Kenawy et al., 2018, AJMS 1(2): 5-11 DOI:10.5455/ajms.

Arabian Journal of Medical Sciences

http://www.ajms.tk

Synthesis of antimicrobial polymers with some selected quinazolinone

derivatives
EL-Refaie Kenawy a*, Abd EL-Basset Shokr a, Nayera A.M. Abdel-Wahed b and Tarek M. Zieda
a
Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt
b
Chemistry of Natural and Microbial Products Department, Pharmaceutical Industries Division, National Research
Centre, 33 El Buhouth St, Dokki, Giza, Egypt
Article Info Abstract
Antimicrobial polymers of quinazolinone core represent a class of biocides that has
Keywords:
Antimicrobial polymers; gained increasingly importance as an effective antimicrobial agents. Herein, we pre-
2-hydroxyethyl methacrylate; pared some quinazolinone derivatives followed by their immobilization onto some mon-
quinazolinone derivatives omers. The obtained monomers were then homopolymerized or copolymerized with dif-
Received Sep 6, ferent monomers to produce new polymeric products. The produced copolymers based
Revised Sep 27, on methyl methacrylate monomers had highly enhanced antibacterial activities as com-
Published Sep 30, 2018 pared to their parent compounds. These results proved the efficacy of contribution
of polymeric entities in improving the antimicrobial activities of certain derivatives.
*Corresponding author:
ekenawy@yahoo.com

