-3,4′-biquinolin-1′(2′H)-yl)iso-
nicotinamide (G39) Yield: 86%; mp: 266–268 °C; IR
(KBr, νmax, cm−1): 3163 (NH str.), 2962 (Ar C–H str.),
1
N-(1-allyl-7′,7′-dimethyl-2,2′,5′-trioxo-1,2,3′,4′,5′,6′,7′,8′-
octahydro-3,4′-biquinolin-1′(2′H)-yl)isonicotinamide (G37)
Yield: 84%; mp: 255–257 °C; IR (KBr, νmax, cm−1): 3402
1728, 1682, and 1582 (C=O str.); H NMR (400 MHz,
DMSO-d6) δ ppm: 1.08 (s, 3H, CH3 of dimedone ring), 1.12
(s, 3H, CH3 of dimedone ring), 2.21–2.69 (m, 4H, 2 × CH2

Med Chem Res
of dimedone ring), 2.80 (dd, 1H, J1 = 17.2 Hz, J2 = 17.6
Hz, H-3), 3.22 (dd, 1H, J1 = 7.6 Hz, J2 = 7.6 Hz, H-3), 3.82
(s, 3H, OCH3), 4.49 (t, 1H, J1 = 7.6, J2 = 8.0 Hz, CH, H-4),
4.91 (d, 2H, J = 8.0 Hz, N–CH2–CH), 4.95 (d, 1H, J =
18.8 Hz, N–СН2СН=СН-trans), 5.14 (d, 1H, J = 11.2 Hz,
N–СН2СН=СН-cis), 5.91 (m, 1H, CH=CH2), 7.13–8.84
(m, 8H, Ar–H), 11.43 (s, 1H, NH); 13C NMR (APT) (100
MHz, DMSO-d6) δ ppm: 26.94, 28.39 (2 × CH3 of dime-
done ring), 28.93 (quinolone C-4), 32.56 (CH2), 35.81
(quinolone C-3), 37.77 (C(CH3)2), 44.20 (CH2–CO), 49.33
(allylic N–CH2–CH), 55.45 (OCH3), 110.61, 114.56,
116.24, 116.42, 118.28, 120.58, 122.39, 130.24, 132.51,
132.61, 135.07, 138.24, 150.61, 154.09, and 155.43 (15C,
Ar–C+allylic C=C), 159.71 (C=O), 165.10 (C=O),
166.90 (C=O), 194.72 (C=O); MS (ESI) m/z 526.4 [M]+;
anal. calcd. for C30H30N4O5 (526.58 g/mol): C, 68.43; H,
5.74; N, 10.64; found: C, 68.52; H, 6.05; N, 10.80.
B(1–4) were synthesized by electrophilic favoured N-ally-
lation of A(1–4) in the presence of K2CO3 in DMF at room
temperature (Jardosh and Patel 2012). To insert the variety
of spacers at the N-1 position, various β-enaminones E(1–
10) were synthesized by nucleophilic addition reaction of
1,3-cyclohexanedione/dimedone C(1–2) with aniline D1/
benzyl amine D2/BHZ D3/ INHD4 at 120 °C for 30 min
under solvent free condition and β-enaminones of PHZ E5
were prepared by a reported procedure of Fatiadi (Fatiadi
1970) (Scheme 1).
A general synthetic protocol has been established for the
synthesis of 3,4′-bicarbostyril derivatives G (1–40) and
depicted in (Scheme 1). These title derivatives were pre-
pared via one-pot three component cyclo-condensation
reaction between B(1–4), Meldrum’s acid F and β-enam-
inones E(1–10) in ethanol containing a catalytic amount of
piperidine in good to excellent yields (61–89%). The key
features of this protocol are, ease to afford complex and
hybrid heterocyclic scaffolds without isolating any inter-
mediates, and exemption from the tedious purification
procedure.
