Conventional spectroscopic identification of biologically active imidazo-pyrimido fused acridines: In vitro anti-bacterial and anti-feedant activity

Article abstract of DOI:10.1016/j.molliq.2017.01.010

A series of imidazo-pyrimido fused acridines were synthesized and identified using conventional spectroscopic techniques. All the synthesized title compounds were subjected to in vitro antibacterial and insecticidal screenings. For insecticidal activity,

Full text of DOI:10.1016/j.molliq.2017.01.010

Conventional spectroscopic identification of biologically active imidazo-
pyrimido fused acridines: In vitro anti-bacterial and anti-feedant activity
Jayakannu Palaniraja, Sekar Santhosh Kumar, Settu Ramki, Prabhakarn
Arunachalam, Selvaraj Mohana Roopan
PII:
DOI:
Reference:
S0167-7322(16)33758-8
doi:10.1016/j.molliq.2017.01.010
MOLLIQ 6806
To appear in:
Journal of Molecular Liquids
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Revised date:
Accepted date:
24 November 2016
11 December 2016
4 January 2017
Please cite this article as: Jayakannu Palaniraja, Sekar Santhosh Kumar, Settu
Ramki, Prabhakarn Arunachalam, Selvaraj Mohana Roopan, Conventional spec-
troscopic identification of biologically active imidazo-pyrimido fused acridines: In
vitro anti-bacterial and anti-feedant activity, Journal of Molecular Liquids (2017),
doi:10.1016/j.molliq.2017.01.010
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ACCEPTED MANUSCRIPT
Conventional spectroscopic identification of biologically active imidazo-
pyrimido fused acridines: In vitro anti-bacterial and anti-feedant activity
Jayakannu Palanirajaa, Sekar Santhosh Kumara, Settu Ramkia, Prabhakarn
Arunachalamb, Selvaraj Mohana Roopana,*
aChemistry of Heterocycles & Natural Product Research Laboratory, Department of Chemistry, School of Advanced
Sciences, VIT University, Vellore 632 014, Tamil Nadu, India.
bElectrochemistry Research Group, Chemistry Department, College of Science, King Saud University, Riyadh
11451, Saudi Arabia.
*E-mail: mohanaroopan.s@vit.ac.in, selvarajmohanaroopan@gmail.com (S.M. Roopan) Tel.: +91 416 220 2336;
+91 98656 10356.
Abstract: A series of imidazo-pyrimido fused acridines were synthesized and identified using
conventional spectroscopic techniques. All the synthesized title compounds were subjected to in
vitro antibacterial and insecticidal screenings. For insecticidal activity, the synthesized fused
compounds are testing against two pests namely, Sitophilus oryzae (S. oryzae) and
Callosobruchus
maculatus
(C. maculatus). For antibacterial screening, the compounds are testing against four bacteria,
Bacillus subtilis (B. subtilis), Proteus mirabilis (P. mirabilis), Staphylococcus aureus (S. aureus)
and Vibrio parahaemolyticus (V. parahaemolyticus). Notably, compound 8-(4-isopropylphenyl)-
16-phenyl-6,7-dihydrobenzo[4',5']imidazo[1',2':1,2]pyrimido[4,5-a]acridine
and
8-(2,4-
dimethoxyphenyl)-16-phenyl-6,7-dihydrobenzo[4',5']imidazo[1',2':1,2]pyrimido[4,5-a]acridine
were identified as the most promising applicant for further studies.
Keywords: Acridine, Fused heterocyclic compounds, Synthesis, Anti-feedant activity, Bioassay.
1. Introduction
The use pesticides are an efficient way to protect crops and increases procurements in
cultivations, among which insecticides plays a vital role. Nevertheless, the problem of insecticide
resistance has risen in recent years. There is an urgency to develop new active compounds with
lower dose and certainty for environmental friendly in order to overcome the resistance of food
grains [1-3]. Heterocyclic compounds were gained a special attention in the organic synthesis
due to their natural abundance. There is a need to design and synthesis of novel heterocyclic
motif for therapeutic applications. Recent literature surveys were enriched with overviews about
design, synthesis and biological properties of fused heterocyclic compounds [4-9]. Unfortunately,
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the natural availability nitrogen bridge headed compounds are in very less [10, 11]. Generally,
acridine nucleus is an important scaffold which is found in a numerous pharmacologically active
compounds which includes synthetic drug and natural product [12, 13]. With the prompt search
for easy, readily available starting materials and atom economy reactions are certainly desirable
[14]. Imidazole and pyrimidine derivatives also possessed diverse biological activities [15, 16].