1. Introduction
The heterocyclic compounds occupy nearly the first place
among the other categories of natural mixes regarding to the variety
of their biological activities. The quinazolinone skeleton is frequent-
ly encountered heterocycle in medicinal chemistry. It displayed a
broad range of biological properties such as antihypertensive, where
different quinazolinone analogous having antihypertensive activity
and are available in the market (eg. prazosin, terazosin, doxazosin,
bunazosin, tiodazosin, trimazosin and alfuzosin) (Patel et al., 2013),
CNS depressant (Jatav et al., 2008), analgesic and anti-inflammatory
(Alagarsamy et al., 2007), antibacterial and antifungal (Alagarsamy
et al., 2006; Somers et al., 2001; Sukriti Srivastava et al., 2015),
antiviral and anticancer activities (Jessy et al., 2007).
Nowadays microbial infections have been gotten great concern
because they are among the main reasons of death worldwide (Lin et
al., 2014; Ross et al., 2013; Valenti et al., 2000). The growing global
concern of emerging infectious diseases has greatly stimulated re-
search activity for polymeric biocides, especially in the biomedical
field and healthcare-related areas (Kenawy et al., 2002) and numer-
ous antimicrobial drugs have been developed to kill or inhibit mi-
crobes (Ventola and Siedenbiedel, 2015). However, many infectious
diseases remain difficult to be treated (Chan et al., 2014; Sun et al.,
2015).
The antimicrobial polymers were discovered since 1965 (Sie-
denbiedel et al., 2012) and have attracted considerable attention in
both academic and industrial research. Antimicrobial polymers rep-
resent a very promising class of therapeutics with unique characteris-
tics for fighting microbial infections; as the classic antibiotics exhibit
an increasingly low capacity to effectively act on microorganisms
and the uncontrolled use of antibiotics may led to the appearance of
multidrug-resistant microbes (Gonzales, 2010; Lode, 2009; Xue et
al., 2015). As compared to the classic antibiotics, the antimicrobial
5
polymers have low molecular weight, long-term activity, limited re-
sidual toxicity, chemical stability, non-volatility and non- permeable
through the skin (Bowersock et al., 1994; Jain et al., 2014; Kenawy
et al., 2007; Xue, 2015).
The overall objective of this study was to prepare some
quinazolinone derivatives followed by their immobilization onto
some monomers, which then homo-polymerized or copolymerized
with different monomers, and to evaluate their antimicrobial activ-
ities.
2. Experimental
2.1. Materials
2-Hydroxyethyl methacrylate [HEMA], Methacryloyl chloride
were acquired from Sigma-Aldrich (St. Louis, MO) and were pu-
rified by distillation, Triethylamine (Et3N). Dimethyl formamide
(DMF) and dichloromethane (DCM) were distilled prior to use.
Benzoyl peroxide was obtained from Acros (Geel, Belgium) and
was utilized without facilitate refinement.MeOH, ethanol (EtOH),
petroleum ether (PE) were bought as spectroscopic grade materials
and were used without further purification.
2.2. Characterization
Melting points (uncorrected) were recorded on an Electro ther-
mal melting apparatus. IR spectra were recorded on a Perkin-El-
mer spectrometer, at Faculty of Science, Tanta University. 1HNMR
were recorded in DMSO-d6 on a Bruker 400 MHz instrument using
TMS as internal standard (chemical shifts in δ ppm), at Faculty of
Science, Kafrelshiekh University. TGA analysis was recorded on
Shimadzu 50, at Faculty of Science, Kafrelshiekh University. Mi-
croanalytical data (C, H, N) were performed on Perkin Elmer 240 B
analyzer, at the Center of Microanalysis, Faculty of Science, Cairo
University. Solvent evaporation was performed under reduced pres-
 Kenawy et al., 2018, AJMS 1(2): 5-11 DOI:10.5455/ajms.8
sure using Buchi Rotatory Evaporator unless otherwise stated. T.L.C.
was performed on silica gel plates (60-F254, 0.2 mm), manufactured by
E.M. Sciences, Inc, and shortwave UV (254) nm was used to detect the
UV absorbing compounds (CHCl3, acetone 5:2).
2.3. Synthesis of 3-(4-aryl)-2-thioxo-4(3H)quinazolinones 1
,2
Anthranilic acid (0.01 mole) and potassium hydroxide (0.012
mole), and carbon di sulphide (0.03 mole) and p-chloroaniline (1.53
g, 0.012 mole) or p-methoxyaniline (1.476 g ,0.012 mole) were
added as intervals during the refluxing time. On cooling, the solid prod-
uct was filtered, washed with methanol and was dissolved in potassium
hydroxide solution (10 ml, 10%), filtered, then conc. HCl was added
to the filtrate. The obtained solid was filtered, washed with water and
crystallised from n-Butanol (Abdel-Megeed et al.,1995 and El-Hiti et
al., 2002).
3-(4-chlorophenyl)-2-thioxo-4(3H)quinazolinone 1
White powder, yield 88%, m p 310 – 315, IR(KBr disc): 1683 (C
= O), 1194 (C-O), 1616 (C = N), 1525 (C = C), 3025 (C - H) aromatic,
812 (C-H ) aromatic for p-di substituted phenyl ring, 1261 (C = S),
2620 (SH), 676 (C – Cl) , 3266 (-NH). 1HNMR [d6-DMSO : δ , 13.0 (
S,1H, NH), 7.94 -7.33 ppm (complex spectra, 8H, aromatic rings pro-
tons). C13 NMR [d6-DMSO]:175.93, 159.81, 139.63, 138.28, 135.68,
132.77, 131.105, 129.05, 127.45, 124.45, 116.24, 115.77.
3-(4-bromophenyl)-2-thioxo-4(3H)quinazolinone 2
Yellowish-white powder, yield 75%, m p 285-287, IR (KBr disc):
1683 (C = O), 1194 (C - O), 1616 (C = N), 1525 (C = C), 3025 (C - H)
aromatic, 812 (C - H) aromatic for p-di substituted phenyl ring, 1261 (C
= S), 2620 (SH), 676 (C – Cl), 3266 (-NH).
2.4. Synthesis of 3-amino- 2-phenyl-quinazolin-4(3H) one
and its 6,8-dibromo derivatives 3, 4
A weight of 2.38 g, 0.01 mole 2-phenyl-3,1-benzoxazin-4(3H)-one
or 6,8-dibromo -2-phenyl-3,1-benzoxazin-4(3H)-one (3.79 g , 0.01
mole) was dissolved in ethanol, an equimolar amount of hydrazine
hydrate (0. 384 ml , 0.12 mole ) mole was added and the mixture was
refluxed for 2-3 h, and then the solid product was cooled , filtered,
washed with ethanol, dried and recrystallized from methanol (Manju-
natha et al., 2007).
2.5. Synthesis of S-3-(4-aryl)-3,4-dihydro-4-oxoquinazolin-
2-yl-2-methylprop-2-enethioates 5,6
A solution of 3-(4-chloro phenyl)-2-thioxo-4(3H) quinazolinone 1
(2.8 g, 10 mmol) or 3-(4-bromo phenyl)-2-thioxo-4(3H) quinazolinone
2 (3.32 g, 10 mmol) and triethylamine (29.2 mL, 210 mmol) in dichlo-
roethane (20 mL) was prepared and cooled to 0oC with continuous stir-
ring in ice bath, then methacryloyl chloride (0.86 mL, 15 mmol) was
