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European	Journal	of	Chemistry	5	(4)	(2014)	557‐562	

	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2014	Eurjchem	Publishing	‐	Printed	in	the	USA	

http://dx.doi.org/10.5155/eurjchem.5.4.557‐562.1077	

	
	

	

	

European	Journal	of	Chemistry	
Journal	homepage:	www.eurjchem.com	

	 	 	

Synthesis	and	evaluation	of	antibacterial	activity	for	a	series	of		
N‐phthaloylglycine	derivatives	

Samreen	Begum	a,	Shaikh	Sirajuddin	Nizami	a,	Sumayya	Saied	a,		
Syed	Muhammad	Shahid	b	and	Fatima	Zehra	Basha	c,*	

a	Department	of	Chemistry,	University	of	Karachi,	Karachi‐75270,	Pakistan	
b	The	Karachi	Institute	of	Biotechnology	and	Genetic	Engineering	(KIBGE),	University	of	Karachi,	Karachi‐75270,	Pakistan	
c	Hussain	Ebrahim	Jamal	Research	Institute	of	Chemistry,	International	Center	for	Chemical	and	Biological	Sciences,	University	of	Karachi,	Karachi‐75270,	Pakistan	

*Corresponding	author	at:	Hussain	Ebrahim	Jamal	Research	Institute	of	Chemistry,	International	Center	for	Chemical	and	Biological	Sciences,	University	of	Karachi,	
Karachi‐75270,	Pakistan.		
Tel.:	+92.21.99261767.	Fax:	+92.21.4819018.	E‐mail	address:	bashafz@gmail.com	(F.Z.	Basha).	

	
	

	 	

	 	 	
ARTICLE	INFORMATION	 	 ABSTRACT	

	
DOI:	10.5155/eurjchem.5.4.557‐562.1077	

Received:	19	April	2014	
Received	in	revised	form:	16	June	2014	
Accepted:	16	June	2014	
Online:	31	December	2014	

KEYWORDS	

	 Two	 series	 of	 N‐phthaloylglycine	 derivatives	 were	 synthesized	 under	 Schotten‐Baumann
conditions.	The	first	series	consists	of	N‐phthaloylglycine	amides	(4a‐h),	and	the	second	one
consists	 of	 benzimidazole	 derivatives	 of	 N‐phthaloylglycine	 (6a‐d).	 All	 the	 synthesized
analogues	 were	 evaluated	 for	 their	 in	 vitro	 antimicrobial	 activity	 by	 using	 disc	 diffusion
method.	In	the	first	series,	compounds	4h	(MIC,	0.5	mg/L),	4a	(MIC,	0.6	mg/L),	and	4e	(MIC,
0.7	 mg/L)	 were	 found	 to	 be	 the	 most	 potent	 against	 vancomycin‐resistant	 Staphylococcus
aureus	 (VRSA).	 Furthermore,	 three	 compounds	 i.e.	 4g	 (MIC,	 0.8	mg/L),	 6b	 (MIC,	 1.5	mg/L),
and	 4h	 (MIC,	 1.6	mg/L)	 displayed	 good	 activity	 against	methicillin‐resistant	 Staphylococcus
aureus	(MRSA).	All	the	synthesized	compounds	exhibited	a	wide	range	of	antibacterial	activity
against	 all	 of	 the	 Staphylococcus	 aureus	 resistant	 strains	 tested.	 The	 structures	 of	 the
synthesized	compounds	were	characterized	by	IR,	1H	NMR,	13C	NMR	and	MS	(EI).	

Antibacterial	
Benzimidazole		
Phthaloylglycine	derivatives	
Schotten‐Baumann	reaction	
Methicillin‐resistant	Staphylococcus	aureus		
Vancomycin‐resistant	Staphylococcus	aureus	

	
1.	Introduction	
	

The	 frequent	 use	 and	 misuse	 of	 most	 antibiotics,	 in	
particular,	 methicillin	 and	 vancomycin,	 has	 caused	 many	
bacteria	 to	 develop	 resistance	 to	 these	 agents	 [1,2].	 Anti‐
bacterial	resistance	has	increased	globally,	and	has	emerged	as	
a	 serious	 medical	 challenge	 worldwide.	 Therefore,	 the	
development	 of	 novel	 antibacterial	 agents	 to	 treat	 patients	
infected	 with	 methicillin‐resistant	 Staphylococcus	 aureus	
(MRSA)	 and	 vancomycin‐resistant	 Staphylococcus	 aureus	
(VRSA),	 in	 addition	 to	 many	 other	 drug	 resistant	 microbes	
remains	an	important	challenge	[3‐7].	

N‐Phthaloyl	derivatives	of	amino	acids	and	benzimidazoles	
are	 important	 pharmacophores	 of	 a	 number	 of	 medicinally	
important	classes	of	compounds.	Benzimidazole	derivatives	are	
very	 useful	 intermediates	 of	 pharmaceutically	 important	
compounds	 [8].	 They	 are	 applicable	 as	 antiulcer,	 antihyper‐
tensive,	 antifungal,	 antiviral,	 antihistamine,	 antimicrobial,	
antiallergic,	antioxidant,	antitubercular,	and	 in‐vitro	anti‐HIV‐1	
[9].	 Likewise,	 derivatives	 of	 N‐phthaloyl	 amino	 acids	 have	
demonstrated	 a	 number	 of	 biological	 activities,	 including	
antimicrobial	[10],	hypolipidemic	[11],	analgesic	[12]	and	DNA	

cleaving	 abilities	 [13].	 In	 addition,	 their	 amides	 represent	 a	
new	 class	 of	 antiepileptic	 agents	 [14].	 The	 derivatives	 of												
N‐phthaloylglycine	 have	 been	 studied	 most	 widely,	 including	
the	 formation	 of	 complexes	 with	 different	 transition	 metals	
[15]	 and	 adducts	 formation	 with	 different	 aromatic	 amines	
[16].	Some	heterocyclic	derivatives	of	N‐phthaloyl	amino	acids,	
such	 as	 oxadiazole,	 benzoxinone,	 1,2,4‐triazoles	 are	 also	
reported	[17,18].	

In	this	context,	we	were	intrigued	by	the	number	of	reports	
that	derivatives	of	N‐phthaloylglycine	and	benzimidazole	have	
a	 wide	 range	 of	 important	 biological	 activities.	 Consequently,	
we	synthesized	analogues	that	contain	both	pharmacophores	in	
the	 framework	 of	 one	 molecule.	 In	 addition,	 the	 synthesized						
N‐phthaloylglycine	derivatives	were	 subjected	 to	 antibacterial	
activity.	Herein	we	report	 the	 result	of	 that	study	and	discuss	
their	structure‐activity	relationship.	
	

