Lanthanum triflate-triggered synthesis of tetrahydroquinazolinone derivatives of N-allylquinolone and their biological assessment

Article abstract of DOI:10.2298/JSC120121039J

A series of 24 derivatives of tetrahydroquinazolinone has been synthesized by the one-pot cyclocondensation reaction of N-allyl quinolones, cyclic β-diketones and (thio)urea/N-phenylthiourea in the presence of lanthanum triflate catalyst. This methodology allowed the products to be achieved in excellent yield by stirring at room temperature. All the synthesized compounds were investigated against a representative panel of pathogenic strains using the broth microdilution MIC (minimum inhibitory concentration) method for their in vitro antimicrobial activity. Amongst these sets of heterocyclic compounds 5h, 6b, 6h, 5f, 5l, 5n and 6g were found to have admirable activity. Copyright

Full text of DOI:10.2298/JSC120121039J

J. Serb. Chem. Soc. 77 (11) 1561–1570 (2012)
JSCS–4371
UDC 546.654+547.831.7:542.913+
544.478:615.28
Original scientific paper
Lanthanum triflate-triggered synthesis of
tetrahydroquinazolinone derivatives of N-allylquinolone
and their biological assessment
*
HARDIK H. JARDOSH and MANISH P. PATEL
Department of Chemistry, Sardar Patel University, Vallabh
Vidyanagar-388120, Gujarat, India
(Received 21 January, revised 27 March 2012)
Abstract: A series of 24 derivatives of tetrahydroquinazolinone has been syn-
thesized by the one-pot cyclocondensation reaction of N-allyl quinolones,
cyclic β-diketones and (thio)urea/N-phenylthiourea in the presence of lan-
thanum triflate catalyst. This methodology allowed the products to be achieved
in excellent yield by stirring at room temperature. All the synthesized com-
pounds were investigated against a representative panel of pathogenic strains
using the broth microdilution MIC (minimum inhibitory concentration) method
for their in vitro antimicrobial activity. Amongst these sets of heterocyclic
compounds 5h, 6b, 6h, 5f, 5l, 5n and 6g were found to have admirable activity.
Keywords: quinolone; Biginelli reaction; one-pot synthesis; catalyst; antimic-
robial activity.
INTRODUCTION
Quinazolinones possess diverse pharmacological and biological activities as-
1
sociated with the pyrimidine core, such as hypotensive, analgesic and anti-in-
2
3
4
flammatory, calcium antagonist and central nervous system (CNS) depressant.
Furthermore, quinazolinones were found to exhibit antimicrobial activity against
5
Staphylococcus aureus, Escherichia coli and Candida albicans. Therefore, the
synthesis of quinazolinone derivatives still attract much attention of modern-day
medicinal chemistry research. On other hand, quinolones have maintained their
pharmacological importance since their discovery based on nalidixic acid in the
6
7
early 1960s. Quinolones possess various biological activities, such as anti-HIV,
8
9
10
antitumor, anti-anaerobe and antimicrobial. It is well established that hydro-
phobicity is one of the factors that directly correlates to antimicrobial activity and
11,12
intensifies the potency of a molecule.
In view of this, an allyl group was in-
*Corresponding author. E-mail: patelmanish1069@yahoo.com
doi: 10.2298/JSC120121039J
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JARDOSH and PATEL
serted at the N of quinolone ring to increase the hydrophobicity of the com-
pounds. Thus, based on the above reports, an attempt was undertaken to syn-
thesize N-allylquinolone-incorporated quinazolinone derivatives based on the
premise that allylic compounds have an additive effect to antimicrobial potency
and the amalgamation of two bioactive moieties into a single scaffold may pro-
duce novel heterocycles with appealing antimicrobial activities.
Tetrahydroquinazolinone derivatives have been synthesized under Biginelli
reaction conditions (protic acid) but these methods suffer from low to moderate
13
yields, lengthy reaction time and harsh reaction conditions. It was found that
not only protic, but also Lewis acids could be used as a catalyst for the synthesis
14
of tetrahydroquinazolinone derivatives. More recently, a number of reports ex-
pressing the utility of triflates as a Lewis acid catalyst in Biginelli protocols to
give excellent yields, shorter reaction time and mild reaction conditions were
15
published.