added drop wise via dropping funnel with a continuous stirring at 00C
within 2 h. Upon completion, the temperature was kept at room tem-
perature overnight under nitrogen atmosphere, then the reaction mix-
ture was washed with 1 M HCl (2X200 mL), saturated solution of NaH-
CO3 (1x200 mL). The organic layer was dried over anhydrous MgSO4,
filtered; the filtrate was concentrated by rotary evaporation; the solid
residue was purified by column chromatography [solid support, silica
gel (200 mesh); eluent, n-hexane /ethyl acetate gradient] (Sanda et al.,
1997).
6
S-3-(4-chlorophenyl)-3,4-dihydro-4-oxoquinazolin-2-yl-2-
methylprop-2-enethioate 5
Pale-white solid, yield = 40 %, m p over 300 °C, IR (KBr disc):
1663 (C = O) quinazolinone ring, 1742 (C = O) side chain, 1619 (C =
N), 1337 (C - N), 1591 (C = C), 3069 (C - H) aromatic, 713 (C - H) aro-
matic for p-di substituted phenyl ring, 880 (CH =CH ), 2854 (CH3), 844
(C - Cl), 593 (C - S). 1HNMR [d6-DMSO]: δ , 2.51 (S, 2H, CH2), 3.35
(S, 3H, CH3), 7.36–7.97ppm (complex spectra, 5H, aromatic protons).
S-3-(4-bromophenyl)-3,4-dihydro-4-oxoquinazolin-2-yl-2-
methylprop-2-enethioate 6
Pale-white solid, m p over 300 °C, yield = 40 %, IR (KBr disc):
1740 (C = O) of quinazolinone ring, 1532 (C = O) of side chain, 1619
(C = N), 1694 (C = C), 1264 (C - N), 3025 (C - H) aromatic, 810 (C
- H) aromatic for p-disubstituted phenyl ring, 883 (CH = CH), 2776
(-CH3), 642 (C – Br), 577 (C – S). 1HNMR [d6-DMSO]: δ , 2.5(S,
2H, CH2), 3.34 (S, 3H, CH3), 7.28 –7.97 ppm (complex spectra, 5H,
aromatic protons).
2.6. Synthesis of N-(4-oxo-2-phenylquinazolin-3(4H)yl)
methacrylamides 7, 8
A solution of 2-phenyl-3-amino–quinazolin-4(3H)-one 3 (2.73 g,
10 mmol) or 6,8 dibromo-2-phenyl-3-amino–quinazolin-4(3H)-one 4
( 2.93 g, 10 mmol) and triethylamine (29.2 mL, 210 mmol) in dichloro-
methane (20 mL) was prepared and cooled to 5-0oC with continuous
stirring in ice bath, then methacryloyl chloride (0.86 mL, 15 mmol)
was added drop wise via dropping funnel with a continuous stirring
at 00C within 2 h, upon completion, the temperature was kept at room
temperature overnight under nitrogen, then the reaction mixture was
washed with 1 M HCl (2 X 200 mL), saturated solution of NaHCO3
(1x200 mL). The organic layer was dried over anhydrous MgSO4, fil-
tered, and the filtrate was concentrated by rotary evaporation. The solid
residue was purified by column chromatography [solid support, silica
gel (200 mesh); eluent, n-hexane /ethyl acetate gradient] (Sanda et al.,
1997).
N-(4-oxo-2-phenylquinazolin-3(4H)yl) meth acrylamide 7
Yellowish-white solid, m p 235-237°C, yield = 55 %, IR (KBr
disc):1658 (C = O) of quinazolinone ring, 1523 (C = O) of side chain,
1758 (C = N), 1597 (C = C), 1223 (C - N), 3062 (C - H) aromatic, 756
(C - H) aromatic for p-mono-substituted phenyl ring, 853 (CH = CH),
2755 (CH3), 3484 (NH).
6,8 di bromo- N-(4-oxo-2-phenylquinazolin-3(4H)yl) meth
acrylamide 8
Yellowish-white solid , m p 228- 230 °C , yield = 50 % , IR (KBr
disc): 1671 (C = O) of quinazolinone ring, 1565 (C = O) of side chain,
1624 (C = N), 1515 (C = C), 1237 (C - N), 3076 (C - H) aromatic,
696 (C - H) aromatic for p-mono-substituted phenyl ring, 845 (CH =
CH), 2842 (CH3), 647 (C–Br), 3423 (NH). 1HNMR [d6-DMSO]: δ,
2.51(S,2H, CH2), 3.34 (S, 3H, CH3), 5.7 (S,1H,NH), 7.51 – 8.58 ppm
(complex spectra , 4H, aromatic protons).
2.7. Synthesis of copolymers based on methacryloyl chloride
monomers with 2-Hydroxyethyl methacrylate (HEMA)
9-12
 Kenawy et al., 2018, AJMS 1(2): 5-11 DOI:10.5455/ajms.8
A mixture of the respective monomers 5-8 (10 mmol) and 2-Hy- 2-methylbutanethioate) 14
droxyethyl methacrylate [HEMA] (1.302 g, 10 mmol) were dissolved
in MeOH (60 mL) under slow stream of nitrogen at 60oC for 30 min White solid, m p 163-165 °C, yield = 58 % , IR (KBr disc):
prior to the addition of benzoyl peroxide (0.72 g, 3 mmol) the reaction 1662 (C = O) of quinazolinone ring, 1532 (C = O) of side chain, 1154
mixture was then stirred under reflux at nitrogen atmosphere for 23 h, (C - O), 1619 (C = N), 1271 (C - N), 3035 (C - H) aromatic, 813 (C -
after which it was cooled and diluted by pouring onto ether. A white H) aromatic for p-di-substituted phenyl ring, 2856 (-CH3), 692 (C–Br),
powder is then formed which was dried, dissolved in methanol (100 510 (-C-S) .
ml), and reprecipitated into ether, dried to give purified polymers 9 – 12 Poly 2-methyl-N-(4-oxo-2-phenylquinazolin-3(4H)-yl)penta-
(Nasirtabbrizi et al., 2012). namide 15
Poly [S-3-(4-chlorophenyl)-3,4-dihydro-4-oxoquinazolin-2- White solid, m p 178-180 °C, yield = 53 % , IR (KBr disc): 1661
yl 2-methylprop-2-enethioate]-CO-2-Hydroxyethyl methac- (C=O) of quinazolinone ring, 1561 (C=O) of side chain, 1153 (C-O),
rylate 9 1732 (C=N), 1248 (C-N), 3000 (C-H) aromatic, 764 (C-H) aromatic for
White solid, m p 292-294 °C, yield = 23 %, IR (KBr disc): 1682 p- mono-substituted phenyl ring, 2849 (CH3), 3213 (NH).
(C = O) of quinazolinone ring, 1545 (C = O) of side chain, 1205 (C - Poly 2-methyl-N-(6,8 dibromo-4-oxo-2-phenylquinazolin-
O), 1605 (C = N), 1263 (C - N), 1545 (C = C), 3073 (C - H) aromatic, 3(4H)-yl)pentanamide 16
812 (C - H) aromatic for p-di-substituted phenyl ring, 2787 (CH3), 694
(C–Cl), 606 (C - S), 3448 (OH). White solid, m p 280-283 °C, yield = 48 % , IR (KBr disc): 1673
(C=O) of quinazolinone ring, 1568 (C=O) of side chain, 1145 (C-O),
Poly [S-3-(4-bromophenyl)-3,4-dihydro-4-oxoquinazolin-2- 1730 (C=N), 1234 (C-N), 3075 (C-H) aromatic, 771 (C-H) aromatic for
yl-2-methylprop-2-enethioate]-CO-2-Hydroxyethyl methac- p-mono-substituted phenyl ring, 2853 (CH3), 687 (C–Br), 3257 (NH).
rylate 10
Table (1): The physical properties of the synthesized products 1-16.
White solid, m p 278-280 °C, yield = 25 % , IR (KBr disc): 1690
Code Molecular Formula M e l t i n g Yield % Solvent of
(C = O) of quinazolinone ring, 1598 (C = O) of side chain, 1110 (C -
(Molecular weight) Point C ◦ crystalliza-
O), 1770 (C = N), 1255 (C - N), 1540 (C = C), 3059 (C - H) aromatic, tion
806 (C - H) aromatic for p-di-substituted phenyl ring, 2968 (CH3), 643
1 C14H9N2OCl S (288.5) 310-315 80 MeOH
(C–Br) , 590 (C - S), 3442 (OH).
2 C14H9N2O Br S (332) 285-287 75 MeOH
Poly [N-(4-oxo-2-phenylquinazolin-3(4H)yl)-meth acryl-
3 C14H11N3O (237) 180-182 73 MeOH
amide]-CO-2-Hydroxyethyl methacrylate 11
4 C14H9N2O2Br2 (393) 231 - 233 80 MeOH
White solid, m p 244-246 °C, yield = 39 %. 5 C18H13N2O2ClS (356.5) Over 300 40 DMSO