2.	Experimental	
	

2.1.	Instrumentation	
	
The	 melting	 points	 of	 all	 the	 compounds	 were	 obtained	

with	digital	Electro	thermal	equipment	and	are	uncorrected.		



558	 Begum	et	al.	/	European	Journal	of	Chemistry	5	(4)	(2014)	557‐562	
	

	

	
	

Scheme	1

 
	

1H	NMR	Spectra	were	recorded	on	Avance	Bruker	300,	400	
MHz	 in	 CDCl3.	 13C	 NMR	were	 recorded	 on	 Bruker	 Aspect	 AB‐
100	 MHz.	 The	 EI‐MS	 were	 measured	 on	 Finnigan	 MAT‐312,	
Germany,	 and	 JEOL	 MS	 Route	 JMS.	 600H,	 Japan	 Instruments.	
TLC	Analysis	was	performed	on	pre‐coated	silica	gel	aluminum	
plates	(Kieselgel	60F254,	E.	Merck,	Germany).	
	
2.2.	Synthesis	
	

The	 synthesis	 of	 N‐phthaloylglycine	 amides	 (4a‐h)	 was	
carried	 out	 from	 commercially	 available	 phthalic	 anhydride	
(Scheme	 1).	 Heating	 an	 equimolar	 mixture	 of	 phthalic	
anhydride	 and	 glycine	 afforded	 the	 N‐phthaloylglycine	 1	 in	
72%	yield	[19].	Subsequently,	compound	1	was	converted	into	
corresponding	acid	chloride	2	by	treating	with	thionyl	chloride	
(SOCl2).	 The	 resulting	 phthaloylglycyl	 chloride	 (2‐(1,3‐dioxo	
isoindolin‐2‐yl)acetyl	 chloride)	 2	 is	 treated	 with	 different	
amines	(3a‐h)	to	give	the	N‐phthaloylglycine	amides	(4a‐h)	 in	
30‐32%	 yield	 (Scheme	 1).	 The	 substituted	 benzimidazole	
derivatives	 (5a‐d)	 were	 synthesized	 by	 treating	 o‐phenylene	
diamine	 with	 different	 carboxylic	 acids	 (Scheme	 2)	 [19].	 To	
synthesize	 the	 desired	 benzimidazole	 derivatives	 of	 N‐phtha	
loylglycine	 (6a‐d),	 we	 utilized	 the	 environmentally	 benign	
Schotten‐Baumann	reaction	condition	(Scheme	3)	[20].	
	
2.2.1.	Procedure	for	the	preparation	of	N‐phthaloylglycine	
(1)	
	

A	well	pulverized	mixture	of	phthalic	anhydride	(6.0	g,	0.02	
moles)	 and	 glycine	 (3.0	 g,	 0.02	 moles)	 was	 heated	 with	 a	
burner	 until	 the	 solid	 melted.	 The	 molten	 mass	 was	 stirred	
gently	with	a	glass	rod,	and	heated	again	at	150‐190	°C	for	15	
minutes.	 The	 mixture	 was	 allowed	 to	 cool	 and	 then	
recrystallized	with	water	(100	mL)	(Scheme	1)	[21].	

N‐Phthaloylglycine	(1)	[21]:	Color:	White.	Yield:	72%.	M.p.:	
196‐198	°C.	Rf	 :	0.78	(EtOAc:MeOH)	(9:1).	FT‐IR	(KBr,	,	cm‐1):	
3450‐3000	 (OH)	 (br,	 carboxylic	 acid),	 1770,	 1721	 (C=O)	
(imide),	 1669	 (C=O)	 (acid),	 1560	 (Ar	 C=C),	 1398	 (C‐O),	 711	
(ortho	 substituted	Ar).	 1H	NMR	 (300	MHz,	DMSO‐d6,	δ,	 ppm):	
4.30	(s,	2H,	N‐CH2‐C=O),	7.85‐7.93	(m,	4H,	Ar‐H),	13.22	(s,	1H,	
OH).	MS	(EI,	m/z	(%)):	205	(M+,	10),	160	(100),	149	(4),	133.0	
(70),	104	(70),	77	(65),	50	(30).	
	
2.2.2.	Procedure	for	the	preparation	of	N‐phthaloylglycyl	
chloride	(2)	
	

Pure	 phthaloylglycine	 (1)	 (2.4	 g)	was	 refluxed	with	 SOCl2	
(9.0	mL)	 for	1	h.	The	 condenser	was	 removed	and	 the	excess	
SOCl2	 was	 evaporated	 from	 the	 reaction	 mixture	 (Scheme	 1)	
[21].	

N‐Phthaloylglycyl	chloride	(2‐(1,3‐dioxoisoindolin‐2‐yl)acetyl	
chloride)	(2)	 [21]:	Color:	Light	yellow.	Yield:	96%.	M.p.:	82‐84	
°C.	 Rf:	 0.75	 (EtOAc:MeOH)	 (9:1).	 FT‐IR	 (KBr,	 ,	 cm‐1):	 1755,	
1765	(C=O)	(imide),	1750	(C=O)	(acid	chloride),	1654	(Ar	C=C),	
711	(ortho	subst.	Ar),	605	(C‐Cl).	1H	NMR	(300	MHz,	DMSO‐d6,	
δ,	ppm):	4.30	(s,	2H,	N‐CH2‐CO),	7.85‐7.93	(m,	4H,	Ar‐H).	
	
2.2.3.	Procedure	for	the	preparation	of	benzimidazole	(5a)	
and	its	derivatives	(5b‐d)	
	

The	o‐phenylenediamine	 (10.0	 g,	 0.09	moles)	was	 treated	
with	 appropriate	 carboxylic	 acid	 (0.135	 moles).	 The	 mixture	
was	heated	at	100	°C	for	2	h.	After	cooling,	10%	NaOH	solution	
was	added	slowly	until	the	mixture	was	just	alkaline	to	litmus.	
The	crude	product	was	collected,	washed	with	cold	water	and	
recrystallized	 without	 drying.	 Recrystallization	 was	 done	 by	
dissolving	 in	boiling	water	 then	treated	with	a	2	g	of	charcoal	
for	 10	 to	15	minutes	 and	 filtered	 the	hot	mixture	which	 gave	
pure	crystals	of	Benzimidazole	on	cooling	(Scheme	2)	[19].	

