Synthesis and characterization of pyrrolo[1,2-a]quinoline derivatives for their larvicidal activity against Anopheles arabiensis

Article abstract of DOI:10.1007/s11224-020-01516-w

Certain tetrahydropyrido[1,2-a]quinolines and pyrroloquinoline homologs have shown various biological activities such as antimicrobials, crop-protectings, diuretics, antioxidants, anticoagulants, and antimalarial activities. Keeping this observation in mi

Full text of DOI:10.1007/s11224-020-01516-w

Structural Chemistry
https://doi.org/10.1007/s11224-020-01516-w
ORIGINAL RESEARCH
Synthesis and characterization of pyrrolo[1,2-a]quinoline
derivatives for their larvicidal activity against Anopheles arabiensis
Vijayakumar Uppar1 & Sandeep Chandrashekharappa2 & Katharigatta N. Venugopala3,4 & Pran Kishore Deb5
&
Supratik Kar6 & Osama I. Alwassil7 & Raquel M. Gleiser8,9 & Daniel Garcia10 & Bharti Odhav4 & Mahendra K. Mohan2
Rashmi Venugopala11 & Basavaraj Padmashali1
&
Received: 23 October 2019 /Accepted: 27 February 2020
#
Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
Certain tetrahydropyrido[1,2-a]quinolines and pyrroloquinoline homologs have shown various biological activities such as
antimicrobials, crop-protectings, diuretics, antioxidants, anticoagulants, and antimalarial activities. Keeping this observation in
mind, we envisaged to synthesize and characterize a series of novel ethyl 1-(substituted benzoyl)-5-methylpyrrolo[1,2-a-
]quinoline-3-carboxylates and dimethyl 1-(substituted benzoyl)-5-methylpyrrolo[1,2-a]quinoline-2,3-dicarboxylates (2a-k).
Quaternary salts of lepidine such as 1-[2-(substituted phenyl)-2-oxoethyl]-4-methylquinolin-1-ium bromide (1a-f) were obtained
by stirring lepidine with different phenacyl bromides in acetone at room temperature separately. These quaternary salts of lepidine
(1a-f) were then treated with electron-deficient ethyl propiolate and dimethyl-but-2-yne-dioate separately, in the presence of
anhydrous K2CO3 and dimethylformamide (DMF) solvent to obtain ethyl 1-(substituted benzoyl)-5-methylpyrrolo[1,2-a-
]quinoline-3-carboxylates and dimethyl 1-(substituted benzoyl)-5-methylpyrrolo[1,2-a]quinoline-2,3-dicarboxylates, respective-
ly (2a-k). The newly synthesized compounds were assessed by spectroscopic techniques to determine their structures. Based on
our previous study on the similar pharmacophore, the synthesized compounds 2a-k were screened for their larvicidal activity
against Anopheles arabiensis using a standard World Health Organization larvicidal assay; compounds 2b and 2e at 8.12 and
9.2 μM exhibited the highest larval mortality at 78 and 89%, respectively, when compared with the negative control acetone, and
it demonstrated less activity, which was similar to the positive control, temephos. Finally, the test compound 2e at 9.2 μM,
resulted in an 89% mortality rate after 48 h of exposure, followed by compound 2b at 8.12 μM with a 78% mortality rate.
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s11224-020-01516-w) contains supplementary
material, which is available to authorized users.
6
* Katharigatta N. Venugopala
Interdisciplinary Center for Nanotoxicity, Department of Chemistry,
Physics and Atmospheric Sciences, Jackson State University,
Jackson, MS 39217, USA
kvenugopala@kfu.edu.sa
* Basavaraj Padmashali
7
basavarajpadmashali@yahoo.com
Department of Pharmaceutical Sciences, College of Pharmacy, King
Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi
Arabia
1
Department of Chemistry, School of Basic Science, Rani
Channamma University, Belagavi 591156, India
8
CREAN-IMBIV (CONICET-UNC), Av. Valparaíso s.n.,
Córdoba, Argentina
2
Institute for Stem Cell Biology and Regeneration Medicine, NCBS,
TIFR GKVK Campus Bellary Road, Bangalore 560065, India
9
FCEFyN, Universidad Nacional de Cordoba, AV. Sarsfield 299,
5000 Cordoba, Argentina
3
Department of Pharmaceutical Sciences, College of Clinical
Pharmacy, King Faisal University, Al-Ahsa 31982, Kingdom of
Saudi Arabia
10
Instituto de Investigaciones Biológicas y Tecnilógicas
(IIByT-CONICET), Cátedra de Quimica Biológica, Facultad de
Ciencias Exactas, Físicas y Naturales, Universidad Nacional de
Córdoba, Córdoba, Argentina
4
Department of Biotechnology and Food Technology, Faculty of
Applied Sciences, Durban University of Technology, Durban 4001,
South Africa
5
11
Faculty of Pharmacy, Philadelphia University, PO Box (1),
Amman 19392, Jordan
Department of Public Health Medicine, Howard College Campus,
University of KwaZulu-Natal, Durban 4001, South Africa

Struct Chem
Compounds 2f, 2d, and 2c showed intermediate toxicity, and the mortality rate was lower than 60% for larvae exposed to any of
the remaining test compounds.
.
.
.