Poly[N-(6,8-dibromo-4-oxo-2-phenylquinazolin-3(4H)yl) 6 C18H13N2O2 Br S (400) Over 300 40 DMSO

meth acrylamide]-CO-2-Hydroxyethyl methacrylate 12 7 C18H15N3O2 (305.33) 235-237 55 DMSO
8 C18H13N3O2Br2(463.12) 228 -230 50 DMSO
White solid, m p 250-252 °C, yield = 33%, IR (KBr disc): 1676 (C
= O) of quinazolinone ring, 1592 (C = O) of side chain, 1154 (C - O), 9 C24H23N2O5S Cl (486.97) 292 -294 23 DMSO
1314 (C - N), 3071 (C - H) aromatic, 780 (C - H) aromatic for p- mono 10 C24H23N2O5S Br(530.05) 278 – 280 25 DMSO
substituted phenyl ring, 2752 (CH3), 697 (C – Br), 3486 (OH), 3180
11 C24H23N2O5S (451.50) 244-246 39 DMSO
(NH).
12 C24H21N2O5SBr2 (609.31) 250 -252 33 DMSO
2.8. Synthesis of poly(S-3-(4-bromophenyl)-3,4-dihydro-4- 13 C20H19N2O2S Cl (386.9) 180 -182 60 DMSO
oxoquinazolin-2-yl-2-methyl butanethioate 13-16
14 C20H19N2O2S Br(431.35) 163-165 58 DMSO
Poly methyl methacrylate [PMMA] (0.310 g, 3 mmol) was dis- 15 C18H16N3O2 (306.34) 178-180 53 DMSO
solved in THF (3 mL), the respective derivatives 1, 2, 3, 4 (1.5
16 C18H14N3O2Br2 (464.13) 280-283 48 DMSO
mmol) were added, and the mixture was refluxed for 5 h, then THF
was removed under vacuum and the solid was dissolved in di- 2.9. Antimicrobial assessment
chloromethane. The organic phase was washed with MES buf-
fer, dried with MgSO4 and the solvent evaporated, providing the The activities of all compounds were tested in vitro against the
respected polymer derivatives 13-16 (Bañuls et al., 2007) (Ta- Gram-positive bacteria Bacillus subtilis, and Staphylococcus aureus,
ble1). and the Gram-negative bacteria Escherichia coli and Pseudomonas ae-
uroginosa using nutrient agar medium, as well as against Candida albi-
Poly(S-3-(4-chlorophenyl)-3,4-dihydro-4-oxo- cans using Sabouraud dextrose agar medium. All compounds activities
quinazolin-2-yl-2-methylbutanethioate) 13 were screened by agar diffusion method (Cruickshank et al., 1975) as
White solid, m p 180-182 °C, yield = 60 % , IR (KBr disc) : 1665 previously described (Kenawy et al., 2018).
(C = O) of quinazolinone ring, 1530 (C = O) of side chain, 1150 (C - O),
1618 (C = N ), 1271 (C - N), 3030 (C - H) aromatic, 811(C-H) aromatic 3. Results and Discussion
for p- di- substituted phenyl ring, 2785 (CH3), 760 (C–Cl ), 593 (-C-S ). The design and synthesis of the antimicrobial polymers have gained
Poly(S-3-(4-bromophenyl)-3,4-dihydro-4-oxoquinazolin-2-yl increasing attention as a safe and effective strategy to fight against mul-
tidrug-resistant microbes. Antimicrobial polymers can be classified into
7
 Kenawy et al., 2018, AJMS 1(2): 5-11 DOI:10.5455/ajms.8
three categories: (1) biocidal polymers, which are polymers with in- the oth--er evidence was the disappearance of the stretching vibration
trinsic antimicrobial activity, (2) polymeric biocides, which are based bands of C=C within the range 1590-1520 cm-1 (Supplementary file).
on polymer backbones with biocide molecules attached, and (3) bio-
The structure of copolymers 9–16 were confirmed by the appear-
cide-releasing polymers, which consist of polymers loaded with biocide
ance of bands at 2960- 2920 cm-1 due to C-H stretching vibration of
molecules (Beecher, 2003; Hoult et al., 1994). The present study aimed
methyl and methylene groups. Also bands at 3490 – 3440 cm-1 region
to prepare some quinazolinone derivatives followed by their immobi-
are due to the stretching vibration of the hydroxyl group. Band assign-
lization onto some monomers which were then homo-polymerized or
co-polymerized with different monomers to produce new antimicrobial ments of the IR spectrum of compounds 2 – 16 are listed in Table 2.
polymers.