N-(1-allyl-6-chloro-7′,7′-dimethyl-2,2′,5′-trioxo-
1,2,3′,4′,5′,6′,7′,8′-octahydro-3,4′-biquinolin-1′(2′H)-yl)iso-
nicotinamide (G40) Yield: 89%; mp: 276–278 °C; IR
(KBr, νmax, cm−1): 3456 (NH str.), 2962 (Ar C–H str.),
1
1720, 1682, and 1620 (C=O str.); H NMR (400 MHz,
Biological activity
DMSO-d6) δ ppm: 1.08 (s, 3H, CH3 of dimedone ring), 1.12
(s, 3H, CH3 of dimedone ring), 2.20–2.70 (m, 4H, 2 × CH2
of dimedone ring), 2.85 (dd, 1H, J1 = 17.2 Hz, J2 = 17.6
Hz, H-3), 3.24 (dd, 1H, J1 = 7.6 Hz, J2 = 8.4 Hz, H-3), 4.48
(t, 1H, J1 = 7.2, J2 = 7.6 Hz, CH, H-4), 4.88 (d, 2H, J = 8.0
Hz, N–CH2–CH), 5.09 (d, 1H, J = 18.8 Hz, N–
СН2СН=СН-trans), 5.15 (d, 1H, J = 11.2 Hz, N–
СН2СН=СН-cis), 5.91 (m, 1H, CH=CH2), 7.46–8.29 (m,
8H, Ar–H), 11.40 (s, 1H, NH); 13C NMR (APT) (100 MHz,
DMSO-d6) δ ppm: 26.99, 28.45 (2 × CH3 of dimedone
ring), 28.97 (quinolone C-4), 32.48 (CH2), 35.56 (quino-
lone C-3), 37.76 (C(CH3)2), 44.34 (CH2-CO), 49.27 (allylic
N-CH2-CH), 114.25, 116.61, 117.03, 121.03, 121.40,
126.06, 127.30, 129.76, 131.21, 132.28, 134.55, 136.78,
138.27, 150.66, 155.30 (15C, Ar-C+allylic C=C), 159.96
(C=O), 165.24 (C=O), 166.76 (C=O), 194.71 (C=O); MS
(ESI) m/z 530.9 [M]+, 533.2 [M+2]+; anal. calcd. for
C29H27ClN4O4 (531.00 g/mol): C, 65.59; H, 5.13; N, 10.55;
found: C, 65.71; H, 5.06; N, 10.54.
Antimicrobial activity
The in vitro antimicrobial activity of synthesized com-
pounds was carried out against three Gram-positive and
negative bacteria as well as two fungi as per guidelines of
the National Committee for Clinical Laboratory Standards
(NCCLS 2002) (See supplementary material) and the results
are tabulated in (Table 1).
Upon exploration of antimicrobial activity data, it has
been observed that against P. aeruginosa, compound G37
(MIC = 25 µg/mL) found to have fabulous activity com-
pared to chloramphenicol and equal to that of ciprofloxacin.
Compound G8 (MIC = 50 µg/mL) showed comparable
activity to that of chloramphenicol. Against S. typhi, com-
pound G38 (MIC = 50 µg/mL) was found to be more potent
than ampicillin and equipotent to chloramphenicol (MIC =
50 µg/mL). Compounds G1, G6, G13, and G34 (MIC =
100 µg/mL) were found equally potent to ampicillin.
Against E. coli, compounds G18 (MIC = 50 µg/mL) and
G4, G6, G13, and G34 (MIC = 62.5 µg/mL) were found to
have magnificent activity while compounds G10, G16,
G22, G23, G25, and G37 (MIC = 100 µg/mL) were found
to have equivalent activity compared to ampicillin. Against
B. subtillis, compound G37 (MIC = 50 µg/mL) showed
remarkable potency as compared to norfloxacin (MIC =
100 µg/mL), ciprofloxacin (MIC = 50 µg/mL) and chlor-
amphenicol (MIC = 50 µg/mL). Compounds G27 (MIC =
100 µg/mL); G7, G8, G9, G10, G29, G31, G34, and G38
(MIC = 200 µg/mL) were found to be more effective as
Results and discussion
Chemistry
For the better exploration of SAR, a library comprises forty
3,4′-bicarbostyrilderivatives G(1–40) was derived using
DOS. The structural diversity at N-1, C-4 and C-7 positions
was obtained through variations in synthons. The key pre-
cursors 1-allyl-2-oxo-1,2-dihydroquinoline-3-carbaldehydes

Med Chem Res
Scheme 1 Synthesis of
intermediates and 3,4′-
bicarbostyril derivatives
compared to ampicillin (MIC = 250 µg/mL). Against C.
tetani, compounds G6 and G35 (MIC = 62.5 µg/mL); G10,
G13, G31, and G38 (MIC = 100 µg/mL) exhibited sig-
nificant potency as compared to ciprofloxacin (MIC = 100
µg/mL). Compounds G8, G14, G17, G25, G32, and G37
(MIC = 125 µg/mL); G5, G19, G27, G29, G30, and G40
(MIC = 200 µg/mL) were found to be more potent com-
pared to ampicillin (MIC = 250 µg/mL). Against S. aureus,
compounds G6 and G14 (MIC = 100 µg/mL); G8, G10,
G13, G17, G32, G35, and G38 (MIC = 125 µg/mL); G5,
G12, G19, G25, G30, G31, and G37 (MIC = 200 µg/mL)
were found to have more potency compared with ampicillin
(MIC = 250 µg/mL).