Keywords Lepidine Pyrrolo[1,2-a]quinoline Structural elucidation Larvicidal activity
Introduction
derivatives (2a-k) (Scheme 1) for their larvicidal activity
against A. arabiensis using a standard larvicidal assay
The synthesis of heterocyclic compounds [1–4] and
bridgehead nitrogen heterocycles are of great interest,
as they are found in many natural and non-natural
products, particularly those exhibiting useful biological
activities [5–15]. Pyrrolo[1,2-a]quinolines (benzo ana-
logs of indolizines) are heterocycles characterized by
their saturated and partially saturated derivatives and
are found in many biologically active compounds [16,
17]. Among different nitrogen heterocycles, pyrrolo[1,2-
a]quinoline derivatives have garnered much attention
for their unique properties in functional materials [18],
as well as for their biological activities [19] and their
presence in natural products [20–24]. Moreover, certain
t e t r a h y d r o p y r i d o [ 1 , 2 - a] qu i n ol i ne s [2 5] an d
pyrroloquinoline homologs have shown various biologi-
cal activities such as antimicrobials [26–28], crop-
protectings [29], diuretics [30], antioxidants [20, 31],
anticoagulants [32], and antimalarial activities [33, 34].
A number of tricyclic angular heterocycle derivatives
have exhibited a broad spectrum of pharmacological
activities [35] including, most notably, anticancer
[36–39] and anti-inflammatory activities [40, 41].
Pyrrolo[2,3-b]quinoline-4-amino derivatives have also
been tested as a potential treatment for Alzheimer’s
disease [42]. Malaria is one of the most prevalent
infectious diseases around the world, with African being
most affected. The Anopheles arabiensis mosquito is
one of the primary sources of malaria in Southern
Africa, followed by Anopheles funestus [43]. Mosquito
breeding sites serve as interim habitats for these insects,
and larvicides have been used by malaria control
programs. The application of larvicides aims to control
the mosquito population in their larval habitat. One of
the best ways to avoid mosquito bites from adult mos-
quitos is indoor residual spraying; however, the larvi-
cidal application further inhibits the mosquito popula-
tion [44, 45]. Synthesized 2,6-substituted benzo[d]-
thiazole and 2,4-substituted benzo[d]thiazole compounds
reportedly have anti-mosquito properties and they can
be used as repellents, insecticides, and larvicides against
A. arabiensis [46]. In continuation of our efforts to
develop potent larvicidal agents (Fig. 1) to prevent ma-
laria, in the present investigation, we have designed, synthe-
sized, and screened a series of novel pyrrolo[1,2-a]quinoline
[47].
Experimental
Chemistry
All reagents used in this study were of analytical reagent (AR)
grade and purchased from Sigma-Aldrich Co. (St. Louis, MO,
USA). All chemical reactions from Scheme 1 were performed
under a nitrogen atmosphere using a dry solvent. The reaction
was monitored using thin-layer chromatography (TLC). TLC
was performed on Merck silica gel on TLC aluminum foil
with ethyl acetate and hexane as eluent mixture and visualiza-
tion in an ultraviolet (UV) chamber. All melting points were
determined using Thiele melting point apparatus in an open
capillary and were uncorrected. Infrared (IR) spectra were
recorded on a Thermo Fisher Scientific Fourier Transform
(FT)-IR spectrophotometer; H NMR spectra and 13C NMR
1
spectra were recorded with CDCl3 and dimethyl sulfoxide
(DMSO) as a solvent and using a Bruker AV 800 spectrome-
ter. Chemical shifts were expressed in δ ppm and were refer-
enced with TMS as an internal standard. The peak multiplic-
ities were as follows: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet. Mass spectra were performed on a Jole JMS-D
300 mass spectrometer operating at 70 eV. Elemental analysis
was performed on a Thermo Finnigan FLASH FA 1112 CHN
analyzer.
Synthetic procedure for the preparation
of 1-[2-(4-bromophenyl)-2-oxoethyl]
-4-methylquinolin-1-ium bromide (1a)
To a stirred solution of 4-methylquinoline (1 g, 0.00698 mol)
in dry acetone (5 mL), 4-bromophenacyl bromide (1.93 g,
0.00698 mol) was added and stirred at room temperature for
30 min. The formed solid was filtered out and dried under a
vacuum to afford the salt 1-[2-(4-bromophenyl)-2-oxoethyl]-
4-methylquinolin-1-ium bromide (2.7 g, 96.6% yield). The
remaining intermediates (1b-f) were prepared according to a
similar protocol and the characterization details of 1a-f are
described as below.

Struct Chem
a
b
c
d
e
Fig. 1 Larvicidal lead compounds a, b, c, and d obtained from our previous study [7, 9]. Proposed structure e for the potential larvicidal activity
1-[2-(4-Bromophenyl)-2-oxoethyl]-4-methylquinolin-1-ium
bromide (1a)
8.20–8.18 (2H, m, H6, H7), 8.07–8.05 (3H, m, ArH2, ArH6,
ArH3), 7.94–7.93 (2H, m, ArH3, ArH5), 6.90 (2H, s, CH2),
3.09 (3H, s, CH3); 13C-NMR (150 MHz, DMSO-d6); 190.7
(CO), 160.6, 150.0, 138.4, 135.8, 133.2, 132.6, 130.9, 130.1,
129.4, 129.1, 127.5, 123.2, 120.0, 79.6, 63.2(CH2),
20.4(CH3); MS (ESI, positive): m/z = 340.2 (M + H)+ and
Appearance; white color; m.p. = 109–110 °C; yield = 96.6%;
1H-NMR (600 MHz, DMSO-d6); δ = 9.31–9.30 (1H, d; J =
6.6 Hz, H2), 8.60–8.59 (1H, m, H8), 8.42–8.41 (1H, d, H5),
Scheme 1 Synthetic scheme for the construction of novel pyrrolo[1,2-a]quinoline derivatives (2a-k): a) acetone, room temperature, 30 min; b)
dimethylformamide (DMF), potassium carbonate (K2CO3), 30 min

Struct Chem
m/z = 342.2 (M + 2H)+; Anal. calcd for C18H15Br2NO; C,
51.34, H, 3.59, N, 3.33; found C, 51.33, H, 3.56, N, 3.31.