1H‐Benzo[d]imidazole	 (5a)	 [19,22]:	 Color:	 White.	 Yield:	
50%.	 M.p.:	 170‐172	 °C.	 Rf:	 0.75	 (EtOAc:MeOH)	 (8:2).	 FT‐IR	
(KBr,	 ,	 cm‐1):	 3414	 (N‐H	 stretching),	 2620	 (C‐H)	 (aromatic),	
1618	(C=N,	stretch),	1610	(C=C)	(aromatic).	1H	NMR	(300	MHz,	
MEOD,	δ,	ppm):	4.85	(s,	1H,	N‐H),	7.26‐7.21	(q,	 J	=	3.6	Hz,	2H,	
Ar‐H),	7.60‐7.57	(q,	J	=	3.3	Hz,	2H,	Ar‐H),	8.12	(s,	1H,	N=CH‐N).	
MS	(EI,	m/z	(%)):118	(M+,	100),	91	(75),	63	(75),	52	(45).	

2‐Methyl‐1H‐benzo[d]imidazole	 (5b)	 [22,23]:	 Color:	 Light	
yellow.	 Yield:	 35%.	 M.p.:	 174‐176	 °C.	 Rf:	 0.78	 (EtOAc:MeOH)	
(8:2).	 FT‐IR	 (KBr,	,	 cm‐1):	 3412	 (N‐H	 stretching),	 2677	 (C‐H)	
(aromatic),	 1620	 (C=N,	 stretch),	 1448	 (C=C)	 (aromatic).	 1H	
NMR	(300	MHz,	MeOD,	δ,	ppm):	2.53	(s,	3H,	CH3),	4.85	(s,	1H,	N‐
H),	7.16‐7.13	(q,	 J	=	3.3	Hz,	2H,	Ar‐H),	7.46‐7.43	(q,	J	=	3.3	Hz,	
2H,	Ar‐H).	MS	(EI,	m/z	 (%)):	132	(M+,	100),	104	(12),	90	(15),	
77	(10),	63	(30),	51.9	(18).	

2‐Ethyl‐1H‐benzo[d]imidazole	(5c)	[22]:	Color:	White.	Yield:	
32%.	 M.p.:	 178‐179	 °C.	 Rf:	 0.65	 (EtOAc:MeOH)	 (8:2).	 FT‐IR	
(KBr,	 ,	 cm‐1):	 3412	 (N‐H	 stretching),	 2700	 (C‐H)	 (aromatic),	
1620	(C=N,	stretch),	1610	(C=C)	(aromatic).	1H	NMR	(300	MHz,	
MeOD,	δ,	ppm):	1.41‐1.36	(t,	J	=	7.5	Hz,	3H,	CH3),	2.93‐2.86	(q,	J	
=	7.5	Hz,	2H,	CH2),	4.83	(s,	1H,	N‐H),	7.19‐7.14	(q,	J	=	3.6	Hz,	2H,	
Ar‐H),	7.48‐7.45	(q,	J	=	3.0	Hz,	2H,	Ar‐H).	MS	(EI,	m/z	(%)):	145	
(M+,	100),	131	(25),	118	(22),	77	(52),	65	(56),	63.1	(90),	52.1	
(70).	

1‐(1H‐Benzo[d]imidazole‐2yl)ethanol	 (5d)	 [24,25]:	 Color:	
Yellow.	 Yield:	 50%.	 M.p.:	 178‐180	 °C.	 Rf:	 0.78	 (CHCl3:EtOAc)	
(8:2).	 FT‐IR	 (KBr,	,	 cm‐1):	 3411	 (N‐H,	 stretching),	 3300‐2562	
(br,	OH)	(alcohol),	2352	(C‐H)	(aromatic),	1621	(C=N,	stretch),	
1591	 (C=C)	 (aromatic).	 1H	 NMR	 (300	 MHz,	 MeOD,	 δ,	 ppm):	
1.61‐1.59	(d,	J	=	6.6	Hz,	3H,	CH3),	3.30	(s,	1H,	OH),	4.83	(s,	1H,	
N‐H),	5.08‐5.02	(q,	J	=	6.6	Hz,	1H,	CH),	7.19‐7.16	(q,	J	=	3.3	Hz,		



Begum	et	al.	/	European	Journal	of	Chemistry	5	(4)	(2014)	557‐562	 559	
 

	 	

NH2

NH2
HO R

O

N

H
N

R

5a-d

Compounds R
5a H
5b CH3
5c C2H5
5d 1-Ethyl alcohol

	
	

Scheme	2	
	

	

2H,	Ar‐H),	7.53‐7.50	(q,	J	=	3.0	Hz,	2H,	Ar‐H).	MS	(EI,	m/z	(%)):	
160	(M+,	50),	145	(15),	132	(25),	118	(55),	82.9	(100),	43	(78).	
	
2.2.4.	General	procedure	for	the	preparation	of	N‐phthaloyl	
glycine	amides	(4a‐h)	
	

To	a	solution	of	amines	3a‐h	in	CHCl3	(2‐5	mL),	2M	sodium	
acetate	 (10	 mL)	 was	 added	 and	 stirred	 vigorously	 then	 a	
solution	of	phthaloylglycyl	chloride	(1.5	eq)	 in	CHCl3	(3‐5mL),	
was	added	to	a	reaction	mixture	and	left	for	stirring	for	2	h,	the	
organic	layer	was	separated	and	washed	with	Na2CO3	solution	
three	times,	the	resulting	organic	layer	(CHCl3)	was	dried	with	
Na2SO4	 and	 concentrated,	 washed	 the	 solid	 residue	 with	
methanol	to	get	the	pure	product	(Scheme	1)	[26].	

2‐(1,3‐Dioxoisoindolin‐2‐yl)‐N,N‐dimethylacetamide	 (4a)	
[27]:	Color:	White.	Yield:	30%.	M.p.:	168‐170	°C.	Rf:	0.70	(CHCl3:	
EtOAc)	 (7:3).	 FT‐IR	 (KBr,	 ,	 cm‐1):	 1773,	 1721	 (C=O)	 (imide),	
1656	 (C=O)	 (amide),	1614	(aromatic),	1429	(C‐N),	721	(ortho	
subst,	Ar.	ring).	1H	NMR	(400	MHz,	CDCl3,	δ,	ppm):	2.92	(s,	3H,	
N‐CH3),	3.06	(s,	3H,	N‐CH3),	4.44	(s,	2H,	N‐CH2‐C=O),	7.66‐7.83	
(m,	4H,	Ar‐H).	13C	NMR	(100	MHz,	CDCl3,	δ,	ppm):	35.78	(1C,	N‐
CH3),	36.17	(1C,	N‐CH3),	39.19	(1C,	N‐CH2‐C=O),	123.4	(2C,	Ar‐
C),	132.29	(2C‐Ar‐C),	133.95	(2C,	Ar‐C),	165.27	(2C,	C=O),	168.0	
(1C,	C=O).	MS	 (EI,	m/z	 (%)):	232	 (M+,	8.41),	160	 (12.49),	133	
(3.18),	103	(7.28),	72	(100).	