The functionality of compounds governed the choice of supplied O m

S N n
substrates as well as their biological activities. They must have only N2 / reflux O O
N + O Z S N
single site available for reaction to avoid the production of isomeric X Z 23 h
O N
products. Compounds 1- 4 were previously proved to possess certain
[5,6] X
biological activities and were prepared as previously described (El-Hi- Z = -OCH2CH2OH ; HEMA O

ti et al., 2002; Manjunatha et al., 2007). The polymeric moiety was [ 9 , 10 ]

chosen of the acrylates due to their well-known biological profile and
m
for the ease of their reaction conditions, as well as their availability. O
O
n
HN X O O
Chlorine containing phenyl methacrylate and its polymers have been N O
+ O N2 / reflux Z HN X
N
previously applied as biocides (Bowersock et al., 1994). Also, some Ph N Z 23 h
other derivatives have been reported to possess valuable antimicrobial Y Ph N
Z = -OCH2CH2OH ; HEMA Y
activities (Lode, 2009 and Gonzales , 2010). This was inspiring enough [ 7, 8]
[ 11, 12]
to introduce the chlorine-containing derivative 1 into reaction in the
hope to get potent antimicrobial agents. Scheme 2

The selected quinazolinone derivatives 3, 4 reacted with meth-

acroloyl chloride to give the monomer derivatives 5-9, which were
further copolymerized with 2-hydroxyethyl methacrylate (HEMA) in a
1:1 molar ratio to yield the corresponding copolymers 10-13 (Jessy et
al., 2007 ) as shown in (Schemes 1 and 2).
Scheme 2: Preparation of copolymers of monomer based methacryloyl chloride
5-8 with 2-HEMA in the presence of benzoyl peroxide as an initiator in nitrogen
atmosphere under reflux conditions for 23 h to yield the comparing polymeric
derivatives 10–12.

The same compounds 1,2,3,4 were immobilized onto poly(methyl n

methacrylate) (PMMA) directly in DMF in nitrogen atmosphere under AIBN
O O
reflux conditions to afford the respective polymeric derivatives 13-16 as O O
shown in (Scheme 3). The prepared polymers were characterized by IR Methyl methacrylate Poly Methyl methacrylate
( MMA ) ( PMMA )
Spectra , TGA and Elemental analysis.
O H3C CH3 n
X O
N
C CH2 C CH2 X O
+
Et3N O C N n
N SH
O C
N2 / reflux DMF S N
Cl
S N + O
[ 1 ]; X = Cl N SH reflux
Methacyloyl chloride N O N
[ 2 ] ; X= Br
X [ 1 ]; X = Cl X
O O
(M1) [ 5 ]; X = Cl [ 2 ] ; X= Br PMMA
[ 13 ]; X = Cl
[ 6 ] ; X= Br
[ 14 ] ; X= Br
H 3C CH3
O
X NH2 C CH2 C CH2
N Et3N
+ O C O
O n
N2 / reflux
N Ph Cl HN X
O O
Y Methacyloyl chloride N
X NH2 n O
[ 3 ] ; X,Y = H N HN X
Ph + O DMF
[ 4 ] ; X,Y =Br
N
Ph N
Y N reflux
O
(M1) [7 ] ; X,Y = H Y Ph N
[8] ; X,Y =Br
Scheme 1 [ 3 ] , X,Y = H PMMA Y
[4 ] ,X,Y = Br [ 15 ] ,X,Y = H
Scheme 1: Synthesis of monomers based on methacrylol chloride 5–8 through [ 16 ] ,X,Y = Br
the reaction of substrates 1 - 4 with methacroloyl chloride in DMF under Scheme 3
cold-stirring conditions and in the presence of triethylamine (TEA). Scheme 3: Immobilization of quinazolinone derivatives1, 2, 3, 4 onto poly(meth-
yl methacrylate) (PMMA) to give respective products 13-16.
3.1. FT-IR spectra
3.2. The 1HNMR Spectra
IR spectra of compounds 5–8 showed bands in the range 1600–
1700 cm-1 due to the carbonyl group of the quinazolinone structure, The 1HNMR spectrum of compound 5 showed a singlet peak at δ
while the carbonyl group of the ester chain appeared within the range 2.51 ppm due to 2 protons of two CH2 group, and a singlet peak ap-
1550–1600 cm-1. The vinyl group showed stretching frequency in the peared at δ 3.35 ppm due to the three protons of -CH3 group, complex
region 840-890 cm-1, the main evidence of the polymer formation was spectra appeared at (7.36 – 7.97) ppm due to 5 aromatic rings protons
certainly observed by the vanishing of such signals in compounds 9–12, (Supplementary file).
8
 Kenawy et al., 2018, AJMS 1(2): 5-11 DOI:10.5455/ajms.8
Table ( 2 ) : Band Assignments of the IR spectrum of compounds 2 – 16.