6.6 Hz, H2), 8.61–8.59 (1H, m, H8), 8.41–8.40 (1H, m, H5),
8.20–8.18 (2H, m, H7, H6), 8.16–8.15 (2H, m, ArH2, ArH6),
8.07–8.05 (1H, m, H3), 7.84–7.69 (3H, m, ArH3, ArH4,
ArH5), 6.93 (2H, s, CH2), 3.09 (3H, s, CH3); 13C-NMR
(150 MHz, DMSO-d6); 191.3 (CO), 160.3, 150.0, 138.4,
135.8, 135.3, 134.1, 130.1, 129.5, 129.1, 129.0, 127.5,
123.2, 120.0, 79.6, 63.2(CH2), 20.4(CH3); MS (ESI, positive):
m/z = 262.2 (M + H)+; Anal. calcd for C18H16BrNO; C, 63.17,
H, 4.71, N, 4.09, found C, 63.11, H, 4.69, N, 4.00.
1-[2-(2-Nitrophenyl)-2-oxoethyl]-4-methylquinolin-1-ium
bromide (1b)
Appearance; yellow color; m.p. = 134–135 °C; yield =
96.1%;1H-NMR (600 MHz, DMSO-d6); δ = 9.44–9.43 (1H,
d; J = 6.6 Hz, H2), 8.63–8.62 (1H, m, H8), 8.56–8.54 (1H, d;
J = 9.2 Hz, H5), 8.33–8.27 (4H, m, H6, H7, H3, ArH3), 8.11–
8.07 (2H, m, ArH4, ArH6), 7.99–7.95 (1H, m, ArH5), 6.88
(2H, s, CH2), 3.10 (3H, s, CH3); 13C-NMR (150 MHz,
DMSO-d6); 193.3 (CO), 161.1, 150.0, 146.6, 138.2, 135.8,
134.8, 133.7, 131.8, 130.2, 129.7, 129.2, 127.6, 125.1,
123.3, 119.7, 79.6, 64.2(CH2), 20.5(CH3); MS (ESI, positive):
m/z = 307.2 (M + H)+; Anal. calcd for C18H15BrN2O3; C,
55.83, H, 3.90, N, 7.23; found C, 55.79, H, 3.88, N, 7.19.
1-(2-(4-Fluorophenyl)-2-oxoethyl)-4-methylquinolin-1-ium
bromide (1f) [50]
Appearance; white color; m.p. = 138–139 °C; yield = 99.6%;
1H-NMR (600 MHz, DMSO-d6); δ = 9.32–9.31 (1H, d; J =
6.6 Hz, H2), 8.60–8.58 (1H, m, H8), 8.46–8.45 (1H, m, H5),
8.29–8.27 (2H, m, ArH2, ArH6), 8.23–8.05 (4H, m, ArH3,
ArH5, H7, H6), 8.01–7.99 (1H, m, H3), 6.97 (2H, s, CH2),
3.10 (3H, s, CH3); 13C-NMR (150 MHz, DMSO-d6); 190.9
(CO), 167.3, 166.2, 150.0, 138.4, 137.4, 135.8, 133.4, 129.6,
129.1, 128.2, 127.5, 125.0, 123.2, 122.5, 120.0, 116.8, 79.6,
63.4CH2, 20.4 CH3; MS (ESI, positive): m/z = 280.2 (M +
H)+; Anal. calcd for C18H15BrFNO; C, 60.02, H, 4.20, N,
3.89; found C, 59.12, H, 4.10, N, 3.61.
1-(2-(3,5-Bis(trifluoromethyl)phenyl)-2-oxoethyl)
-4-methylquinolin-1-ium bromide (1c)
Appearance; yellow color; m.p. = 120–123 °C; yield =
90.6%;1H-NMR (600 MHz, DMSO-d6); δ = 9.25–9.24 (1H,
d; J = 6.6 Hz, H2), 8.70 (2H, m, H8, H5), 8.63–8.61(2H, m, H6,
H7), 8.51–8.49 (1H, m, ArH4), 8.23–8.20 (2H, m, ArH2,
ArH5), 8.09–8.07 (1H, m, ArH3), 7.03 (2H, m, CH2), 3.10
(3H, s, CH3), 13C-NMR (150 MHz, DMSO-d6); 189.9 (CO),
161.0, 149.9, 138.5, 136.4, 135.9, 131.5, 131.3, 130.2, 129.5,
129.1, 128.0, 127.5, 124.3, 123.3, 122.5, 120.1, 79.6,
63.5(CH2), 20.5(CH3); MS (ESI, positive): m/z = 398.2
(M + H)+; Anal. calcd for C20H14BrF6NO; C, 50.23, H,
2.95, N, 2.93; found C, 50.19, H, 2.93, N, 2.90.
Preparation of ethyl 1-(4-bromobenzoyl)
-5-methylpyrrolo[1,2-a]quinoline-3-carboxylate (2e)
To a stirred solution of 1-[2-(4-bromophenyl)-2-oxoethyl]-4-
methylquinolin-1-ium bromide (1a) (1 g, 0.00237 mol), ethyl
propiolate (0.232 g, 0.00237 mol) and K2CO3 (0.819 g,
0.00593 mol) were added to dry DMF, and stirred at room
temperature for 30 min. Reaction completion was monitored
by TLC. After completion, the reaction mixture was evaporat-
ed under reduced pressure and diluted with ethyl acetate. The
ethyl acetate layer was washed with brine, water, and dried
with anhydrous sodium sulfate. The ethyl acetate was re-
moved under reduced pressure, and the crude compound
was purified with a column chromatography using 60–120
mesh silica gel with ethyl acetate and hexane (7:3) as eluent
to afford 0.30 g (53% yield) of ethyl-1-(4-bromobenzoyl)-5-
methylpyrrolo[1,2-a]quinoline-3-carboxylate. The remaining
compounds (2a–d and 2f–k) were prepared following a sim-
ilar protocol and the characterization details are reported
below.