2‐(1,3‐Dioxoisoindolin‐2‐yl)‐N,N‐diethylacetamide	(4b)	[28]:	
Color:	 White.	 Yield:	 65%.	 M.p.:	 158‐160	 °C.	 Rf:	 0.80	 (CHCl3	
:EtOAc)	 (8:2).	FT‐IR	 (KBr,	,	 cm‐1):	 1769,	1720	 (C=O)	 (imide),	
1659	 (C=O)	 (amide),	1617	(aromatic),	1464	(C‐N),	714	(ortho	
subst,	Ar.	ring).	 1H	NMR	(400	MHz,	CDCl3,	δ,	ppm):	1.08‐1.129	
(t,	J	=	5.4	Hz,	3H,	CH2‐CH3),	1.28‐1.31(t,	J	=	5.4	Hz,	3H,	CH2‐CH3),	
3.34‐3.36	 (q,	 J	=	3.3	Hz,	 4H,	 2	 (CH2‐CH3)),	 4.45	 (s,	 2H,	N‐CH2‐
C=O),	 7.67‐7.85	 (m,	 4H,	 Ar‐H).	 13C	 NMR	 (100	 MHz,	 CDCl3,	 δ,	
ppm):	12.87	 (1C,	CH3),	14.14	 (1C,	CH3),	39.01	 (1C,	N‐CH2‐CO),	
40.77	(1C,	N‐CH2),	41.30	(1C,	N‐CH2),	123.39	(2C,	Ar‐C),	132.32	
(2C,	 Ar‐C),	 133.89	 (2C,	 Ar‐C),	 164.48	 (2C,	 C=O),	 168.05	 (1C,	
C=O).	MS	(EI,	m/z	(%)):	260	(M+,	3.17),	161	(2.04),	133	(2.52),	
100	(52.31),	72(100),	58	(5.74).	

N,N‐Di‐sec‐butyl‐2‐(1,3‐dioxoisoindolin‐2‐yl)acetamide	 (4c):	
Color:	 White.	 Yield:	 34%.	 M.p.:	 130‐132	 °C.	 Rf:	 0.68	 (CHCl3:	
EtOAc)	 (8:2).	 FT‐IR	 (KBr,	 ,	 cm‐1):	 1771,	 1719	 (C=O)	 (imide),	
1647	 (C=O)	 (amide),	1629	(aromatic),	1418	(C‐N),	713	(ortho	
subst,	Ar.	ring).	1H	NMR	(400	MHz,	CDCl3,	δ,	ppm):	0.86‐0.88	(d,	
J	=	6.6	Hz,	6H,	2CH3),	1.01‐1.03	(d,	J	=	6.6	Hz,	6H,	2CH3),	1.96‐
2.13	(m,	2H,	2CH),	3.1‐3.2	(q,	J	=	7.5	Hz,	4H,	2CH2),	4.56	(s,	2H,	
N‐CH2‐CO),	7.79‐7.88	(m,	4H,	Ar‐H).	13C	NMR	(100	MHz,	CDCl3,	
δ,	ppm):	20.30	(2C,	2CH3),	27.64	(2C,	2CH3),	28.79	(2C,	2CH2),	
40.37	 (1C,	 N‐CH2‐CO),	 54.64	 (1C,	 CH),	 55.71	 (1C,	 CH),	 124.28	
(2C,	 Ar‐C),	 133.60	 (2C,	 Ar‐C),	 135.47	 (2C,	 Ar‐C),	 168.63	 (2C,	
C=O),	169.39	(1C,	C=O).	MS	(EI,	m/z	(%)):	316	(M+,	11.1),	188	
(34.4),	160	(30.8),	133	(13.4),	104	(18.9),	78	(2.9).	

2‐(1,3‐Dioxoisoindolin‐2‐yl)‐N‐propylacetamide	 (4d)	 [29]:	
Color:	 White.	 Yield:	 57%.	 M.p.:	 164‐166	 °C.	 Rf:	 0.65	 (CHCl3:	
EtOAc)	 (8:2).	 FT‐IR	 (KBr,	 ,	 cm‐1):	 3412	 (NH)	 (amide),	 1774,	
1726	 (C=O)	 (imide),	 1655	 (C=O)	 (amide),	 1629	 (aromatic),	
1419	 (C‐N),	 712	 (ortho	 subst,	 Ar.	 ring).	 1H	 NMR	 (400	 MHz,	
CDCl3,	δ,	ppm):	0.89‐0.99	(t,	 J	=	8.1	Hz,	3H,	CH2‐CH3),	1.66	(m,	
2H,	 CH2‐CH2‐CH3),	 3.13‐3.33	 (t,	 J	 =	 6.9	 Hz,	 2H,	 CH2‐CH2‐CH3),	
4.83	 (s,	 2H,	N‐CH2‐CO),	 7.49‐7.88	 (m,	4H,	Ar‐H),	 8.02	 (s,	 1H,	 ‐
NH‐).	13C	NMR	(100	MHz,	CDCl3,	δ,	ppm):	11.87	(1C,	CH3),	23.49	

(1C,	CH2),	44.24	(1C,	N‐CH2‐CO),	124.31	(2C‐Ar‐C),	131.65	(2C‐
Ar‐C),	 135.87	 (2C,	 Ar‐C),	 169.33	 (2C,	 C=O),	 171.79	 (1C,	 C=O).	
MS	(EI,	m/z	(%)):	246	(M+,	6.7),	205	(3.4),	188	(5.9),	161	(100),	
148	(3.4),	134	(2.2),	105	(22.6).	

2‐(1,3‐Dioxoisoindolin‐2‐yl)‐N‐pentylacetamide	 (4e):	 Color:	
White.	 Yield:	 35%.	 M.p.:	 180‐182	 °C.	 Rf:	 0.78	 (CHCl3:EtOAc)	
(9:1).	 FT‐IR	 (KBr,	 ,	 cm‐1):	 3290	 (NH)	 (amide),	 1777,	 1728	
(C=O)	(imide),	1659	(C=O)	(amide),	1617	(aromatic),	1420	(C‐
N),	 714	 (ortho	 subst,	 Ar.	 ring).	 1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	
ppm):	 0.74‐0.78	 (t,	 J	 =	 6.6	 Hz,	 3H,	 CH3),	 1.17	 (m,	 4H,	 2CH2),	
1.35‐1.40	(t,	J	=	6.0	Hz,	2H,	CH2),	3.0‐3.11	(t,	J	=	7.2	Hz,	2H,	CH2),	
4.19	(s,	2H,	N‐CH2‐C=O),	7.61‐7.76	(m,	4H,	Ar‐H),	8.02	(s,	1H,	‐
NH‐).	13C	NMR	(100	MHz,	CDCl3,	δ,	ppm):	13.65	(1C,	CH3),	22.05	
(1C,	CH2),	28.73	(2C,	2CH2),	39.51	(1C,	CH2),	40.19	(1C,	N‐CH2‐
CO),	 123.27	 (2C,	 Ar‐C),	 131.78	 (2C,	 Ar‐C),	 134.06	 (2C,Ar‐C),	
166.31	(2C,	C=O),	167.87	(1C,	C=O).	MS	(EI,	m/z	(%)):	274	(M+,	
21.3),	205	(18.6),	188	(34.9),	161	(100),	146	(3.8),	133	(56.9),	
86	(8.3),	78(8.6).	