Band Assignment

Code C=O C-O C=N C-N C=C C - H -NH C-S CH=CH Other
arm

2 1683 1194 1616 - 1525 3025 3266 635 - 1261 C=S 1261 SH
676 C-Br
5 1663,1742 1267 1619 1337 1591 3069 - 593 880 844 C-Cl 2854 CH3
6 1740,1532 1232 1619 1264 1484 3025 - 577 883 642 C-Br 2776 CH3
7 1685,1523 1308 1597 1223 1440 3062 3484 - 853 2755 CH3
8 1671,1565 1315 1624 1237 1515 3076 3423 - 845 2842 CH3 647 C-Br
9 1682,1545 1205 1605 1263 1545 3073 - 606 - 694 C-Cl 3448 OH
10 1690,1598 1110 1770 1255 1540 3059 - 590 - 3442 OH 2968 CH3
643 C-Br
12 1676,1592 1154 1780 1314 1448 3071 3180 - - 697 C- Br 2752 CH3
13 1665,1530 1150 1618 1271 1403 3030 - 593 - 760 C-Cl 2785 CH3
14 1728,1532 1154 1619 1271 1403 3035 - 510 - 692 C- Br 2856 CH3
15 1661,1561 1153 1732 1248 1561 3000 3213 - - 2849 CH3
16 1673,1568 1145 1730 1234 1620 3075 3257 - - 2853 CH3 687 C-Br

Table (3) Elemental analysis of some polymeric derivatives.

%C %H %N
Code
Calc. Found Calc. Found Calc. Found
7 70.81 71.47 4.95 4.73 13.76 18.41
8 46.83 42.39 2.83 2.36 9.07 10.31
9 60.40 55.43 5.65 2.49 5.42 9.16
10 65.43 47.86 5.27 2.32 9.28 8.02
12 65.43 47.86 4.69 2.46 6.74 6.53
13 61.20 15.63 4.60 1.05 7.50 2.11
15 71.62 67.84 6.31 6.06 12.53 11.91
16 50.10 50.22 4.69 3.89 6.74 8.98

Figure 1. B) Thermogravimetric analysis (TGA) of copolymers 13, 14 and 16.

Table (4): TGA for some polymeric derivatives.

Char Yield
5% DT 10 % DT
Polymer code at 800°C
(°C) (°C)
(%)
9 274 286 0
10 280 295 0
12 214 237 0
13 248 270 0
15 200 219 0
16 230 253 0