We have identified from the literature, flufenerim, pyrimidifen, azafenidin, chlorprazophos,
pyrazophos and pirimioxyphos are having pyrimidine as core moiety which exhibits good
pesticidal properties [17, 18]. Several reports states that their antiparasitic, antimicrobial,
anticancer and antibiotic activities. Among these, fused heterocyclic compounds provide
excellent biological activities [19-21]. The incorporation of pyrimidine and imidazole motif into
the acridine ring has considered being a fair way to produce unreported active compounds. In the
earlier reports, authors described a series of unreported nitrogen ring junction compounds with
new synthetic routes [22-24]. In continuation of this, we have designed the synthesis of imidazo-
pyrimido fused acridines and screened for anti-microbial, anti-feedant activities. The molecule 7
was achieved via 3 steps. The first step involved the synthesis dihydro acridine, 3 from the
reaction of (2-amino-5-chlorophenyl) phenyl methanone 1 and cyclohexane-1,3-dione 2 in the
presence of a few drops of sulphuric acid at 150 °C for 6 h. In the second step, compound, 3 was
allowed to react with a series of aromatic aldehydes 4(a-k) to form α,β- unsaturated acridones
5(a-k) with good to excellent yields. The final steps involved the reaction between α,β-
unsaturated acridones 5(a-k) and 1H-benzo[d]imidazol-2-amine 6 in presence of potassium
hydroxide in ethanol at 80 °C for 2 h to formed the products 7(a-k). The synthesized compounds
7(a-k) were characterized by melting point, 1H NMR, 13C NMR and HRMS.
2. Experimental
2.1. Synthesis
2.1.1. Synthetic protocol for the synthesis of 7-chloro-9-phenyl-3,4-dihydroacridin-1(2H)-one 3
A mixture of (2-amino-5-chlorophenyl)(phenyl)methanone 1 (20 mmol), cyclohexane-1,3-
dione 2 (20 mmol), glacial acetic acid (20 ml) and Conc. H2SO4 (5 drops) are refluxed for 6 h
[25]. The reaction mixture was checked by TLC and after reaction mixture came to room
temperature followed by pouring into the crushed ice. The precipitate was filtered out and then it
was washed using water and dried out to give the product 3 as off -white solid. The synthesized
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compound was confirmed by the corresponding spectral analysis (Table S1). The reported
compound has been confirmed by its melting point [25], proton and carbon NMR
(Supplementary document).
2.1.2. Synthetic protocol for the synthesis of (E)-2-benzylidene-7-chloro-9-phenyl-3,4-
dihydroacridin-1(2H)-one 5(a-k)
About 1.2 mmol of potassium hydroxide was added to a stirred solution 7-chloro-9-phenyl-
3,4-dihydroacridin-1(2H-one) 3 (1 mmol)and aromatic aldehydes 4(a-k) in 10 ml of ethanol at
room temperature. After the TLC confirmation, the reaction mixture was transferred into the ice
water. The solid was filtered, rinsed with water and dried to give the product as off -white solid.
1
13
The synthesized compound 5(a-k) was confirmed by its melting point, H NMR and C NMR
summarized in Table S2. The reported compounds have been confirmed by its melting point
[26], proton and carbon NMR (Supplementary document).
2.1.3. Synthetic
protocol
for
the
synthesis
of
2-chloro-16-phenyl-6,7-
dihydrobenzo[4',5']imidazo[1',2':1,2]pyrimido [4,5-a]acridines 7(a-k)
To a round bottom flask, a mixture of (E)-2-benzylidene-7-chloro-9-phenyl-3,4-
dihydroacridin-1(2H)-one 5(a-k) (1.0 mmol), 1H-benzo[d]imidazol-2-amine 6 (1.0 mmol),
potassium hydroxide (1.2 mmol) in 10 ml of DMF were to heated to 80 °C. After the completion
of the reaction, the reaction mixture was chilled at normal temperature and poured into ice
mixture. The solid was filtered using vacuum pump and dried out the product. The crude solid
was purified by column chromatography to afford the pure product. The synthesized compounds
1
7(a-k) were confirmed by its melting point, H NMR, 13C NMR and HRMS (Supplementary
document).