From the aforementioned facts and as a part of ongoing studies in the deve-
lopment of new antimicrobial agents containing various heterocyclic systems
16
having a quinoline nucleus, N-allylquinolone-incorporated tetrahydroquinazo-
linone derivatives 5a–p and 6a–h were prepared via a multiple component con-
densation (MCC) approach using lanthanum triflate (La(OTf) ) as the catalyst
3
and the results are reported herein. The constitution of all the products was cha-
1
13
racterized using elemental analysis, and FT-IR, H-NMR, C-NMR and mass
spectrometry. The synthesized compounds were subjected to an in vitro antimic-
robial study against a representative panel of seven human pathogens using the
17
broth microdilution minimum inhibitory concentration (MIC) method.
RESULTS AND DISCUSSION
Chemistry
In this protocol, 1-allyl-2-oxo-1,2-dihydroquinoline-3-carbaldehydes 1a–d
were selected as model compounds for the one-pot syntheses to give heterocyclic
systems with a quinazolinone core. The key intermediates 1a–d were prepared by
electrophile-favored N-alkylation of 2-oxo-1,2-dihydroquinoline-3-carbaldehydes
18
in presence of K CO in DMF at room temperature.
2
3
All the 4-(1-allyl-2-oxo-1,2-dihydroquinolin-3-yl)-4,6,7,8-tetrahydroquina-
zoline-2,5(1H,3H)-dione derivatives 5a–p and 6a–h were obtained by La(OTf)
3
19–21
catalyzed reaction
of various 1-allyl-2-oxo-1,2-dihydroquinoline-3-carbal-
dehydes 1a–d, cyclohexane-1,3-dione or dimedones 2a–b and (thio)ureas 3a–b
or N-phenylthiourea 4 in ethanol at room temperature (Scheme 1). The reaction
was examined by taking different mol ratios of catalyst, i.e., 2.5, 5, 7.5, 10 and
12.5 mol %. It was observed that when the amount of La(OTf) was increased to
3
10 mol %, the reaction rate accelerated within 1.5–2 h for 5a–p and 3–3.5 h for
6a–h with high conversion, but the further increase in the amount of La(OTf)
3
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TETRAHYDROQUINAZOLINONES OF N-ALLYL QUINOLONE AS ANTIMICROBIALS
1563
had no significant outcome on the reaction. The products were obtained in ex-
cellent yield at room temperature in ethanol only by use of 10 mol % catalyst;
thus, these conditions were considered as the most optimized conditions for the
synthesis of the title quinazolinone derivatives 5a–p and 6a–h.
Scheme 1. Synthetic pathway to compounds 1a–d, 5a–p and 6a–h.
The formation of compounds 5a–p and 6a–h may proceed via two steps
(Scheme 2): i) the formation of arylidene(thio)urea Int-1 and ii) interception of
the acyliminium ion intermediate by an activated cyclic β-diketone to produce an
open chain urea Int-2, which subsequently undergoes cyclization and dehydra-
tion via Int-3 to afford the corresponding quinazolinone. The formation of an
20
acyliminium ion was reported to be the rate-determining step. La(OTf) is
3
thought to accelerate the formation of the arylidene(thio)urea Int-1 and activate
the cyclic β-diketone 2a–b by forming its metal enolate, thus facilitating the
21
addition reaction with a coordinated acyliminium ion.
The identities of all the synthesized compounds 5a–p and 6a–h were deter-
1
13
mined from H-NMR, C-NMR and FT-IR spectral data and elemental analysis.
1
As an example, H-NMR (DMSO-d ) spectrum of 5a, exhibited singlet peaks at
6
δ 9.52 and 7.80 ppm for the (–NH–) protons of the quinazolinone ring. A doublet
was observed at around δ 4.90–5.05 ppm for (N–CH –CH=CH ). Another doub-
2
2
let appeared at δ 5.18 ppm for (N–CH –CH). Multiplets were observed at δ 5.94
2
and around 7.08–7.60 ppm for (CH=CH ) and aromatic protons, respectively.