The antifungal screening data (Table 1) revealed that
against C. albicans, compounds G16, G19 and G36 (MIC
= 100 µg/mL) exhibited marvelous activity compared to
griseofulvin (MIC = 500 µg/mL) and equally potent to
nystatin (MIC = 100 µg/mL). Compounds G1, G6, G12,
G15, G20, and G27 (MIC = 200 µg/mL); G3, G4, G7,
G23, G24, G25, G28, G38, and G39 (MIC = 250 µg/mL)
were showing significant activity compared to
griseofulvin. Against T. rubrum compounds G24 and G40
(MIC = 100 µg/mL) were found to be equally potent
to nystatin (MIC = 100 µg/mL) as well as griseofulvin
(MIC = 100 µg/mL).
Structure–activity relationship (SAR) for antimicrobial
activity
Antimicrobial activity results revealed that against S. aureus,
compounds G6 and G14 having lipophilic –CH3 group at R1
and R2 position as well as –Ph and –Bn at R3 position
improved solubility and gave significant potency compared to
ampicillin. While compounds carrying –PHZ spacer at
R3position reduced the inhibitory action. Against B. subtilis,
increment of spacer length to amide linkage enhanced the
potency and showed excellent activity compared to ampicillin,
e.g. compounds G37 and G27. It can be seen that antibacterial
effectiveness becomes double when a Ph ring of –BHZ replace
with pyridyl ring. However, compounds having R3 = –BHZ
and –INH displayed better activity compared to other spacers
with reference to ampicillin, e.g. G27, G29, G31, G34, G37,
and G38. Against C. tetani, extension of spacer length from
–Ph to –Bn reduced the potency by two-fold, but further
increment from –Bn to –INH improved the power of bacterial
growth inhibition by 3.2-fold and showed significant activity
to ciprofloxacin and ampicillin, e.g. G6 and G35. Also,
compounds G31 and G38 displayed comparable activity to
ciprofloxacin. In case of E. coli, reverse trend was observed
compared to Gram-positive bacteria, because compounds
containing shorter length spacers viz., R3 = –PHZ, –Ph, and

Med Chem Res
Table 1 In vitro antimicrobial activity of title compounds (MIC, μg/mL)
Minimum inhibitory concentration (MIC) in μg/mL
Gram-positive bacteria Gram-negative bacteria
Fungi
Entry
R1
R2
R3
SA
BS
CT
EC
ST
PA
CA
TR
G1
H
H
Ph
250
250
250
250
200
100
250
125
250
125
500
200
125
100
250
250
125
500
200
500
500
500
500
500
200
250
250
500
250
200
200
125
500
500
125
500
200
125
250
250
250
50
500
500
500
500
250
500
200
200
200
200
250
500
250
250
500
500
250
250
500
500
250
250
500
500
250
500
100
500
200
250
200
500
500
200
500
500
50
250
250
500
500
200
500
250
500
100
250
500
200
250
100
250
500
500
200
250
250
100
250
500
200
250
200
250
500
250
250
200
500
200
200
250
500
200
500
250
500
200
100
125
200
125
50
250
200
250
500
250
500
250
50
200
500
500
1000
1000
500
G2
CH3
OCH3
Cl
H
Ph
G3
H
Ph
250
G4
H
Ph
62.5
500
62.5
250
G5
H
CH3
CH3
CH3
CH3
H
Ph
1000
200
1000
1000
500
G6
CH3
OCH3
Cl
Ph
62.5
G7
Ph
500
125
500
100
500
250
100
125
250
250