2.2. Insects rearing
S. oryzae and C. maculatus were collected from Vellore market (Coordinates: 12°98ʹ23ʺN
79°13ʹ23ʺE) and maintain in Chemistry of Heterocycles & Natural Product Research Laboratory,
VIT University under laboratory conditions [27].
2.3. Insecticidal screening
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The insecticidal assay on C. maculatus and S. oryzae were screened in small plastic
containers [6.5 cm (diameter) and 4.0 cm (height)]. The containers were allowing to aeration by
making holes on the top and 20 g of rice (Oryza sativa) was engaged in each container. The
synthesised title compounds 7(a-k) were mixed to the rice at different concentrations of 50, 100,
150, 200, 250 ppm in acetone (Fig. 7). Then, the containers were shaken well for 2 min to attain
equal distribution [28]. Simultaneously, control and blank experiments have been carried out
with five replicates. After 24 h, around 20 adult of C. maculatus and S. oryzae (unsexual) were
placed into each container [29]. The bioassay experiments were run out at 30 ±1 °C under 75 ±
5% RH. After, 1st, 3rd, 5th, 7th and 14th days, the insect mortality was recorded. In the control
experiments, the mortality lies between 0 – 10 %, then the mortality was estimated using Abbots
formula [30].
Corrected % = (1- n in T after treatment/n in C after treatment) * 100
Where n = insect population, T = treated, C = control
All the live pests were removed once the experiments done and then the treated boxes were
held for 60 days beyond the experiment to find out whether any fresh C. maculatus and S. oryzae
progeny in the stored rice or not. Lethal concentrations (LC50 and LC90) were calculated using
probit analysis given by Finney method [31, 32]. LC50 value and the slope level was significantly
considered in the case of associated confidence intervals did not overlap.
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Fig. 1: Graphical representation of steps involved for insects activity a) Empty container with 6.5
cm (diameter) and 4.0 cm (height). b) Aeration of the container. C) Addition of 20 g of rice. d)
Making of different concentrations e) Addition of insects into the container.
2.4. Antibacterial assay
The antibacterial activities are evaluated in-vitro by well diffusion method. Tested bacteria
were S. aureus & B. subtilis and V. parahaemolyticus & P. mirabilis. The Chloramphenicol drug
was diluted in distilled water and kept as a stock solution is prepared which is used as a standard.
The Muller Hinton agar medium is autoclaved and poured in to the petri plates [33]. Then the
culture bacterial strains were spread over the petri plates. Then wells were made by the help of
well puncher. In each well, we have used different concentrations like 25, 50 and 75 mg/mL in
Dimethylsulfoxide as a solvent. Then the plates were incubated at 37 °C for 24 h. After
incubation the zone of inhibition is calculated. Then MIC was evaluated by serial dilution
method. Nutrient broth is prepared and poured in test tubes; the culture is poured in test tube.
The concentrations of the samples were made accordingly 10 mg/mL, 20 mg/mL, 30 mg/mL, 40
mg/mL and 50 mg/mL. Then incubated for 24 h, after that we have to check the growth of
bacteria [34].
3. Results and Discussion
3.1. Synthesis
Our synthetic pathway (Scheme 1) described the synthesis of imidazo-pyrimido fused
acridines 7(a-k) via three steps. In the first step, the intermediate 3 was synthesized using (2-
amino-5-chlorophenyl) (phenyl)methanone 1 and cyclohexane-1,3-dione 2 with a catalytic
○
amount of sulphuric acid at 150 C for 6 h. Followed by in the second step, the isolated
intermediate 3 was treated with various aromatic aldehydes 4(a-k) in presence basic condition
afford the α,β-unsaturated acridones 5(a-k). The final step described, the reaction between α, β -
unsaturated acridones 5(a-k) and 1H-benzo[d]imidazol-2-amine 6 in the presence of ethanolic
○
potassium hydroxide at 80 C for 2 h to give the 2-chloro-16-phenyl-6,7-dihydrobenzo[4',5']
imidazo[1',2':1,2]pyrimido[4,5-a]acridines with 82-95 % isolated yields. The synthesized
compounds 7(a-k) were characterized with respective spectral analysis.