2
The methine proton at C of quinazolinone appeared at δ 5.36 ppm as a singlet. A
4
13
multiplet appeared at around δ 1.97–2.54 ppm for 3CH . The C-NMR spec-
2
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JARDOSH and PATEL
13
trum is in agreement with the assigned structure. Thus, in the C-NMR spectrum
of compound 5a, the signals around δ 105.51–152.04 ppm are attributed to aro-
matic carbons and the allylic C=C. The signals at around δ 21.28–36.80 ppm and
at δ 49.39 ppm arise from aliphatic carbons and the allylic methylene carbon,
respectively. In addition, the signal observed at δ 49.31 ppm is due to C of
4
quinazolinone. The signals due to carbonyl carbons appeared at δ 156.69, 160.72
and 193.67. The IR spectrum of 5a exhibited absorption bands at 3435 and 3352
–1
–1
cm for N–H str. and at 1711, 1639, and 1593 cm for C=O str. The structure
of compound 5a was also confirmed by mass spectral studies. It gave a molecular
+
ion peak at m/z 350.2 [M+1] , corresponding to the molecular formula C H N O .
20 19
3 3
The obtained elemental analysis data are in consonance with the theoretical values.
Scheme 2. Believable mechanistic pathway for the formation of compounds 5a–p and 6a–h
by La(OTf)3 catalysis.
The analytical and spectroscopic characterization data of 5a–p and 6a–h are
given in the Supplementary material to this paper.
Antimicrobial evaluation
The antibacterial screening data (Table I) revealed that compound 5h (MIC =
–1
= 20 µg mL ) had extraordinary antibacterial activity against Pseudomonas
aeruginosa when compared with chloramphenicol and ciprofloxacin. Against Es-
–1
cherichia coli, compounds 6b and 6h (MIC = 50 µg mL ) were found to have
outstanding antibacterial activity when compared with ampicillin and were equi-
–1
potent to chloramphenicol, while compounds 5l and 5n (MIC = 62.5 µg mL )
were found to have better activity than ampicillin. Against Staphylococcus au-
–1
reus, compounds 5f and 6g (MIC = 62.5 µg mL ) were found to have excellent
–1
activity; compounds 5e and 5p (MIC = 100 µg mL ), as well as 5d, 5g and 6e
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TETRAHYDROQUINAZOLINONES OF N-ALLYL QUINOLONE AS ANTIMICROBIALS
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–1
(MIC = 125 µg mL ) showed remarkable results, while compounds 5i, 5k, 5m
–1
and 6h (MIC = 200 µg mL ) exhibited good activity; compounds 5a, 5c, 5h, 5j
–1
and 6f (MIC = 250 µg mL ) were found to be equally potent to ampicillin.
Against Streptococcus pyogenes, compounds 5e, 5g, 5m, 5p and 6e (MIC = 100
–1
µg mL ) were found to have comparable activity to that of ampicillin. Against
–1
E. coli, compounds 5j, 5k, 5m and 6f (MIC = 100 µg mL ) were equipotent to
ampicillin.
TABLE I. Antimicrobial activity (MIC / μg mL-1) of compounds 5a–p and 6a–h
Gram-positive
bacteria
Gram-negative
bacteria
Fungi
S.
S.
E.
P.
C.
A.
A.