The 1HNMR spectrum of compound 6 showed a singlet peak at δ

2.51 ppm due to 2 protons of two CH2 group, and a singlet peak ap-
Figure 1. A) Thermogravimetric analysis (TGA) of copolymers 9, 10, 12. peared at δ 3.34 ppm due to the three protons of -CH3 group, complex
spectra appeared at (7.28 – 7.97) ppm due to 5 aromatic rings protons
The 1HNMR spectrum of compound 8 showed a singlet peak at δ 2.51
ppm due to 2 protons of two CH2 group, and a singlet peak appeared at
9
 Kenawy et al., 2018, AJMS 1(2): 5-11 DOI:10.5455/ajms.8
δ 3.34 ppm due to the three protons of -CH3 group, a singlet peak at δ Conclusion
5.7 ppm due to NH proton, complex spectra appeared at (7.51 – 8.58)
ppm due to 4 aromatic rings protons (Supplementary file). The present study summarized the immobilization of some se-
lected quinazolinone derivatives onto polymers through the reaction
3.3. Elemental microanalysis and Thermogravimetric anal- of these derivatives with methacryloyl chloride, then copolymer-
ysis ized with 2-Hydroxyethyl methacrylate [HEMA] in a 1: 1 products.
Another group of polymers was prepared by reacting the starting
The elemental microanalysis as shown in (Table 3) showed an
materials with poly methyl methacrylate [PMMA] to evaluate the
agreement with the calculated values and also confirmed the obtained
antimicrobial activities of the produced polymers. We have noticed
spectral analysis. The results of thermogravimetric analysis (TGA)
that the introduction of PMMA entity had a great influence on the
of copolymers 9–12 are represented in Table 4 and Figure 1 which
activities of polymeric products comparing with their parent com-
showed that all the polymers underwent single step decomposition in
pounds. Also the produced copolymers based on methyl methacry-
the temperature range of 150-250°C. A ratio of 50% decomposition
late monomers have highly enhanced activities in comparison with
was observed in the temperature range of 300-360°C.
their parent compounds. Moreover, the presence of chlorine and
3.4. Antimicrobial assessment bromine atoms had positively affected the antibacterial characters of
such scaffolds. These results proved the efficacy of contribution of
Table 5 shows the diameter of inhibition zone for the tested com- polymeric compounds in improving the antimicrobial activities of
pounds against selected microorganisms. The best antibacterial activ- certain derivatives , providing a set of effective antimicrobial agents.
ity were displayed by compounds 13-16 as compared to their parent Table (5). Inhibition zone diameters (mm) of compounds 5-16.
quinazolinone derivatives 1- 4 which showed relatively less activities.
This markedly enhanced activity may be due to the presence of PMMA References
moiety in compounds 13-16. 7. Furthermore, compounds with an -NH
linkage 15 , 16 displayed higher activities than quinazolinone deriva- Abdel-Megeed, M. F., El-Hiti, G. A., Aly ,Y.L., Saleh, M A. , Abdo
tives with –S linkage 13,14 indicating the importance of –NH bonding I., and Smith, K., Novel one-pot procedure for the preparation
of 3-substituted 2-thioxo-4(3H)-quinazolinones , Sulfur Lett., 1995
features. On the other hand, the higher activities for compounds 9, 10, ,19(3),129-140.
12 may be due to the presence of two bromine atoms as compared to
Alagarsamy V, Thangathiruppathy A, Mandal SC, Rajasekaran S , Pharma-
their parent compounds which showed slight activity. Also, the copo- cological evaluation of 2-substituted (1,3,4) thiadiazolo quinazolinones ,
lymerization of compound 5 with HEMA afforded the corresponding Indian J Pharm Sci. , 2006, 68 (1):108-111.
compound 9 with highly potential antibacterial activities. Compounds Alagarsamy, V., Dhanabal, K., Parthiban, P. ,Anjana, G. , Murugesan, B. ,.Raj-
8, 10, 12 and 13 showed strong activity against P. aeuroginosa, while kumar S., Beevi, A. , Synthesis and pharmacological investigation of novel
compounds 8, 10 and 16 displayed strong activity against E. coli. Com- 3-(3-methylphenyl)-2-substituted amino-3H-quinazolin-4-ones as analge-
sic and anti-inflammatory agents , J. Pharm. Pharmacol., 2007 ,59(5):669-
pounds 7, 12 and 15 showed good activity against S. aureus followed 77.
by compounds 12, 13 which were moderately active. All compounds
Bañuls, M.-J. , Pedro V. G.-, Puchades R., Maquieira Á. , PMMA Isocy-
showed no antifungal activities except the parent compound 1. anate-Modified Digital Discs as a Support for Oligonucleotide-Based
Table 5. The antimicrobial effect as revealed by inhibition zones. Assays , Bioconjugate Chem., 2007, 18 (5), pp 1408–1414.
Microorganism inhibition zone diameter (mm) *
Beecher, G. R., Overview of dietary flavonoids: nomenclature, occurrence and
Gram +ve bacteria Gram –ve bacteria Fungi intake J. Nutr. , 2003;133(10):3248S-3254S
Code
P. aeu- Bowersock, T.L. ; Woodyard, L. ; Hamilton, A.J. ; DeFord, J.A. Inhibition of
B. subtilis S. aureus E. coli C. albicans
roginosa Staphylococci by vancomycin absorbed on triidodecylmethyl ammoni-
um chloride-coated intravenous catheter , J. Control. Release ,1994 , 31,
1 18 18 21 21 18 237–243.
2 21 21 20 18 -
Chan, C.F.; Huang, K.S.; Lee, M.Y.; Yang, C.H.; Wang, C.Y.; Lin, Y.S. Appli-
3 10 11 9 8 - cations of nanoparticles for antimicrobial activity and drug delivery, Curr.
Org. Chem. 2014, 18, 204–215.
4 19 - - 13 -
5 18 16 17 19 - Cruickshank, R., Duguid, J.P., Marimon, B.P and Swain, R.N.A. ,1975, Medi-
cal Microbiology. 12th edn, Churchill Livingstone, London.
6 12 16 15 13 -
El-Hiti, G. A., Abdel-Megeed, M. F., Zied , T.M.M. , Synthesis and reactions
7 15 18 16 18 - of some 3-aryl-2-thioxoquinazolin-4(3H)-ones, Indian J. Chem., 2002
8 18 13 18 19 - ,41B ,1519 .

9 19 16 17 17 - Gonzales, F.P.; Maisch, T. , XF drugs: A new family of antibacterial, Drug

News Perspect., 2010, 23, 167-174.
10 20 14 18 20 -
11 16 16 15 13 - Hoult, J. R. S.; Moroney, M. A.; Payá , Actions of flavonoids and coumarins
on lipoxygenase and cyclooxygenase , Methods in Enzymology , 1994,
12 16 17 16 18 - 443-454.
13 16 17 16 18 - Jatav V., Mishra P. , Kashaw S. , Stables J.P., Synthesis and CNS depressant
14 16 14 16 15 - activity of some novel 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl
quinazolinone-4(3H)-ones , European Journal of Medicinal Chemistry,
15 16 19 17 16 - 2008 , 43 (1), 135-141.
16 18 16 18 15 - Jessy EM, Sambanthan AT, Alex J, Sridevi CH, Srinivasan KK , Synthesis and
*Antimicrobial activity: inhibition zone ≥ 19 mm (high), 14-18 mm (moderate biological evaluation of some novel quinazolones , Indian J Pharm Sci ,
7-13 mm (slight), 0 (inactive) ( Khalil et al., 2003). 2007,69: 476-478.