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Scheme 1: Synthesis of imidazo-pyrimido fused acridines 7(a-k).
3.2. Spectral analysis
Spectral data of the synthesized compounds 3, 5(a-k) and 7(a-k) were illustrated in Table S1.
The spectroscopic numbering of the compound 2-chloro-16-phenyl-8-(p-tolyl)-6,7-dihydrobenzo
[4',5']imidazo[1',2':1,2]pyrimido[4,5-a]acridine 7b was illustrated in (Fig. 2). The compound 7b
was taken as representative compound and the signals were assigned based on the FTIR, 1D
NMR (proton & carbon) spectra and HRMS. In (Fig. 3), we have plotted the comparative FTIR
spectrum of the compounds 3, 5b and 7b. From the (Fig. 3), we are getting a sharp peak at 1683
cm-1 which is corresponds to the carbonyl group of the compound 3. Another peak at 1667 cm-1
assigned to a carbonyl group for the compound 5b. In the case of 7b, there is no peak in the
carbonyl region confirms the disappearance of the carbonyl group.
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Fig 2: Spectroscopic numbering of compound 2-chloro-16-phenyl-8-(p-tolyl)-6,7-
dihydrobenzo[4',5']imidazo[1',2':1,2]pyrimido[4,5-a]acridine 7b.
Fig 3: Comparative FTIR spectra of compounds 3, 5b and 7b.
The proton NMR and 13-carbon NMR of the compound 3 was analyzed in deuterated
chloroform. The three methylene protons were resonating in the range of δ 2.22-3.36 and
remaining eight aromatic protons resonated in the range of δ 7.15-8.00 (Fig. 4). The compound 3
was further confirmed by its 13-carbon NMR. The delta values of 21.2, 34.5, 40.6 were assigned
for three methylene carbons and a peak at 197.7 was corresponds to carbonyl carbon. The
remaining 15 aromatic carbons were resonating in the range from 124.4 to 162.5. The proton
NMR and 13-carbon NMR of the compound 5b was analyzed in deuterated chloroform.
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Fig 4: Comparative 1H NMR spectra of compounds 3, 5b and 7b.
The methyl protons were resonating as a singlet at δ 2.38 and two methylene protons were
resonating as multiplet in the range from δ 3.23-3.32. The peak at δ 7.74 was assigned for alkene
proton. The remaining 12 aromatic protons were obtained in the range from δ 7.21-8.03. The
compound 5b was confirmed by 13-carbon NMR. The peak at δ 21.4 is corresponds to methyl
carbon and two methylene carbons were assigned at δ 25.8 and δ 33.5. The peak at δ 187.3 was
assigned for carbonyl carbon. The remaining aromatic carbons were resonating in the range of δ
125.6-161.3.
The 1H-NMR and 13C-NMR of the compound 7b was analyzed in deuterated chloroform. In
proton NMR analysis, the methyl proton H-13 was resonate as a singlet at δ 2.57 and two
methylene protons H-6 & H-5 were obtained as triplets at δ 2.88 and δ 3.28 respectively. The
remaining 16 aromatic protons were resonating in the range of δ 6.26-8.02. Further, we have
recorded the 13 carbon NMR of the compound 7b. The methyl carbon C-13 was resonating at δ
21.6. The peaks at 23.7 and 33.9 were assigned for C-6 and C-5 respectively. All other aromatic
carbons were obtained at δ 114.2-157.3. The DEPT-135 NMR reveals that the types of carbon
present in the compound 7b. The methyl carbon C-13 was came as upward signal and two
methylene carbons resonate as two negative signals (Fig. 5). The all aromatic methine carbons
were came as upward signals and we are not getting any signals for quaternary carbons. The
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molecular mass of the compound 7b was supported by HRMS analysis. The theoretical mass is
522.1611 and obtained mass was 522.1610 (Fig. 6).