1-(2-(4-Cyanophenyl)-2-oxoethyl)-4-methylquinolin-1-ium
bromide (1d)
Appearance; white color; m.p. = 123–124 °C; yield = 97.6%;
1H-NMR (600 MHz, DMSO-d6); δ = 9.31–9.30 (1H, d; J =
6.6 Hz, H2), 8.61–8.59 (1H, m, H8), 8.47–8.46 (1H, m, H5),
8.29–8.28 (2H, m, ArH2, ArH6), 8.21–8.18 (4H, m, ArH3,
ArH5 H7, H6), 8.08–8.05 (1H, m, H3), 6.95 (2H, s, CH2),
3.09 (3H, s, CH3); 13C-NMR (150 MHz, DMSO-d6); 190.9
(CO), 168.6, 150.0, 138.4, 137.4, 135.8, 133.4, 129.6, 129.1,
128.2, 127.5, 125.0, 123.2, 122.5, 120.0, 118.4, 116.8, 79.6,
63.4(CH2), 20.4(CH3); MS (ESI, positive): m/z = 287.2 (M +
H)+; Anal. calcd for C19H15BrN2O; C, 62.14, H, 4.12, N,
7.63; found C, 62.12, H, 4.10, N, 7.61.
Dimethyl-1-(3,5-bis(trifluoromethyl)benzoyl)
-5-methylpyrrolo[1,2-a]quinoline-2,3-dicarboxylate (2a)
1-[2-Phenyl-2-oxoethyl]-4-methylquinolin-1-ium bromide
(1e) [48, 49]
Appearance; yellow color; FT-IR (neat cm−1); 1785, 1780,
1743, 1706, 1650, 1620; H-NMR (800 MHz, CDCl3); δ =
1
Appearance; white color; m.p. = 127–128 °C; yield = 88.2%;
1H-NMR (600 MHz, DMSO-d6); δ = 9.34–9.33 (1H, d; J =
8.55 (2H, s, ArH2, ArH6), 8.21 (1H, s,ArH4), 8.19 (1H, s, H4),
8.02–8.01 (1H, m, H9), 7.67–7.66 (1H, m, H6), 7.58–7.54

Struct Chem
(2H, m, H7, H8), 3.92 (3H, s, OCH3), 3.45 (3H, s, OCH3), 2.75
(3H, s, CH3); 13C-NMR (200 MHz, CDCl3); 183.2 (Bz),
165.3 (COOMe), 163.3 (COOMe), 139.6, 138.8, 137.4,
132.3, 132.2, 132.1, 132.0, 131.4, 129.8, 129.0, 126.4,
126.0, 125.8, 125.8, 123.9, 123.4, 122.1, 119.7, 117.0,
105.0, 52.4 (OCH3), 51.8 (OCH3), 19.6 (CH3); LC-MS
(ESI, positive): m/z = 538.2 (M + H)+; Anal. calcd for
C26H17F6NO5; C, 58.11, H, 3.19, N, 2.61; found C, 58.06,
H, 3.21, N, 2.58.
130.1, 129.9, 128.4, 128.4, 127.8, 125.4, 125.3, 125.2,
120.6, 117.3, 106.6, 60.1 (CH3), 19.58 (CH3); LC-MS (ESI,
positive): m/z = 403.2 (M + H)+; Anal. calcd for C23H18N2O5;
C, 68.65, H, 4.51, N, 6.96; found C, 68.66, H, 4.58, N, 5.98.
Ethyl-1-(4-bromobenzoyl)-5-methylpyrrolo[1,2-a]
quinoline-3-carboxylate (2e)
Appearance; yellow color; FT-IR (neat cm−1); 2973, 1704,
1
1632, 1539; H-NMR (800 MHz, CDCl3); δ = 8.25 (1H, s,
Ethyl-1-(3,5-bis(trifluoromethyl)benzoyl)
-5-methylpyrrolo[1,2-a]quinoline-3-carboxylate (2b)
H2), 8.14 (1H, m, H9), 7.98–7.97 (3H, m, H6, ArH3, ArH5),
7.72–7.71 (2H, d, ArH2, ArH6), 7.62–7.54 (2H, m, H7, H8),
7.28 (1H, s, H4), 4.41–4.37 (2H, q, J = 7.2 Hz, CH2), 2.73
(3H, s, CH3), 1.42–1.40 (3H, t, J = 7.2 Hz, CH3); 13C-NMR
(200 MHz, CDCl3); 183.3 (Bz), 164.1 (COOEt), 140.7 (C3a),
137.4 (C5), 136.8, 132.9, 131.7, 131.5, 130.0, 128.5, 127.7,
127.3, 125.4, 125.4, 120.5, 117.2, 106.8 (C3), 60.1 (CH2),
19.5 (CH3), 14.5 (CH3); LC-MS (ESI, positive): m/z = 436.2
(M + H)+, 438.2 (M + 2H)+; Anal. calcd for C23H18BrNO3; C,
63.32, H, 4.16, N, 3.21; found C, 63.30, H, 4.16, N, 3.28.