2‐(1,3‐Dioxoisoindolin‐2‐yl)‐N‐(4‐methoxyphenyl)acetamide	
(4f)	 [30]:	 Color:	 Light	 grey.	 Yield:	 18%.	 M.p.:	 128‐132	 °C.	 Rf:	
0.76	 (CHCl3:EtOAc)	 (9:1).	 FT‐IR	 (KBr,	 ,	 cm‐1):	 3416	 (NH)	
(amide),	1775,	1729	(C=O)	(imide),	1660	(C=O)	(amide),	1643	
(aromatic),	 1414	 (C‐O),	 716	 (ortho	 subst,	 Ar.	 ring).	 1H	 NMR	
(400	MHz,	CDCl3,	 δ,	 ppm):	3.66	 (s,	 3H,	O‐CH3),	4.37	 (s,	 2H,	N‐
CH2‐CO),	6.71‐6.73	 (d,	 J	=	6.6	Hz,	2H,	Ar‐H),	7.25‐7.34	 (m,	4H,	
Ar‐H),	7.76‐7.78	(d,	J	=	2.1	Hz,	2H,	Ar‐H),	7.25	(s,	1H,	‐NH‐).	13C	
NMR	 (100	 MHz,	 CDCl3,	 δ,	 ppm):	 41.71	 (1C,	 N‐CH2‐CO),	 55.47	
(1C,	 OCH3),	 114.21	 (2C,	 Ar‐C),	 121.86	 (2C,	 Ar‐C),	 123.74	 (2C,	
Ar‐C),	 134.35	 (2C,	 Ar‐C),	 135.40	 (2C,	 Ar‐C),	 139.40	 (1C,	 Ar‐C‐
NH),	 156.50	 (1C,	 Ar‐COCH3),	 165.55	 (2C,	 C=O),	 167.82	 (1C,	
C=O).	MS	(EI,	m/z	(%)):	310	(M+,	99.1),	161	(50.9),	160	(100),	
133	(13.0),	123	(86.3),	108	(17.8),	78	(14.8).	

2‐(1,3‐Dioxoisoindolin‐2‐yl)‐N‐(pyridin‐2‐yl)acetamide	 (4g)	
[28]:	Color:	Light	yellow.	Yield:	21%.	M.p.:	134‐138	°C.	Rf:	0.76	
(CHCl3:EtOAc)	 (9:1).	 FT‐IR	 (KBr,	,	 cm‐1):	 3414	 (NH)	 (amide),	
1771‐1722	 (C=O)	 (imide),	 1693	 (C=O)	 (amide),	 1662	 (aro‐
matic),	 1421	 (C‐N),	 714	 (ortho	 subst,	 Ar.	 ring).	 1H	NMR	 (400	
MHz,	CDCl3,	δ,	ppm):	4.50	(s,	2H,	N‐CH2‐CO),	7.67‐7.84	(m,	4H,	
Ar‐H),	7.76‐7.77	(d,	J	=	5.6	Hz,	1H,	Ar‐H),	7.50	(d,	J	=	1.6	Hz,	1H,	
Ar‐H),	8.05‐8.07	(d,	 J	=	6.4	Hz,	1H,	Ar‐H),	8.16‐8.17	(d,	 J	=	4.0	
Hz,	1H,	Ar‐H),	9.30	(s,	1H,	‐NH‐).	 13C	NMR	(100	MHz,	CDCl3,	δ,	
ppm):	41.39	(1C,	N‐CH2‐CO),	110.04	(1C,	Ar‐C),	114.49	(1C,	Ar‐
C),	 123.69	 (2C,	 Ar‐C),	 132.01	 (2C,	 Ar‐C),	 134.26	 (2C,	 Ar‐C),	
138.55	(1C,	Ar‐C),	147.65	(1C,	Ar‐C),	150.99	(1C,	Ar‐C),	164.76	
(1C,	C=O),	167.72	(2C,	C=O).	MS	(EI,	m/z	(%)):	281	(M+,	23.8),	
188	 (4.1),	 160	 (99.5),	 134	 (56.5),	 121	 (100),	 105	 (10.4),	 78	
(20.7).	

2‐(1,3‐Dioxoisoindolin‐2‐yl)‐N‐(2‐hydroxyethyl)acetamide	
(4h)	 [31]:	Color:	White.	Yield:	87%.	M.p.:	110‐112	 °C.	Rf:	0.65	
(CHCl3:MeOH)	 (8:2).	 FT‐IR	 (KBr,	,	 cm‐1):	 3472	 (NH)	 (amide),	
3590	(OH)	(alcohol),	1770	(C=O)	(imide),	1699	(C=O)	(amide),	
1650	 (aromatic),	 1056	 (C‐O),	 725	 (ortho	 subst,	 Ar.	 ring).	 1H	
NMR	(400	MHz,	CDCl3,	δ,	ppm):	3.73	(t,	J	=	5.4	Hz,	2H,	CH2),	3.79	
(t,	J	=	5.1	Hz,	2H,	CH2),	4.50	(s,	1H,	OH),	4.84	(s,	2H,	N‐CH2‐CO),	
7.75‐7.84	(m,	4H,	Ar‐H),	8.02	(s,	1H,	‐NH‐).	13C	NMR	(100	MHz,	
CDCl3,	δ,	ppm):	29.14	(1C,	CH2),	39.15	(1C,	CH2),	44.23	(1C,	N‐
CH2‐CO),	124.10	(2C,	Ar‐C),	136.09	(2C,	Ar‐C),	140.96	(2C,	Ar‐
C),	165.35	 (2C,	C=O),	169.05	 (1C,	C=O).	FAB	MS	 (+,	m/z):	249	
[M+H].	