Fig 5: Comparative 13C NMR and DEPT-135 spectrum of compound 7b.
Fig 6: HRMS spectrum of compound 7b.
3.3. Antibacterial assay
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The antibacterial study of all the title compounds 7(a-k) were assessed in-vitro by well
diffusion method. All the synthesized acridine fused compounds 7(a-k) were injected to
antibacterial activity on S. aureus, B. subtilis, and V. parahaemolyticus, P. mirabilis using
Chlormphenicol as a standard. The compounds 7(a-k) were dissolved in DMSO at concentration
of 0.5 mg/mL. The solvent, DMSO did not show any inhibitory effect on the growth of the test
organism. Table S2 shows the result of the in-vitro activity determination by the disc diffusion
method. Most of the compounds 7(a-k) displays a remarkable zone of inhibitions compared with
the Chloramphenicol. Among these, the compounds 7e and 7h shows better zone of inhibitions.
The MIC values of the compounds were determined by the two-fold serial dilution technique for
the antibacterial Mueller- Hinton broth [33, 34]. The compounds 7e and 7h showed a bigger
inhibition zone which are picked to determine their MIC values. Both compounds 7e and 7h
were found no active against S. aureus, B. subtilis and P. mirabilis compared with ciprofloxacin.
The tested compounds showed slight inhibition against V. parahaemolyticus in Table 1.
Table 1
In-vitro antibacterial activity of the synthesized compounds 7e &7h [MIC; μg/mL]
Entry
7e
S.
aureus
95.5
B.
subtilis
55.5
V. parahaemolyticus
P. mirabilis
10.0
110.5
7h
73.5
3.21
32.5
1.71
8.5
85.5
2.12
Chlorm
3.01
phenicol
3.4. Anti-feedant assay
The synthesized target molecules 7(a-k) were screened for their insecticidal activity by anti-
feedant method as per standard procedure recommended by the World Health Organization
(WHO) [32]. All the synthesized compounds 7(a-k) have substantial anti-feedant activity against
adult insects like S. oryzae and C. maculatus at the concentration of 200 and 250 ppm. Among
the series of 7(a-k) compounds 7e and 7h attained 100 % mortality at 250 ppm after 7th day of
the experiments against S. oryzae (Fig. 7a). In the case of C. maculatus, the compounds 7e
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showed 100 % mortality at 250 ppm after 14th day experiments (Fig. 7b). But the compound 7h
attained 100 % mortality at 250 ppm in after a week. The LC50 and LC90 value of the
compounds 7e and 7h exhibits 128.34, 229.07, 105.51 and 214.01 respectively against S. oryzae.
Where it exhibits 72.36, 192.73, 124.55 and 232.82 against C. maculatus summarized in Table 4.
a
b
Fig 7: 100 % mortality a) 7th day against S. oryzae b) 14th day against C. maculatus
4. Conclusion
A series of unreported imidazo-pyrimido fused acridines 7(a-k) were synthesized. The
synthesized compounds 7(a-k) were tested against S. oryzae and C. maculatus. The results
obtained in the present study states that the compound 7e and 7h were identified as the most
promising candidates for future examinations. These results will encourage us to do further
research in new insecticidal agents.
Acknowledgments
Dr. S. M. Roopan thank to DST-SERB (No.SB/FT/CS-126/ 2012), Government of India,
New Delhi for providing the research grant. One of the author Palaniraja wishes to express their
gratitude to DST for providing Research Assistant Position. Further, we thank to VIT
management for providing a research facility, and thanks to VIT-SIF, DST-FIST for providing
NMR facilities to carry out this work. Prabhakarn Arunachalam thanks to support by the
Deanship of Scientific Research, College of Science Research Centre, King Saud University,
Saudi Arabia
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Forsch. Drug Res. 49 (1999) 853-857. B) S.M. Roopan, V.R. Hathwar, F.N. Khan, A.K.
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Graphical abstract
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Highlights
 A series of imidazo-pyrimido fused acridines were synthesized
 Conventional spectroscopic technique has been adopted to confirm the molecules
 In vitro antibacterial testing were carried out
 Insecticidal screenings was evaluated for the synthesized molecules
 S.oryzae and C. maculatus was used in this work.
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