Appearance; yellow color; FT-IR (neat cm−1); 1785, 1780, 1709,
1
1639; H-NMR (800 MHz, CDCl3); δ = 8.55 (2H, s, ArH2,
ArH6), 8.03 (1H, s, H2), 8.02–8.01 (1H, m, H9), 7.66 (1H, m,
H6), 7,66 (1H, s, ArH4), 7,65 (1H, s, H4), 7.63–7.58 (2H, m, H7,
H8), 4.42–4. 38 (2H, q, J = 7.2 Hz, CH2), 2.76 (3H, s, CH3),
1.42–1.40 (3H, t, J = 7.2 Hz, CH3); 13C-NMR (200 MHz,
CDCl3); 180.7 (Bz), 163.7 (COOEt), 141.5 (CF3), 140.8 (CF3),
137.9, 132.8, 132.4, 132.2, 132.04, 131.8, 130.9, 130.0, 129.8,
128.7, 126.5, 120.8, 125.5, 125.4, 123.8, 122.0, 120.4, 117.2,
107.6 (C3), 60.3 (CH2), 19.6 (CH3), 14.4 (CH3); LC-MS (ESI,
positive): m/z = 494.2 (M + H)+; Anal. calcd for C25H17F6NO3;
C, 60.86, H, 3.47, N, 2.84; found C, 60.88, H, 3.43, N, 2.81.
Dimethyl-1-(4-cyanobenzoyl)-5-methylpyrrolo[1,2-a]
quinoline-2,3-dicarboxylate (2f)
Appearance; yellow color; FT-IR (neat cm−1); 2957, 2232,
1
1737, 1703, 1646, 1535; H-NMR (800 MHz, CDCl3); δ =
Dimethyl-5-methyl-1-(2-nitrobenzoyl)pyrrolo[1,2-a]
quinoline-2,3-dicarboxylate (2c)
8.22 (1H, d, H9), 8.21–8.19 (2H, m, ArH3, ArH5), 7.78 (1H, s,
H4), 7.61–7.60 (2H, m, ArH2, ArH6), 7.51–7.47 (3H, m, H6,
H7, H8), 3.93 (3H, s, OCH3), 3.49 (3H, s, OCH3), 2.72 (3H, s,
CH3); 13C-NMR (200 MHz, CDCl3); 185.0 (Bz), 165.2
(COOMe), 163.4 (COOMe), 141.1, 138.1, 136.6, 132.3,
132.1, 130.2, 130.0, 128.9, 125.9, 125.7, 125.7, 124.8,
119.5, 117.8, 117.2, 116.6, 104.9, 52.4 (OCH3), 51.8
(OCH3), 19.5 (CH3); LC-MS (ESI, positive): m/z = 427.2
(M + H)+; Anal. calcd for C25H18N2O5; C, 70.42, H, 4.25,
N, 6.57; found C, 70.54, H, 4.20, N, 6.60.
Appearance; yellow color; FT-IR (neat cm−1); 2951, 1726,
1
1702, 1633, 1605, 1556; H-NMR (800 MHz, CDCl3); δ =
8.15 (1H, m, H9), 8.01–7.95 (2H, m, ArH3, ArH4), 7.63–7.62
(1H, m, H6), 7.51–7.50 (1H, s, H4), 7.49 (1H, m, H7), 7.48–
7.37 (3H, m, H8, ArH5, ArH6), 3.92 (3H, s, COOCH3), 3.45
(3H, s, COOCH3), 2.70 (3H, s, CH3); 13C-NMR (200 MHz,
CDCl3); 187.4 (Bz), 165.3(COOMe), 163.8 (COOMe), 137.7,
137.4, 135.5, 133.7, 132.3, 129.8, 128.7, 128.6, 128.5, 126.0,
125.6, 125.5, 119.5, 117.3, 104.4, 52.2 (OCH3), 51.6 (OCH3),
19.5 (CH3); LC-MS (ESI, positive): m/z = 447.2 (M + H)+;
Anal. calcd for C24H18N2O7; C, 64.57, H, 4.06, N, 6.28; found
C, 64.55, H, 4.01, N, 6.31.
Ethyl-1-(4-cyanobenzoyl)-5-methylpyrrolo[1,2-a]
quinoline-3-carboxylate (2 g)
Appearance; black color; FT-IR (neat cm−1); 2228, 1703,
1
1629, 1542; H-NMR (800 MHz, CDCl3); δ = 8.30 (1H, s,
Ethyl-5-methyl-1-(2-nitrobenzoyl)pyrrolo[1,2-a]
quinoline-3-carboxylate (2d)
H9), 8.14–8.12 (2H, m, ArH3, ArH5), 8.01 (1H, s, H2),
7.88–7.87 (2H, m, H6, H4), 7.65–7.59 (2H, m, ArH2, ArH6),
7.58–7.57 (2H, m, H7, H8), 4.41–4.37 (2H, q, J = 7.2 Hz,
CH2), 2.75 (3H, s, CH3), 1.42–1.40 (3H, t, J = 7.2 Hz,
CH2CH3); 13C-NMR (200 MHz, CDCl3); 182.1 (Bz), 167.2
(COOEt), 142.4, 141.2, 137.6, 132.9, 132.3, 131.0, 130.3,
128.6, 127.1, 125.7, 125.4, 125.3, 120.6, 118.1, 117.2,
115.8, 107.3, 60.2 (CH2), 19.6 (CH3); 14.5 (CH3); LC-MS
(ESI, positive): m/z = 383.2 (M + H)+; Anal. calcd for
C24H18N2O3; C, 75.38, H, 4.74, N, 7.33; found C, 74.33, H,
4.54, N, 7.31.