Compounds
aureus pyogenes coli aeruginosa albicans niger clavatus
MTCC MTCC MTCC MTCC MTCC MTCC MTCC
96
5a (R1=H, R2=R3=H, X=O) 250
442
250
500
443
125
200
1688
200
250
227
500
1000
282
1000 1000
500 500
1323
5b (R1=H, R2=R3=CH3,
500
X=O)
5c (R1=H, R2=R3=H, X=S) 250
500
200
250
200
250
200
1000 >1000 >1000
>1000 >1000 >1000
5d (R1=H, R2=R3=CH3,
X=S)
5e (R1=CH3, R2=R3=H,
X=O)
5f (R1=CH3, R2=R3=CH3,
X=O)
5g (R1=CH3, R2=R3=H,
X=S)
5h (R1=CH3, R2=R3=CH3,
X=S)
5i (R1=OCH3, R2=R3=H,
X=O)
125
100
62.5
125
250
200
100
125
100
250
250
250
200
500
100
200
125
500
250
250
125
100
100
62.5
100
62.5
125
250
250
20
500
500
250
500
1000 1000
250
500
1000
500
1000
500
250
200
125
200
100
200
125
1000
500
5j (R1=OCH3, R2=R3=CH3, 250
X=O)
>1000 >1000 >1000
>1000 >1000 >1000
5k (R1=OCH3, R2=R3=H,
200
X=S)
5l (R1=OCH3, R2=R3=CH3, 500
X=S)
500
250
500
5m (R1=Cl, R2=R3=H,
X=O)
5n (R1=Cl, R2=R3=CH3,
X=O)
200
500
1000 >1000 >1000
>1000 >1000 >1000
>1000 >1000 >1000
5o (R1=Cl, R2=R3=H, X=S) 500
250
100
250
200
250
200
5p (R1=Cl, R2=R3=CH3,
X=S)
100
500
250
500
6a (R1=H, R2=R3=H)
6b (R1=H, R2=R3=CH3)
6c (R1=CH3, R2=R3=H)
500
500
500
250
500
500
125
50
200
100
125
250
1000 >1000 >1000
200
500
500
1000 1000
500
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TABLE I. Continued
Gram-positive
bacteria
S. S.
Gram-negative
bacteria
Fungi
E.
P.
C.
A.
A.
Compounds
aureus pyogenes coli aeruginosa albicans niger clavatus
MTCC MTCC MTCC MTCC MTCC MTCC MTCC
96
6d (R1=CH3, R2=R3=CH3) 500
6e (R1=OCH3, R2=R3=H) 125
6f (R1=OCH3, R2=R3=CH3) 250
442
500
100
200
200
250
100
50
443
200
250
100
500
50
100
50
25
1688
250
250
100
250
100
–
227
1000
1000
500
500
250
–
282
500
500
1323
500
500
1000 1000
6g (R1=Cl, R2=R3=H)
6h (R1=Cl, R2=R3=CH3)
Ampicillin
Chloramphenicol
Ciprofloxacin
62.5
200
250
50
500
100
–
–
–
100
250
–
–
–
50
25
–
–
50
50
Nystatin
Griseofulvin
–
–
–
–
–
–
–
–
100
500
100
100
100
100
The antifungal screening data (Table I) revealed that compounds 6b (MIC =
–1
–1
= 200 µg mL ), 5g, 5h and 6h (MIC = 100 µg mL ) were found to have ex-
cellent activity against Candida albicans, while compounds 5a, 5e, 5f, 5l, 5p, 6c,
–1
6f and 6g (MIC = 500 µg mL ) had comparable activity to that of griseofulvin.
Compounds 6h and 6g (MIC = 100 µg mL ) were found to be equally potent
–1
against Aspergillus niger and A. clavatus, respectively.
The newly synthesized compounds 5a–p and 6a–h exerted significant inhi-
bitory activity against the growth of the tested bacterial and fungal strains. The
data also revealed that insertion of an allyl chain at the N of the quinolone moiety
and derivatization at positions R , R , R , X and N-1 of tetrahydroquinazolinone
1
2
3
produced marked changes in the potency of the synthesized analogues as anti-
microbial agents and demonstrated the following assumptions about the struc-
ture–activity relationship (SAR):
Compounds having a –CH substituent at the R and R positions have
3
2
3
intensified antibacterial effectiveness against Gram negative bacteria, e.g., 5h, 5l,
5n, 6b and 6h, but not 5f. Moreover, an S-atom at the C position and a phenyl
2
group at N-1 of tetrahydroquinazolinone may play a significant role in enhancing
antifungal activity, e.g., 5h, 5l, 6b, 6h and 6g. However, only phenyl substituted
compounds displayed similar inhibitory action against the Aspergillus family
when compared with standard drugs. Compounds with electron withdrawing
group –Cl at R of the N-allylquinolone ring may have improved activity against
1
E. coli, S. aureus and all fungal species, e.g., 5m, 5n, 6g and 6h. On the other
hand, the electron donating –OCH group may increase the activity against E.