	



560	 Begum	et	al.	/	European	Journal	of	Chemistry	5	(4)	(2014)	557‐562	
	

	

	
	

Scheme	3
	
	

2.2.5.	General	procedure	for	the	preparation	of	
benzimidazole	derivatives	of	N‐phthaloylglycine	(6a‐d)	
	

To	a	solution	of	Benzimidazole	derivatives	(5a‐d)	in	CHCl3	
(2‐5	mL),	 2M	 sodium	 acetate	 (10	mL)	was	 added	 and	 stirred	
vigorously	 then	a	 solution	of	phthaloylglycyl	 chloride	 (1.5	eq)	
in	CHCl3	(3‐5mL),	was	added	to	a	reaction	mixture	and	left	for	
stirring	 for	 2	 h,	 the	 organic	 layer	was	 separated	 and	washed	
with	aqueous	Na2CO3	solution	three	times,	the	resulting	organic	
layer	 was	 dried	 with	 Na2SO4	 and	 concentrated,	 washed	 the	
solid	residue	with	methanol	to	get	the	pure	product	(Scheme	3)	
[26].	

2‐[2‐(1H‐Benzimidazol‐1‐yl)‐2‐oxoethyl]‐1H‐isoindole‐1,3	
(2H)‐dione	(6a):	Color:	White.	Yield:	32	%.	M.p.:	230‐232	°C.	Rf:	
0.53	 (CHCl3:MeOH)	 (9:1).	 FT‐IR	 (KBr,	 ,	 cm‐1):	 1776,	 1715	
(C=O)	(imide),	1674	(C=O)	(amide),	1650	(aromatic),	1423	(C‐
N),	 725	 (ortho	 subst,	 Ar.	 ring).	 1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	
ppm):	5.13	 (s,	 2H,	N‐CH2‐C=O),	7.75‐7.80	 (m,	4H,	Ar‐H),	7.82‐
7.91	 (m,	4H,	Ar‐H),	8.52	 (s,	 1H,	N‐CH=N).	 13C	NMR	 (100	MHz,	
CDCl3,	δ,	ppm):	40.52	(1C,	N‐CH2‐O),	115.27	(1C,	Ar‐C),	120.06	
(1C,	Ar‐C),	123.66	(2C,	Ar‐C),	125.51	(1C,	Ar‐C),	126.26	(1C,	Ar‐
C),	 130.90	 (1C,	 Ar‐C),	 131.58	 (2C,	 Ar‐C),	 134.13	 (2C,	 Ar‐C),	
140.33	 (1C,	 N‐CH=N),	 142.76	 (1C,	 Ar‐C),	 163.85	 (1C,	 C=O),	
167.40	(1C,	Ar‐C).	MS	(EI,	m/z	(%)):	305	(M+,	7.5),	188	(12.4),	
160	(100),	119	(29.42),	104	(9.96),	78	(4.04).	

2‐[2‐(2‐Methyl‐1H‐benzimidazol‐1‐yl)‐2‐oxoethyl]‐1H‐iso	
indole‐1,3(2H)‐dione	 (6b):	 Color:	White.	 Yield:	 32%.	M.p:	232‐
234	°C.	Rf:	0.65	(CHCl3:EtOH)	(8:2).	FT‐IR	(KBr,	,	cm‐1):	1769,	
1713	 (C=O)	 (imide),	 1686	 (C=O)	 (amide),	 1614	 (aromatic),	
1425	 (C‐N),	 725	 (ortho	 subst,	 Ar.	 ring).	 1H	 NMR	 (400	 MHz,	
CDCl3,	δ,	ppm):	2.81	(s,	3H,	CH3),	5.10	(s,	2H,	N‐CH2‐CO),	7.13‐
7.37	(m,	4H‐Ar‐H),	7.65‐7.78	(m,	4H,	Ar‐H).	13C	NMR	(100	MHz,	
CDCl3,	δ,	ppm):	18.91	 (1C,	CH3),	42.84	 (1C,	N‐CH2‐CO),	113.76	
(1C,	Ar‐C),	119.88	(1C,	Ar‐C),	123.50	(2C,	Ar‐C),	124.93	(1C,	Ar‐
C),	 125.06	 (1C,	 Ar‐C),	 131.78	 (1C,	 Ar‐C),	 134.21	 (2C,	 Ar‐C),	
142.23	 (1C,	 N‐CH=N),	 153.22	 (2C,	 Ar‐C),	 165.63	 (1C,	 C=O),	
167.40	(2C,	C=O).	MS	(EI,	m/z	 (%)):	319	(M+,	4.6),	291	(11.5),	
160	(100),	147	(34.2),	132	(55.8),	104	(45.5),	78	(3.5).	

2‐[2‐(2‐Ethyl‐1H‐benzimidazol‐1‐yl)‐2‐oxoethyl]‐1H‐iso	
indole‐1,3(2H)‐dione	 (6c):	Color:	White.	Yield:	30%.	M.p.:	208‐
210	°C.	Rf:	0.65(CHCl3:EtOAc)	(8:2).	FT‐IR	(KBr,	,	cm‐1):	1774,	
1710	 (C=O)	 (imide),	 1686	 (C=O)	 (amide),	 1650	 (aromatic),	
1425	 (C‐N),	 1056	 (C‐O),	 725	 (ortho	 subst,	 Ar.	 ring).	 1H	 NMR	
(400	 MHz,	 CDCl3,	 δ,	 ppm):	 1.09‐1.28	 (t,	 J	 =	 7.2	 Hz,	 3H,	 CH3),	
3.02‐3.08	 (q,	 J	=	7.2	Hz,	2H,	CH2‐CH3),	5.03	 (s,	 2H,	N‐CH2‐CO),	
7.24‐7.27	(m,	4H,	Ar‐H),	7.76‐7.80	(m,	4H,	Ar‐H).	13C	NMR	(100	
MHz,	 CDCl3,	 δ,	 ppm):	 11.83	 (1C,	 CH3),	 25.28	 (1C,	 CH2),	 42.97	
(1C,	 N‐CH2‐CO),	 113.47	 (1C,	 Ar‐C),	 120.01	 (1C,	 Ar‐C),	 123.26	
(1C,	Ar‐C),	123.48	(1C,	Ar‐C),	124.88	(2C,	Ar‐C),	131.57	(1C,	Ar‐
C),	 134.0	 (1C,	 Ar‐C),	 134.48	 (2C,	 Ar‐C),	 142.23	 (N‐CH=N),	
158.44	 (1C,	 C=O),	 167.47	 (2C,	 C=O).	 MS	 (EI,	m/z	 (%)):	 333.1	
(M+,	58),	305	(4.3),	188	(5.4),	173	(46.6),	160	(100),	147	(96),	
133	(11.4),	78	(2).	