125
500
200
500
500
500
500
500
125
250
200
500
200
200
100
125
500
500
250
500
250
100
200
200
250
G8
Ph
500
>1000
500
G9
H
Bn
100
500
200
250
500
250
500
100
500
500
250
500
250
500
250
100
500
500
200
100
200
500
200
100
500
250
500
200
25
1000
1000
500
G10
CH3
OCH3
Cl
H
Bn
500
G11
H
Bn
1000
>1000
250
G12
H
Bn
200
G13
H
CH3
CH3
CH3
CH3
H
Bn
62.5
500
G14
CH3
OCH3
Cl
Bn
200
250
100
200
50
>1000
200
100
1000
>1000
100
200
1000
500
250
250
250
1000
200
250
500
1000
500
500
1000
500
500
100
1000
250
250
1000
–
>1000
1000
500
G15
Bn
G16
Bn
G17
H
PHZ
PHZ
PHZ
PHZ
PHZ
PHZ
PHZ
PHZ
BHZ
BHZ
BHZ
BHZ
BHZ
BHZ
BHZ
BHZ
INH
INH
INH
INH
INH
INH
INH
INH
1000
>1000
500
G18
CH3
OCH3
Cl
H
G19
H
250
500
250
100
100
250
100
200
500
500
200
500
500
500
250
G20
H
500
G21
H
CH3
CH3
CH3
CH3
H
1000
500
G22
CH3
OCH3
Cl
G23
>1000
100
G24
G25
H
500
G26
CH3
OCH3
Cl
H
>1000
>1000
>1000
500
G27
H
G28
H
G29
H
CH3
CH3
CH3
CH3
H
G30
CH3
OCH3
Cl
>1000
1000
>1000
1000
>1000
1000
1000
>1000
1000
1000
100
G31
G32
G33
H
G34
CH3
OCH3
Cl
H
62.5
G35
H
62.5
125
125
100
250
200
200
100
25
G36
H
500
125
100
250
200
250
100
50
G37
H
CH3
CH3
CH3
CH3
G38
CH3
OCH3
Cl
200
250
250
250
50
200
250
250
nda
25
G39
250
200
100
25
G40
Ampicillin
Ciprofloxacin
Chloramphenicol
Norfloxacin
–
–
–
50
50
50
50
50
–
–
10
100
50
10
10
10
–
–

Med Chem Res
Table 1 continued
Minimum inhibitory concentration (MIC) in μg/mL
Gram-positive bacteria Gram-negative bacteria
SA BS CT EC ST PA
Fungi
Entry
R1
R2
R3
CA
TR
Griseofulvin
Nystatin
–
–
–
–
–
–
–
–
–
–
–
–
500
100
100
100
nd not determine, SA Staphylococcus aureus (MTCC 96), BS Bacillus subtilis (MTCC 441), CT Clostridium tetani (MTCC 449), EC Escherichia
coli (MTCC 443), ST Salmonella typhi (MTCC 98), PA Pseudomonas aeruginosa (MTCC 1688), CA Candida albicans (MTCC 227), TR
Trichophyton rubrum(MTCC 296)
–Bn displayed magnificent results, e.g. G18 demonstrated
equal potency to chloramphenicol; while G4, G6, and G13
except G34 showed higher potential than ampicillin. Both
EDG –CH3 and EWG –Cl at R1 along with –CH3 at R2
position took part in the enhancement of potency of title
compounds. Against S. typhi, only compound G38 having
–CH3 group at R1 and R2 position increased the lipophilicity
(ClogP 3.34) and became equipotent to chloramphenicol.
Further, it carries drug-like spacer –INH (amide linkage) at R3
position which provides more flexibility to facilitate molecule
to transport through the cell membrane of the bacteria
(Waterbeemd 2007). Against P. aeruginosa, the increment of
spacer length –Ph to –INH increased activity by two-fold, e.g.
compound G37 found to have remarkable activity; while G8
possessed comparable activity with chloramphenicol. These
compounds possessed lipophilic –CH3 group at R2 position
and found equipotent to ciprofloxacin and chloramphenicol,
respectively. Eventually, the bactericidal effect is increased in
the order of INH > Ph > PHZ > BHZ > Bn.