Appearance; yellow color; FT-IR (neat cm−1); 2979, 1705,
1
1698, 1633; H-NMR (800 MHz, CDCl3); δ = 8.31(1H, s,
H2), 8.25 (1H, m, H9), 8.21–8.12 (2H,, ArH3, ArH4), 7.69–
7.68 (1H, m, H6), 7.67–7.62 (1H, m, H7), 7.61–7.53 (3H, m,
H8, ArH5, ArH6), 7.28 (1H, s, H4), 4.40–4.37 (2H, q, J =
7.2 Hz, CH2), 2.73 (3H, s, CH3), 1.42–1.40 (3H, t, J =
7.2 Hz, CH2CH3); 13C-NMR (200 MHz, CDCl3); 184.6
(Bz), 164.2 (COOEt), 140.5, 138.5, 136.5, 132.7, 130.1,

Struct Chem
Dimethyl-1-benzoyl-5-methylpyrrolo[1,2-a]
quinoline-2,3-dicarboxylate (2 h)
H9), 8.20–8.12 (2H, d, ArH3, ArH5), 8.00 (1H, m, H4),
7.99–7.97 (1H, m, H6), 7.61–7,54 (3H, s, ArH2, ArH4, H2),
7.27–7.24 (2H, d, H7, H8), 4.41–4.37 (2H, q, J = 7.2 Hz,
CH2), 2.73 (3H, s, CH3), 1.57–1.27 (3H, t, J = 7.2 Hz,
CH2CH3); 13C-NMR (200 MHz, CDCl3); 184.6 (Bz), 164.2
(COOEt), 140.5, 136.6, 134.8, 132.9, 132.5, 132.5, 129.7,
128.5, 127.4, 125.4, 125.2, 120.5, 117.3, 115.7, 115.5,
106.7, 60.1 (CH2), 19.5 (CH3), 14.5 (CH3); LC-MS (ESI,
positive): m/z = 376.2 (M + H)+; Anal. calcd for
C23H18FNO3; C, 73.59, H, 4.83, N, 3.73; found C, 73.56, H,
4.81, N, 3.77.
Appearance; brick red color; FT-IR (neat cm−1); 2952, 1726,
1
1702, 1634, 1445; H-NMR (800 MHz, CDCl3); δ = 8.21
(1H, s, H9), 8.02–7.76 (5H, m, ArH3, ArH4, ArH5, H6, H7),
7.51–7.43 (4H, m, ArH2, ArH6, H8, H4), 3.92 (3H, s, OCH3),
3.45 (3H, s, OCH3), 2.70 (3H, s, CH3); 13C-NMR (200 MHz,
CDCl3); 187.4 (Bz), 165.3 (COOMe), 163.8 (COOMe),
137.7, 137.4, 135.5, 133.7, 132.3, 129.8, 128.7, 128.6,
128.5, 126.0, 125.6, 125.5, 119.5, 117.3, 104.4, 52.2
(OCH3), 51.6 (OCH3), 19.5 (CH3); LC-MS (ESI, positive):
m/z = 402.2 (M + H)+; Anal. calcd for C24H19NO5; C, 71.81,
H, 4.77, N, 3.49; found C, 71.82, H, 4.71, N, 3.58.
In vitro larvicidal activity against Anopheles
arabiensis
Ethyl-1-benzoyl-5-methylpyrrolo[1,2-a]
quinoline-3-carboxylate (2i) [51, 52]
The designed test compounds 2a-k were dissolved in acetone
solvent and screened for their in vitro larvicidal activity
against A. arabiensis.
Appearance; yellow color; FT-IR (neat cm−1); 2980,
1700, 1634, 1465; 1H-NMR (800 MHz, CDCl3); δ =
8.25 (1H, s, H2), 8.18–8.10 (3H, m, H9, ArH3, ArH5),
8.01–8.00 (1H, m, H4), 7.90–7.89 (1H, m, ArH4,) 7.68–
7.53 (5H, m, ArH2, ArH6, H6, H7, H8), 4.40–4.37 (2H,
q, J = 7.2 Hz, CH2), 2.73 (3H, s, CH3), 1.58–1.27 (3H,
t, J = 7.2 Hz, CH2CH3); 13C-NMR (200 MHz, CDCl3);
184.6 (Bz), 164.2 (COOEt), 140.5, 138.5, 136.5, 133.0,
132.7, 130.1, 129.9, 128.4, 128.4, 127.8, 125.4, 125.3,
125.2, 120.6, 117.3, 106.6, 60.1 (CH2), 19.5 (CH3),
14.5 (CH3); LC-MS (ESI, positive): m/z = 358.2 (M +
H)+; Anal. calcd for C23H19NO3; C, 77.29, H, 5.36,
N, 3.92; found C, 77.24, H, 5.21, N, 3.99.
Larvicidal activity
The larvicidal activity was assessed in triplicate in
A. arabiensis larvae from a colonized strain obtained from
Zimbabwe. The larvae were reared following the WHO
(1975) guidelines [47]. The temperature (27.5 °C), humidity
(70%), and lighting (12/12) conditions of the insectary simu-
lated those of a malaria-endemic environment. Further, 30
third-instar larvae were placed in a container with 250 mL of
distilled water and one of the following: [a] 1 mL of the test
compound (1 mg/mL; final concentration: 4 μg/mL); [b] a
solvent (acetone) representing a negative control; or [c] the
emulsifiable organophosphate larvicidal temephos (Mostop;
Agrivo), used by the malaria control program as a positive
control. Larval mortality in each container was monitored at
24h intervals for a period of 3 days. During that period, the
larva was fed a cat food with reduced oil/fat content at regular
intervals. The mortality percentage was calculated relative to
the initial number of exposed larvae.