2‐(2‐(2‐(1‐Hydroxyethyl)‐1H‐benzo[d]imidazol‐1‐yl)‐2‐oxo	
ethyl)isoindoline‐1,3‐dione	(6d):	Color:	White.	Yield:	32%.	M.p.:	
180‐200	 °C.	Rf:	 0.65	 (CHCl3:EtOAc)	 (8:2).	 FT‐IR	 (KBr,	,	 cm‐1):	
3590‐2625	 (OH)	 (alcohol),	 1775,	 1722	 (C=O)	 (imide),	 1699	
(C=O)	 (amide),	 1650	 (aromatic),	 1420	 (C‐N),	 1056	 (C‐O),	 725	
(ortho	subst,	Ar.	ring).	1H	NMR	(400	MHz,	CDCl3,	δ,	ppm):	1.76	
(d,	J	=	6.6	Hz,	3H,	CH3),	3.76	(s,	1H,	OH),	4.64	(s,	2H,	N‐CH2‐CO),	
5.25	(q,	J	=	16.8	Hz,	1H,	CH‐CH3),	7.66‐7.72	(m,	4H,	Ar‐H),	7.90‐
7.94	 (m,	4H,	Ar‐H).	 13C	NMR	 (100	MHz,	CDCl3,	 δ,	 ppm):	18.41	
(1C,	CH3),	42.95	(1C,	CH‐OH),	68.77	(1C,	N‐CH2‐CO),	113.24	(1C,	
Ar‐C),	121.80	 (1C,	Ar‐C),	123.50	 (1C,	Ar‐C),	123.98	 (1C,	Ar‐C),	
125.28	 (2C,	Ar‐C),	 131.47	 (2C,	Ar‐C),	 131.97	 (1C,	Ar‐C),	 134.0	
(2C,	 Ar‐C),	 134.5	 (1C,	 Ar‐C),	 142.58	 (1C,	 N‐C=N),	 154.51	 (1C,	
C=O),	 167.47	 (2C,	 C=O).	MS	 (EI,	m/z	 (%)):	 349	 (M+,	 23),	 331	
(8.1),	305	(26.4),	288	(36.9),	273	(67.5),	258	(17.5),	187	(15.6),	
160	(100),	145	(77.9),	132	(27.1),	104	(42.3),	78(2).	
	
2.2.6.	Antimicrobial	activity	assay	
	

Disc	 diffusion	 method	 was	 adopted	 to	 determine	 the	
antimicrobial	activity	of	compounds	4a‐h	and	6a‐d	using	6	mm	
sterile	 filter	 disc.	 Clinical	 isolates	 of	 Staphylococcus	 aureus	
(KIBGE:	 MBSA‐01	 to	 MBSA‐43),	 strains	 of	 Staphylococcus	
aureus	 (ATCC	 6538),	 Enterococcus	 faecalis	 (ATCC	 29212),	
Bacillus	 cereus	 (ATCC	 11778),	 Salmonella	 typhi	 (ATCC	 3632)	
and	Pseudomonas	aeruginosa	(KIBGE:	IB‐67)	were	used	[32].	

Solutions	 of	 the	 compounds	were	 prepared	 in	 chloroform	
(Merck,	Germany),	 concentrations	 ranging	 from	7.5	 to	350	µg	
per	disc.	As	positive	control	antimicrobial	susceptibility	discs	of	
vancomycin	 (30	 µg),	 oxcillin	 (1	 µg)	 and	 ciprofloxacin	 (5	 µg)	
(Oxoid,	UK)	were	used,	whereas	chloroform	disc	were	used	as	
negative	control.	

Microorganisms	were	culture	in	Luria	Broth	(Oxoid,	UK)	at	
35	°C,	overnight.	1.5×106	cells/mL	(0.5	McFarland	index)	were	
inoculated	on	Mueller	Hinton	Agar	(Oxoid,	UK)	[33,34].	On	each	
plate	 filter	 disc	 with	 given	 compounds,	 positive	 and	 negative	
control	discs	were	placed.	After	an	incubation	period	of	24	h	at	
35‐37	 °C,	 zone	 of	 inhibition	 (in	 mm)	 were	 measured	 under	
bright	light	and	on	non‐reflecting	background.	
	
3.	Result	and	discussions	
	

In	 the	 present	 study,	 two	 series	 of	 N‐phthaloylglycine	
derivatives	 (4a‐h	 and	 6a‐d)	 were	 prepared	 under	 Schotten‐
Baumann	 reaction	 conditions	 and	 were	 evaluated	 for	
antibacterial	 activity	 against	 methicillin‐resistant	 S.	 aureus	
(MRSA)	 and	 vancomycin‐resistant	 S.	 aureus	 (VRSA).	 In	 disc	
diffusion	 method,	 antimicrobial	 activities	 were	 evaluated	 by	
measuring	 the	 diameter	 of	 zone	 of	 inhibition	 against	 test	
organisms	 and	 minimal	 inhibitory	 concentration	 (MIC),	 the	
values	of	which	are	displayed	in	Tables	1,	2	and	3,	respectively	
[29].	 Almost	 all	 the	 compounds	 showed	 some	 activity	 against	
VRSA	and	MRSA.		



Begum	et	al.	/	European	Journal	of	Chemistry	5	(4)	(2014)	557‐562	 561	
 

	
Table	1.	Antibacterial	activity	of	N‐phthaloylglycine	derivatives	(i.e.	4a‐h,	and	6a‐d)	against	vancomycin	resistant	Staph.	aureus	(VRSA)	(N	=	40).	
Compounds	 Zone	of	inhibition	(mm)	 No	inhibition	

(Number	of	strains)	
Inhibition		
(Number	of	strains)	

%	Inhibition	
	Minimum	 Maximum	

4a	 2±0.07	 10±1.5	 29	 11	 27.50	
4b	 3±0.10	 8±1.3	 10	 30	 75.00	
4c	 2±0.08	 10±1.8	 08 32 80.00	
4d	 3±0.09	 6±1.1	 13 27 67.50	
4e	 3±0.06	 8±1.8	 11 29 72.50	
4f	 2±0.04	 6±1.4	 12 28 70.00	
4g	 2±0.06	 8±1.6	 10 30 75.00	
4h	 3±0.80	 8±1.1	 18 22 55.00	
6a	 2±0.04	 8±1.8	 30	 10	 25:00	
6b	 3±0.10	 8±1.5	 25	 15	 37.50	
6c	 3±0.08	 6±0.9	 15	 25	 62.50	
6d	 2±0.06	 8±1.1	 23 17 42.50	
	
	
Table	2.	Antibacterial	activity	of	N‐phthaloylglycine	derivatives	(i.e.	4a‐h,	and	6a‐d)	against	methicillin	resistant	Staph.	aureus	(MRSA)	(N	=	44).	
Compounds	 Zone	of	inhibition	(mm)	 No	inhibition