Kenawy, E. R ., Worley, S.D.; Broughton, R. , The Chemis-

10
 Kenawy et al., 2018, AJMS 1(2): 5-11 DOI:10.5455/ajms.8
try and Applications of Antimicrobial Polymers:  A State-of-the-
Art Review, Biomacromolecules, 2007, 8 (5), pp 1359–1384.
Jain, A.; Duvvuri, L.S. ; Farah, S.; Beyth, N.; Domb, A.J. ; Khan, W., Anti-
microbial Polymers , Adv. Healthc. Mater. ,2014, 3, 1969–1985.

Kenawy, E., Shokr, A., Abdel-Wahed, N., Zied, T. Synthesis and Anti-microbial
Activities of Some (aryl)-N’-benzylidene-2-hydroxybenzohydrazide deriv-
atives. AJMS, 2018; 1(1): 19-25.

Kenawy, E.R. and Abdel-Fattah, Y.R.. Antimicrobial Activity of Modified and

Electrospun Poly(vinyl Phenol), Macromolecular Bioscience,.Biologically
Active Polymers ,2002, 261–266,109.

Khalil, A. A. , Abdel Hamide, S. G. ,Abd-ulrahman , M. Al-Obaid, Hussein I.

El-Subbagh , Arch. Pharm. Pharm. Med. Chem., 2003 , 336, 95–103 .

Lin L.-C , Kuo Y.-C., Chou C.-J., Cytotoxic Biflavonoids from Selaginella del-
icatula , J. Nat. Prod., 2000, 63 (5), 627–630

Lin, Y.S.; Lee, M.Y.; Yang, C.H.; Huang, K.S. Biomedical devices for pathogen
detection using microfluidic chips. Curr. Proteom. 2014, 11, 116–120.

Lode, H.M., Clinical impact of antibiotic-resistant Gram-positive pathogens ,

Clin. Microbiol. Infect., 2009, 15, 212-217 .

Manjunatha, N. R.; Thampi ,P.; Gurubasavarajaswamy P. M.; Sriram D. D.,

Synthesis and Antimicrobial Activities of Some Novel Substituted 2-Im-
idazolyl-N-(4-oxo-quinazolin-3(4H)-yl)-acetamides ,Chem.Pharm.Bull,
2007, 55 (11),1615-1619.

Muñoz-Bonilla, A.; Fernández-García, M., Polymeric materials with antimicro-

bial activity, Prog. Polym. Sci., 2012 , 37(2) , 281–339. Xue, Y. ; Xiao, H.;
Zhang, Y. Antimicrobial Polymeric Materials with Quaternary Ammonium
and Phosphonium Salts , Int. J. Mol. Sci., 2015, 16, 3626–3655.

Nasirtabrizi M.H., Zargin L., Khodabandlou S., Mansour S. R. , Functional-

ization and Chemical Modification of 2-Hydroxyethyl Methacrylate with
Carboxylic Acid , E-Journal of Chemistry , 2012, 9(3), 1135-1144 .

Patel H.U., Patel R.S., Patel C. N., Synthesis and Antihypertensive Activity of
Some Quinazolinone Derivatives , Journal of Applied Pharmaceutical Sci-
ence , 2013,3 (3),171-174 .

Ross, A.G.P.; Olds, G.R.; Cripps, A.W.; Farrar, J.J.; McManus, D.P. Entero-
pathogens and chronic illness in returning travelers. N. Engl. J. Med. 2013,
368, 1817–1825.

Sanda , H.; Abe ,T.; and T. Endo, T. ,Syntheses and Radical Polymerizations of
Optically Active (Meth)acrylamides Having Amino Acid Moieties , jour-
nal of polymer Science, 1997 , part A, 35 ,2619-2629.

Siedenbiedel, F.; Tiller, J.C. , Antimicrobial Polymers in Solution and on Surfac-

es: Overview and Functional Principles , Polymers ,2012 , 4, 46–71.

Siedenbiedel, F.; Tiller, J.C. Antimicrobial polymers in solution and on surfac-

es: Overview and functional principles. Polymers 2012, 4, 46–71

Somers, F., Ouedraogo, R., Antoine, M. H. , Tullio, P. de , Becker, B. , Fon-

taine, J., Damas, J., Dupont, L., Rigo, B. , Delarge, J., Lebrun, P. , Pirotte,
B. , Original 2-Alkylamino-6-halogenoquinazolin-4(3H)-ones and KATP
Channel Activity , J. Med. Chem., 2001, 44, 2575.

Sukriti Srivastava , Sujiti Srivastava , Biological activity of Quinazolinone: A

Review , International Journal of Pharma Sciences and Research (IJPSR),
2015 , 6(9), 1206.

Sun, D.; Shahzad, M.B.; Li, M.; Wang, G.; Xu, D. Antimicrobial materials with
medical applications. Mater. Technol. 2015, 30, B90–B95

Valenti P., Bisi A., Rampa A., Belluti F., Gobbi S., Zampiron A., Carrara M.,
Synthesis and biological activity of some rigid analogues of flavone-8-ace-
tic acid , Biorg. Med. Chem., 2000, 239.

Ventola, C.L. The Antibiotic resistance Crisis: Part 1: Causes and Threats.
2015, 40, 277–283.

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