Dimethyl-1-(4-fluorobenzoyl)-5-methylpyrrolo[1,2-a]
quinoline-2,3-dicarboxylate (2j)
Appearance; golden yellow color; FT-IR (neat cm−1); 2956,
1
1737, 1704, 1643, 1598; H-NMR (800 MHz, CDCl3); δ =
8.15 (1H, d, H9), 8.10–7.92 (2H, m, ArH3, ArH5), 7.65–7.45
(4H, m, H6, H7, H8, H4), 7.19–7.16 (2H, s, ArH2, ArH6), 3.92
(3H, m, OCH3), 3.52 (3H, s, OCH3), 2.70 (3H, s, CH3); 13C-
NMR (200 MHz, CDCl3); 185.8 (Bz), 166.7, 165.4
(COOMe), 163.7 (COOMe), 137.4, 135.6, 134.1, 132.5,
132.5, 132.2, 128.7, 128.5, 125.6, 125.5, 119.4, 117.3,
115.9, 115.8, 104.4, 52.3 (OCH3), 51.7 (OCH3), 19.5 (CH3);
LC-MS (ESI, positive): m/z = 420.2 (M + H)+; Anal. calcd for
C24H18FNO5; C, 68.73, H, 4.33, N, 3.34; found C, 68.76, H,
4.27, N, 3.38.
Data analysis
Differences between treatments in terms of mortality (larvi-
cide assays) were explored via general linear mixed models
[53]. The dependent variable was A. arabiensis mortality, the
fixed effects were test compound (test compounds 2a to 2k,
acetone, and temephos) and the observation period (24 and
48 h), and the random effects were groups of mosquitoes
within a container during the larvicidal tests. A value of
P < 0.05 was considered to indicate statistically significant
effects. The results are presented as the adjusted mean the
standard error.
Ethyl-1-(4-fluorobenzoyl)-5-methylpyrrolo[1,2-a]
quinoline-3-carboxylate (2 k)
Appearance; yellow color; FT-IR (neat cm−1); 2980, 1701,
1
1636, 1542; H-NMR (800 MHz, CDCl3); δ = 8.25 (1H, s,

Struct Chem
Results and discussion
Synthesis of designed compounds
which was at the first position of 5-methylpyrrolo[1,2-a-
]quinoline nucleus when compared to standard substance
temephos (Table 2). The second most promising compound
2b at 8.12 μM from the series exhibited activity at 77.8%
having 3,5-bis(trifluoromethyl) on the benzoyl group. The
most promising larvicidal agents 2e and 2b from the series
exhibited the highest cLogP at 6.90 and 7.83, according to
ChemDraw professional 16.0 calculation. Compounds 2f
(9.39 μM) and 2d (9.95 μM) having nitrile and nitro groups
on benzoyl ring at the 1-position of 5-methylpyrrolo[1,2-
a]quinoline nucleus exhibited larvicidal activity at 75.6%
and 71.1%, respectively. Compounds 2c, 2g, 2 k, 2a, and 2j
at 8.97, 10.47, 10.67, 7.45, and 9.55 μM, having nitro,
nitrile, fluoro, 3,5-bis(trifluoromethyl), and fluoro groups
benzoyl ring at the 1-position of 5-methylpyrrolo[1,2-a]
quinoline nucleus exhibited moderate larvicidal activity at
65.6, 57.8, 55.6, 54.4, and 41.1%, respectively. The
unsubstituted benzoyl group derivatives 2h, and 2i at 9.97
and 11.20 μM exhibited the lowest larvicidal activity at,
32.2, and 20.0%, respectively. It can be understood from
the larvicidal results that electronic withdrawing groups on
benzoyl group influences the larvicidal activity. There is a
direct relationship between electronegative groups on
pyrrolo[1,2-a]quinoline nucleus and lipophilicity, which
influence the larvicidal activity on most promising com-
pounds 2e and 2b. Overall, the mortality rates of
A. arabiensis larvae exposed to any of the synthetic com-
pounds were significantly higher than the negative controls
(P < 0.05; Table 2). However, the mortality rates associated
with test samples treatment was near to the positive control
(temephos). Among the synthetic compound treatments,
larval mortality was highest for larvae exposed to com-
pound 2e, resulting in an 89% mortality rate after 48 h of
exposure, followed by compound 2b with a 78% mortality
rate. Compounds 2f, 2d, and 2c showed intermediate tox-
icity, and the mortality rate were lower than 60% for larvae
exposed to any of the remaining test compounds. Although
the overall mortality was higher after 48 h, for any of the
test compounds, in particular, mortality did not significantly
increase with exposure time.
Synthesis of novel designed pyrrolo[1,2-a]quinoline deriva-
tives (2a-h) and (2j-k) incorporating a methyl group at 4-
position was obtained according to the synthetic strategy de-
scribed in Scheme 1. All the substituted pyridinium bromides
(1a-f) as intermediates were prepared [54] by reacting lepidine
with substituted phenacyl bromides at room temperature in an
acetone medium, as illustrated at first step of Scheme 1. At
the second step of Scheme 1, the substituted pyrrolo[1,2-a-
]quinoline derivatives (2a-k) were prepared by stirring a solu-
tion of 1-[2-(4-substitutedphenyl)-2-oxoethyl]-4-
methylquinolin-1-ium bromides (1a-f), ethyl propiolate (or
dimethyl but-2-ynedioate), and potassium carbonate in dry
dimethylformamide, and by stirring at room temperature for
30 min; the yield obtained was in the range of 50.5–66.7%
after purification by column chromatography. All the synthe-
sized compounds were characterized using spectroscopic
techniques. The FT-IR spectra of pyrrolo[1,2-a]quinoline de-
rivatives (2a-k) revealed ester carbonyl in the range of 1698–
1743 cm−1 and ketone carbonyl in the range of 1629–
1706 cm−1. In the 1H NMR of compounds 2a-k, three protons
for methyl group at the 5-position of pyrrolo[1,2-a]quinoline
are observed as a singlet in the range of δ = 2.70–2.76. In case
of compounds 2a, 2c, 2f, 2 h, and 2j, six protons for two
methyl groups in dimethyl ester at 2 and 3-positions of
pyrrolo[1,2-a]quinoline are observed as singlets in the range
of δ = 3.92–3.93 and δ = 3.45–3.52, respectively. In the case of
compounds 2b, 2d, 2e, 2g, 2i, and 2k, ethyl ester group at the
second position of pyrrolo[1,2-a]quinoline exhibited triplet
for –CH2- and quartet for –CH3 in the range of δ = 4.41–
4.37 and δ = 1.58–1.27, respectively. However, in compounds
2b, 2d, 2e, 2g, 2i, and 2 k, singlet for a proton on second
carbon of five-membered ring is observed in the range of
δ = 8.01–8.31. In 13C-NMR, the C-atoms of the benzoyl and
ester functional group were observed in the range of δ =
187.45–180.5 and δ = 166.78–163.78, respectively. With re-
spect to the mass spectrum, the molecular ion peak of the title
compounds complied with the molecular weight of the com-
pounds 2a-k. ChemBioDraw Ultra 16.0v was used to calcu-
late the cLogP of the title compounds (2a-k), and the values
were in the range of 3.94–7.83 (Table 1). A plausible reaction
mechanism for the construction of substituted pyrrolo[1,2-a-
]quinoline derivatives (2a-k) is base-catalyzed reaction
followed by rearrangement reaction, as described in Fig. 2.