(Number	of	strains)	
Inhibition	
(Number	of	strains)	

%	Inhibition
	Minimum	 Maximum	

4a	 3±0.10	 6±0.8	 18 26 59.09	
4b	 1±0.07	 8±0.9	 17 27 61.36	
4c	 2±0.08	 6±0.7	 12	 32	 72.72	
4d	 2±0.04	 6±0.8	 10	 34	 77.27	
4e	 1±0.06	 4±0.5	 18 26 59.09	
4f	 1±0.04	 7±0.6	 18	 26	 59.09	
4g	 2±0.10	 9±0.8	 15	 29	 65.90	
4h	 1±0.08	 8±0.7	 19 25 56.81	
6a	 1±0.09	 5±0.2	 12 32 72.72	
6b	 2±0.08	 4±0.09	 18 26 59.09	
6c	 1±0.09	 5±0.4	 16 28 63.63	
6d	 3±0.07	 5±0.08	 10 34 77.27	
	
	
Table	3.	Antibacterial	activity	of	N‐phthaloylglycine	derivatives	(i.e.	4a‐h,	and	6a‐d)	against	various	strains	of	Staph.	aureus.	
Compounds	 MIC	(mg/L),	VRSA,	(N	=	40)	 MIC	(mg/L),	MRSA,	(N	=	44)	
4a	 0.6 2.5
4b	 4.0 3.6
4c	 5.5 7.0
4d	 4.2	 6.3	
4e	 0.7	 2.9	
4f	 7.5	 4.2	
4g	 3.6 0.8
4h	 0.5	 1.6	
6a	 1.5 8.2
6b	 2.4 1.5
6c	 3.0 3.2
6d	 2.0 4.6
Vancomycin	(Standard	drug)	 4.0 ‐
Methicillin	(Standard	drug)	 ‐ 4.0
	

	
	
Compound	4c,	was	 found	 to	 be	 the	most	 effective	 against	

the	highest	number	of	clinical	 isolates	of	VRSA	(80%),	with	an	
inhibitory	zone	ranging	from	2	to	6	mm	(Table	1).	Compounds	
6a	and	4c	were	found	to	be	the	most	effective	against	highest	
number	 of	 clinical	 isolates	 of	 MRSA	 (77.7%),	 with	 a	 zone	 of	
inhibition	ranging	from	2	to	10	mm	(Table	2).	

In	particular,	compounds	4h	(MIC,	0.5	mg	/L),	4a	(MIC,	0.6	
mg	/L),	and	4e	 (MIC,	0.7	mg	/L)	were	 found	 to	be	6	 to	8	 fold	
more	 potent	 against	 VRSA	 as	 compared	 to	 the	 standard	
vancomycin	 (MIC,	 4.0	 mg	 /L).	 Compounds	 4g,	 6b	 and	 4h	
displayed	excellent	activity	against	MRSA	(MIC,	0.8,	1.5	and	1.6	
mg/L,	 respectively)	 as	 compared	 to	 the	 standard	 methicillin	
(MIC,	 4.0	mg	 /L)	 (Table	3).	Moreover,	 compounds	4c,	4d,	6a,	
and	 6d	 showed	 significant	 growth	 inhibitory	 activity	 against	
most	 of	 the	 tested	 strains	 for	 MRSA	 (Table	 2),	 whereas	
compounds	 4b,	 4c	 and	 4g,	 showed	 significant	 growth	
inhibitory	 action	 against	 most	 of	 the	 tested	 strains	 for	 VRSA	
(Table	1).	Interestingly,	acylic	amides	provide	the	most	potent	
analogs	against	VRSA.		

The	 compound	 4h	 is	 found	 to	 be	 the	 most	 active,	 as	 it	
exhibited	 an	 MIC	 of	 0.5	 mg/L	 against	 VRSA,	 and	 MIC	 of	 1.6	
mg/L	 against	 MRSA,	 as	 well	 (Table	 3).	 This	 observation	
indicates	 that	 the	 presence	 of	 hydroxyl	 group	 enhances	 the	
antimicrobial	activity	when	compared	 to	4d	 that	 lacks	 the	OH	
group.	 The	 antibacterial	 activity	 of	 N‐phthaloylglycine	

derivatives	 (i.e.	 4a‐h	 and	 6a‐d)	 were	 also	 illustrated	
graphically	in	Figures	1,	2	and	3.	
	

	

Figure	1.	Antibacterial	 activity	 of	N‐phthaloylglycine	 derivatives	 (i.e.	4a‐h,	
and	6a‐d)	against	vancomycin	resistant	Staph.	aureus	(VRSA).	
	
4.	Conclusion	
	

The	 development	 of	 antimicrobial	 resistance	 in	 many	
pathogenic	 microbes	 possesses	 one	 of	 the	 most	 serious	



562	 Begum	et	al.	/	European	Journal	of	Chemistry	5	(4)	(2014)	557‐562	
	
problems	 in	 the	 control	of	 infectious	diseases.	 In	 this	 context,	
two	 series	 of	 the	 N‐phthaloylglycine	 derivative	 were	
synthesized	and	evaluated	against	in	vitro	antibacterial	activity.	
The	 compounds	4h,	4e,	 and	4a	 were	 found	 to	 be	 6	 to	 8	 fold	
more	 potent	 against	 VRSA	 as	 compare	 to	 the	 standard	
vancomycin.	 The	 results	 suggest	 that	 the	 N‐phthaloylglycine	
derivatives	 are	 interesting	 lead	molecules	 for	 further	 studies.	
More	extensive	work	is	still	needed	to	confirm	the	preliminary	
results	 and	 mode	 of	 action	 to	 design	 and	 synthesize	 the	
potential	antimicrobial	agents.	
	

	
	

Figure	2.	Antibacterial	 activity	 of	N‐phthaloylglycine	 derivatives	 (i.e. 4a‐h,	
and	6a‐d)	against	methicillin	resistant	Staph.	aureus	(MRSA).	
	
	

	
	

Figure	3.	Antibacterial	 activity	 of	N‐phthaloylglycine	 derivatives	 (i.e. 4a‐h,	
and	6a‐d)	against	various	strains	of	Staph.	aureus.	
	
Acknowledgement	
	

The	authors	would	like	to	thank	the	Hussain	Ebrahim	Jamal	
Research	 Institute	 of	 Chemistry,	 International	 Center	 for	
Chemical	and	Biological	Sciences,	University	of	Karachi,	for	the	
spectral	analysis	and	the	Karachi	Institute	of	Biotechnology	and	
Genetic	 Engineering	 (KIBGE),	 University	 of	 Karachi	 for	
conducting	the	antibacterial	assay.	
	
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