3
coli and S. aureus, e.g., 5j, 5k, 5l and 6f. A lipophilic –CH group at the R posi-
3
1
tion may intensify the potency against P. aeruginosa, S. aureus and C. albicans.
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TETRAHYDROQUINAZOLINONES OF N-ALLYL QUINOLONE AS ANTIMICROBIALS
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Furthermore, the allyl chain makes the compounds more hydrophobic and may
enhance the antimicrobial potency of the title compounds. The study revealed that
changes in substitutions have a vast impact on the antimicrobial effectiveness.
16b
Upon comparison with a previous report,
it could be stated that i) in-
sertion of an allyl group at N of the quinolone ring increases the antimicrobial
properties of the title compounds; ii) both electron withdrawing and donating
constituents at the R position contribute to enhancement of the antimicrobial
1
effectiveness; iii) a phenyl group at N-1 of the tetrahydroquinazolinone ring in-
fluences the microbial inhibitory action and iv) the lipophilic –CH group at the
3
R position has an additive effect on the inhibition of microbial pathogens.
1
EXPERIMENTAL
Materials, instruments and methods
All the reagents were commercially available and used without further purification. Sol-
vents of analytical grade were used. Melting points were determined by the open tube ca-
pillary method (using silicon oil 350 cSt) and are uncorrected. Thin-layer chromatography
60
(TLC, on aluminum plates pre-coated with silica gel,
F
, 0.25mm thickness) (Merck,
254
Darmstadt, Germany) was used for monitoring the progress of all reactions, as well as the
purity and homogeneity of the synthesized compounds; eluent n-hexane:ethyl acetate 1:1. UV
radiation and/or iodine were used as the visualizing agents. Elemental analysis (% C, H, N)
was realized using a Perkin-Elmer 2400 series-II elemental analyzer (Perkin-Elmer, USA) and
the results for all compounds were within ±0.4 % of the theoretical value. The IR spectra were
recorded in KBr on a Perkin-Elmer Spectrum GX FT-IR Spectrophotometer (Perkin-Elmer,
1
USA) and only the characteristic peaks are reported in cm-1. H-NMR and 13C-NMR spectra
were recorded in DMSO-d6 on a Bruker Avance 400F (MHz) spectrometer (Bruker Scientific
Corporation Ltd., Switzerland) at 400 and 100 MHz, respectively, using the solvent peak as an
internal standard. Chemical shifts are reported in parts per million (ppm). Mass spectra were
scanned on a Shimadzu LCMS 2010 spectrometer (Shimadzu, Tokyo, Japan).
General procedure for the synthesis of 4-(1-allyl-2-oxo-1,2-dihydroquinolin-3-yl)-4,6,7,8-tetra-
hydroquinazolin-2,5(1H,3H)-diones 5a–p and 6a–h
A 100 mL round bottomed flask, was charged with a mixture of 1-allyl-6-(un)substi-
tuted-2-oxo-1,2-dihydroquinoline-3-carbaldehydes 1a–d (3 mmol), cyclohexane-1,3-dione or
dimedone 2a–b (3 mmol) and (thio)urea 3a–b/N-phenylthiourea 4 (3 mmol) in ethanol (15
mL) containing La(OTf)3 (10 mol %). The mixture was allowed to stir at rt for 1.5–3.5 hr and
the progress of the reaction was monitored by TLC. After the completion of reaction (as evi-
denced by TLC), the solid mass separated was collected by filtration, washed well with etha-
nol (15 mL) and purified by leaching in equal volume ratio of chloroform and methanol (20
mL) to obtain pure solid sample.
Methodology for screening the antimicrobial activity
All the glass apparatus were sterilized before use. The antimicrobial activity of all the
synthesized compounds was screened by the broth microdilution method.17 Mueller–Hinton
broth was used as the nutrient medium to grow and dilute the compound suspension for the
test bacteria and Sabouraud dextrose broth was used for fungal nutrition. Inoculum size for
test strain was adjusted to 108 CFU ml-1 (colony forming unit per milliliter) by comparing the
turbidity (turbidimetric method). The strains used for the activity were obtained from Mic-
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robial Type Culture Collection (MTCC) of the Institute of Microbial Technology, Chandigarh,
India. Each synthesized compound was diluted to a concentration of 2000 µg mL-1, as a stock
solution. DMSO was used as the vehicle to obtain the desired concentrations of the com-
pounds to test upon microbial strains. The results were recorded in the form of primary and
secondary screenings. The compounds 5a–p and 6a–h were screened for their antibacterial
activity against the Gram-positive bacteria: S. aureus (MTCC 96) and S pyogenes (MTCC
442), and Gram-negative bacteria: E. coli (MTCC 443) and P. aeruginosa (MTCC 1688), and
antifungal activity against the fungi: C. albicans (MTCC 227), A. niger (MTCC 282) and A.