Against fungi C. albicans, both the EDG-OCH3 and
EWG -Cl containing compounds G16, G19, and G36
exhibited marvelous inhibition of growth of fungi compared
to nystatin and griseofulvin. Compounds G1, G6, G12,
G15, and G27 exhibited excellent potency than griseoful-
vin. Against T. rubrum, only the compounds G24 and G40
having –Cl group at R1 position and –CH3 group at R2
position exhibited excellent antifungal effectiveness and
became equally potent to griseofulvin and nystatin. The
antifungal potency is increased in order of PHZ > Bn > Ph
> INH > BHZ. By reviewing the antimicrobial activity
results it can be seen that compounds those exhibited
MIC ≤ 100 µg/mL displayed excellent CLogP values
(1.97–4.79) less than 5 and polar surface area (PSA)
(57.69–108.38 Å2) less than 140 Å (Waterbeemd 2007; Ertl
2007). Consequently, it may be expected that the molecules
should be transferred through the bacterial cells.
compounds for their antitubercular activity. In vitro anti-
tubercular activity of all the newly synthesized compounds
was carried out against M. tuberculosis H37Rv strain by
Loweinstein-Jensen (Rattan 2000) (L. J. slope) method
(Rattan 2000) (See supplementary material) and the biolo-
gical results are shown in (Table 2).
Of the compounds screened for antitubercular activity,
eleven compounds were found to exhibit >90% inhibition of
M. tuberculosis bacteria. Compounds G22 (MIC = 12.5 µg/
mL) and G38 (MIC = 25 µg/mL) found to possess the highest
potency against M. tuberculosis with 99% inhibition. These
two compounds found to have fabulous activity as compared
to rifampicin (MIC = 40 µg/mL). Compounds G24 (MIC =
50 µg/mL); G10 and G40 (MIC = 62.5 µg/mL) exhibited
better inhibition of 98%. Compounds G20 (MIC = 62.5 µg/
mL) and G30 (MIC = 50 µg/mL) were found to have 97 and
96% inhibition of M. tuberculosis bacteria, respectively. Also,
compounds G3 (MIC = 62.5 µg/mL); G14 and G32 (MIC =
100 µg/mL); G7 (MIC = 125 µg/mL) displayed moderate
inhibition of 94, 93, 92, and 91%, respectively. Compounds
G22 and G38 (R1 = CH3, R2 = CH3) were emerging out as
the most potent member of the series and opens up a new door
to optimize this series for new a class of antitubercular agents.
Structure–activity relationship (SAR) for antitubercular
activity
Compounds G38 and G22 carrying –CH3 group at R1 and
R2 position and exhibited highest potency against MTB
when compared with rifampicin. These molecules may be
considered as good hits, in terms of MIC values, good
lipophilicity (ClogP 4.48, 3.34) and PSA (69.72, 99.15 Å2),
respectively. Moreover, compounds G24, G10 and G40,
G20 and G30 bearing R1 = –Cl/–CH3 and long spacer
length showed >95% inhibition. The order of antitubercular
activity was found to be PHZ > INH > Bn > BHZ > Ph.
Antitubercular activity
Antimalarial activity
Some excellent results from the antimicrobial studies
encouraged us to go to the preliminary screening of the title
In vitro antimalarial activity of all the newly synthesized
compounds were carried out against Plasmodium

Med Chem Res
Table 2 In vitro antitubercular
activity of title compounds at
250 µg/mL (% Inhibition and
MIC, μg/mL)
M. tuberculosis (H37Rv)
M. tuberculosis (H37Rv)
Entry % Inhibition MIC
ClogPa PSA
(Å2)a
Entry % Inhibition MIC
ClogPa PSA
(Å2)a
(µg/mL)
(µg/mL)
G1
G2
G3
G4
G5
G6
G7
G8
G9
21
66
94
54
16
70
91
46
54
ndb
nd
2.77
3.27
2.94
3.58
3.81
4.31
3.98
4.62
2.65
3.15
2.81
3.45
3.69
4.19
3.85
4.49
2.94
3.44
3.11
3.75
3.98
57.69
57.69
66.92
57.69
57.69
57.69
66.92
57.69
57.69
57.69
66.92
57.69
57.69
57.69
66.92
57.69
69.72
69.72
78.95
69.72
69.72
G22 99
G23 51
G24 98
G25 56
G26 12
G27 20
G28 38
G29 16
G30 96
G31 61
G32 92
G33 56
G34 48
G35 32
G36 24
G37 46
G38 99
G39 65
G40 98
RIF 98
INH 99
12.5
nd
4.48
4.15
4.79
2.61
3.11
2.77
3.42
3.65
4.15
3.81
4.45
1.80
2.30
1.97
2.61
2.84
3.34
3.00
3.65
–
69.72
78.95
69.72
86.79
86.79
96.02
86.79
86.79
86.79
96.02
86.79
99.15
99.15
108.38
99.15
99.15
99.15
108.38
99.15
–
62.5
nd
50
nd
nd
nd
nd
nd
125
nd
nd
nd
nd
50
G10 98
G11 45
G12 31
G13 84
G14 93
G15 63
G16 23
G17 12
G18 69
G19 74
G20 97
G21 45
62.5
nd
nd
100
nd
nd
nd
nd
100
nd
nd
nd
nd
nd
nd
25
nd
nd
nd
62.5
40
62.5
nd
0.20
–
–
a CLogP and PSA (Polar surface area) calculated using the Chem Bio Draw Ultra, version 11.0, software by
Cambridge Soft
b
nd not determine, RIF Rifampicin, INH Isoniazid
falciparum (3D7) strain employing the microassay protocol
of Rieckmann (1978), and the biological results are shown
in (Table 3).