Conclusion
In this investigation, we described the chemical profile and the
in vitro larvicidal activity against A. arabiensis for the de-
signed compounds, 2a-k. All the reactions performed to ob-
tained pyrrolo[1,2-a]quinoline derivatives (2a-k) were eco-
friendly and performed at room temperature with good yields.
The test compounds were toxic to A. arabiensis larvae, but
none were as toxic as temephos. Among the synthetic com-
pound treatments, larval mortality was highest for larvae ex-
posed to compound 2e at 9.2 μM, resulting in an 89%
Larvicidal activity
The title compound 2e at 9.2 μM from the series emerged as
a promising larvicidal agent by exhibiting activity at 88.9%
having bromine atom at the 4-position of benzoyl group,

Struct Chem
Table 1 Physicochemical
characteristics of substituted
pyrrolo[1,2-a]quinoline
derivatives (2a-k)
Compound
code
Molecular formulae
(molecular mass)
R
R1
R2
Yield(%)a,b m.p.(°C) cLogPc
2a
2b
2c
C26H17F6NO5 (537)
C25H17F6NO3 (493)
C24H18N2O7 (446)
C23H18N2O5 (402)
C23H18BrNO3 (435)
C25H18N2O5 (426)
C24H18N2O3 (382)
C24H19NO5 (401)
C23H19NO3 (357)
C24H18FNO5 (419)
C23H18FNO3 (375)
3,5-CF3 CH3
3,5-CF3 C2H5
COOCH3 66.5
53.7
COOCH3 61.8
188–189 6.24
174–175 7.83
186–188 4.04
182–186 5.63
186–187 6.90
184–185 3.94
179–180 5.53
158–160 4.46
154–156 6.03
196–197 4.61
193–194 6.18
H
2-NO2
2-NO2
4-Br
4-CN
4-CN
4-H
CH3
2d
2e
C2H5
C2H5
CH3
H
H
54.8
55.0
2f
COOCH3 66.7
50.5
COOCH3 65.5
58.9
COOCH3 63.9
56.1
2 g
2 h
2i
C2H5
CH3
H
4-H
C2H5
CH3
H
2j
4-F
2 k
4-F
C2H5
H
a All the synthetic compounds were characterized by physical and spectral data
b Yield was calculated after column chromatography purification and confirmation
c ChemBioDraw Ultra 16.0v program was used to calculate cLogP
mortality rate after 48 h of exposure, followed by compound
2b at 8.12 μM with a 78% mortality rate. Compounds 2f, 2d,
and 2c at 9.39, 9.95, and 8.97 μM, respectively, showed in-
termediate toxicity, and the mortality rate was lower than 60%
for larvae exposed to any of the remaining test compounds. In
general various functional groups such as trifluoromethyl, ni-
tro, bromo, and nitrile on benzoyl group at the second position
of pyrrolo[1,2-a]quinoline nucleus enhances larvicidal
Fig. 2 The proposed plausible reaction mechanism of the synthesis of substituted pyrrolo[1,2-a]quinoline derivatives (2a-k)

Struct Chem
Table 2 Larvicidal activity of substituted pyrrolo[1,2-a]quinoline
derivatives (2a-k) against Anopheles arabiensis and their positive
(temephos) and negative (acetone) controls
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48 h
2a
2b
7.45
8.12
52.2 2.7ghi 54.4 2.7gh
76.6 2.7bc 77.8 2.7b
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2c
8.97
62.2 2.7ef
65.6 2.7de 71.1 2.7bcd
85.6 2.7a 88.9 2.7a
68.9 2.7cde 75.6 2.7bc
53.3 2.7ghi 57.8 2.7fg
26.7 2.7mn 32.2 2.7lm
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9.97
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35.6 2.7kl
50.0 2.7hi
1.1 2.7p
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41.1 2.7jk
55.6 2.7fgh
2.2 2.7p
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Temephos
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a-q Test compounds not sharing a letter differ significantly (p < 0.05)
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Data availability statement The data supporting the findings
of the article (FT-IR, 1H-NMR, and 13C-NMR) is available as
Electronic Supporting Information.
Acknowledgements The authors are thankful to the Department of
Chemistry, Rani Channamma University, Belagavi, for providing the fa-
cilities. We are also thankful to the Medical Research Council for its
facilities to screen the compounds for larvicidal activity. The authors are
grateful to the National Research Foundation, South Africa and the
Durban University of Technology for support and encouragement. The
funders had no role in study design, data collection and analysis, decision
to publish, or preparation of the manuscript.
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Conflict of interest The authors declare that they have no competing
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