clavatus (MTCC 1323) at concentrations of 1000, 500, and 250 µg mL-1 as primary screening.
Compounds that were found to be active in the primary screening were further screened in a
second set of dilution at concentrations of 200, 100, 62.5, 50, 25, 12.5, and 6.25 µg mL-1. Ten
microliters suspension from each well was further inoculated and growth of the bacteria and
fungi was noted after 24 and 48 h, respectively. The lowest concentration which resulted in no
visible growth (turbidity) after spot subculture was considered as the MIC for each compound.
The standard drugs used for comparison in this study were ampicillin, chloramphenicol and
ciprofloxacin for evaluating the antibacterial activity and griseofulvin and nystatin for the
antifungal activity.
CONCLUSIONS
In present protocol, the synthesis and antimicrobial evaluation of 24 new
derivatives 5a–p and 6a–h of tetrahydroquinazolinone possessing an N-allylqui-
nolone nucleus at C of quinazolinone were presented. La(OTf) as catalyst al-
4
3
lowed the smooth synthesis of the title derivatives at room temperature in ex-
cellent yield. It could be concluded from the antimicrobial screening data that
many of the compounds were more or equipotent against a panel of human pa-
thogens when compared with the standard drugs. It is noteworthy that derivati-
zation of the title compounds alter their antimicrobial activity. Further synthetic
work to intensify the potency of these derivatives by changing their molecular
configuration is in progress. The present study highlights the identification of this
new structural class of compounds as antimicrobials, which could be of interest
for further detailed pre-clinical investigations.
SUPPLEMENTARY MATERIAL
Analytical and spectroscopic characterization data of the compounds 5a–p and 6a–h are
available electronically from http://www.shd.org.rs/JSCS/, or from the corresponding author
on request.
Acknowledgements. The authors are thankful to the Head of the Department of Che-
1
mistry, Sardar Patel University, for providing the H-NMR and 13C-NMR data and research
facilities. We are also thankful to SICART, Vallabh Vidyanagar, for the FT-IR and elemental
analysis, Oxygen Health Care Pvt. Ltd., Ahmedabad for the mass spectra and Dhanji P.
Rajani, Microcare Laboratory, Surat, for the antimicrobial screening of the compounds
reported herein.
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TETRAHYDROQUINAZOLINONES OF N-ALLYL QUINOLONE AS ANTIMICROBIALS
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И З В О Д
СИНТЕЗА ТЕТРАХИДРОХИНАЗОЛИНОНСКИХ ДЕРИВАТА N-AЛИЛХИНОЛОНА
ПОМОЋУ ЛАНТАН-ТРИФЛАТА И ОДРЕЂИВАЊЕ ЊИХОВЕ БИОЛОШКЕ АКТИВНОСТИ
HARDIK H. JARDOSH и MANISH P. PATEL
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar-388120, Gujarat, India
Синтетисана је серија од 24 деривата тетрахидрохиназолинона циклокондензацио-
ном реакцијом N-aлилхинолона, цикличног β-дикетона и (тио)урее/N-фенилтиоурее у
присуству лантан-трифлата као катализатора. Примењена методологија омогућава
добијање производа у високом приносу. Сви добијени производи тестирани су према
репрезентативном панелу патогена, а in vitro антимикробне активности одређене су
применом метода микроразблаживања и изражене као MIC (минимална инхибиторна
концентрација). Утврђено је да седам деривата, 5h, 6b, 6h, 5f, 5l, 5n и 6g, има запажене
активности.
(Примљен 21. јануара, ревидиран 27. марта 2012)
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