Of the compounds screened for antimalarial activity,
thirteen compounds gave better results than the standard
drugs employed. Compounds G40 (IC50 = 0.019 µg/mL)
R3 position improved the antiplasmodial characteristic by
3.5 fold. Moreover, hybrids possessed EDGs -CH3 and
–OCH3, elicited good to moderate inhibitory action against
P. falciparum e.g., G31, G3, G14, G7, and G38. Excep-
tionally, parent hybrids G9 and G21 displayed significant
activity. Only compound G40 showed marvelous efficacy
than chloroquine and quinine. This derivative may be
considered as a good hit. From the antimalarial activity data,
it can be observed that the inhibitory action against P. fal-
ciparum is increased in the order of INH > PHZ > BHZ >
Ph > Bn.
elicited fabulous activity compared to chloroquine (IC50
=
0.020 µg/ml)and quinine (IC50 = 0.268 µg/ml). Compounds
G20 (IC50 = 0.028 µg/mL), G31 (IC50 = 0.042 µg/mL), G3
(IC50 = 0.056 µg/mL), G32 (IC50 = 0.068 µg/mL), G14
(IC50 = 0.079 µg/mL), G9 (IC50 = 0.081 µg/mL), G7 (IC50
= 0.084 µg/mL), G24 (IC50 = 0.089 µg/mL), G21 (IC50
0.113 µg/mL), G28 (IC50 = 0.135 µg/mL), G38 (IC50
=
=
0.148 µg/mL) and G36 (IC50 = 0.256 µg/mL) displayed
significant activity when compared with the quinine.
Conclusion
A diversity-oriented synthesis approach has been adopted
for the synthesis of novel 3,4′-bicarbostyril library which
yields skeletally diverse molecules and hence provide better
explanations about SAR. The satisfactory biological activity
results verify a proposed hypothesis of the present work.
Compounds G37,G8, G38, andG18 were found to be most
efficient antibacterial members; while compounds G16,
Structure–activity relationship (SAR) for antimalarial
activity
Compounds G40, G20, G32, G24, G28, and G36 carrying
EWG -Cl demonstrated better inhibition of P. falciparum
compared to quinine. The replacement of BHZ with INH at

Med Chem Res
Table 3 In vitro antimalarial activity of title compounds (IC50, µg/
mL)
SICART, Vallabh Vidyanagar, for FT-IR and elemental analysis and
Microcare Laboratory, Surat, Gujarat, India for antimicrobial, anti-
tubercular and antimalarial screening of the compounds reported
herein. Hardik H. Jardosh and Nileshkumar D. Vala are grateful to
UGC, New Delhi for a RFSMS and BSR Research Fellowship,
respectively.
P. falciparum (3D7)
IC50 (µg/mL)
P. falciparum (3D7)
IC50 (µg/mL)
Entry
Entry
G1
0.871
0.865
0.056
1.473
0.790
0.746
0.084
1.325
0.081
1.294
0.946
0.845
1.402
0.079
1.734
0.653
1.127
0.977
0.564
0.028
0.113
G22
G23
G24
G25
G26
G27
G28
G29
G30
G31
G32
G33
G34
G35
G36
G37
G38
G39
G40
CLQ
QUIN
1.159
0.454
0.089
1.104
1.207
0.830
0.135
1.401
1.546
0.042
0.068
0.428
1.477
1.322
0.256
0.650
0.148
0.891
0.019
0.020
0.268
G2
Compliance with ethical standards
G3
G4
Conflict of interest The authors declare that they have no conflict of
interest.
G5
G6
G7
G8
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