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European	Journal	of	Chemistry	4	(2)	(2013)	92‐97	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2013	EURJCHEM	

DOI:10.5155/eurjchem.4.2.92‐97.615	

	
	

	

	

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

	 	 	

Synthesis	of	some	novel	1,2,4‐triazole	derivatives		
as	potential	antimicrobial	agents	

Mohamed	Sayed	Behalo	*,	Aly	Abdelmaboud	Aly,	Ashraf	Farouk	Wasfy	and	Marwa	Mohamed	Rizk	

Chemistry	Department,	Faculty	of	Science,	Benha	University,	Benha,	13518,	Egypt	

*Corresponding	author	at:	Chemistry	Department,	Faculty	of	Science,	Benha	University,	Benha,	13518,	Egypt.	
Tel.:	+2.010.1599607;	fax:	+2.013.3222578.	E‐mail	address:	mohamedbehalo@hotmail.com	(M.	Behalo).	

	
	

	 	

	 	 	
ARTICLE	INFORMATION	 	 ABSTRACT	
Received:	18	April	2012	
Received	in	revised	form:	05	June	2012	
Accepted:	05	June	2012	
Online:	30	June	2013	

KEYWORDS	

	 An	efficient	synthesis	of	1,2,4‐triazole	derivatives,	fused	to	five	and	six	membered	rings	from
4‐amino‐5‐[(quinolin‐8‐yloxy)methyl]‐4H‐1,2,4‐triazole‐3‐thiole	 (2)	 was	 described.	 The
structural	 formula	of	all	 derivatives	was	 confirmed	and	 characterized	by	elemental	 analysis
and	 spectral	 studies.	 Some	 of	 the	 synthesized	 compounds	 were	 also	 investigated	 for	 their
antibacterial	and	antifungal	activities	and	compared	with	standard	drugs.	Most	of	the	tested
compounds	demonstrated	potent	to	weak	antimicrobial	activities.	

Quinoline	
1,2,4‐Triazole	
Spectroscopy	
Antifungal	activities	
Antibacterial	activities	
1,2,4‐Triazolo[3,4‐b]thiadiazole	

	
1.	Introduction	
	

The	 triazole	 ring	 is	 a	 frequent	 partner	 in	 polycyclic	
heterocyclic	 systems	 of	 biological	 significance	 and	 industrial	
applications.	 Compounds	 containing	 a	 fused	 1,2,4‐triazole	
moiety	have	attracted	attention	in	the	past	few	years	owing	to	
their	biological	activity.	A	number	of	these	class	of	compounds	
act	 as	 antibacterial	 [1‐3],	 antifungal	 [4‐6],	 anti‐inflammatory	
[7],	 analgesic	 [8‐10],	 antituberculosis	 [11]	 and	 anticonvulsant	
agents	 [12‐14].	 In	 addition,	 a	 large	 number	 of	 triazole	
derivatives	 have	 antiulcer	 [15,16],	 antidepressant[17,18],	
insecticidal	 [19],	 hypolipidemic	 [20],	 antidiabetic	 [21]	 and	
antimitotic	activity	[22].	

Also,	 azetidin‐2‐ones	 of	 3‐pyridyl‐4‐amino‐5‐mercapto‐
1,2,4‐triazoles	[23]	and	4‐(N‐pyridylcarboxamido)‐5‐mercapto‐
3‐substitued	1,2,4‐triazoles	[24]	have	been	reported	to	possess	
significant	 activity	 as	 antitumor	 and	 antiviral	 agents.	 On	 the	
other	 hand,	 quinoline	 derivatives	 have	 been	 proven	 as	
privileged	 core	 structures	 and	 confirmed	 in	 bioactive	 natural	
products	 and	 in	 various	 pharmaceutical	 agents.	 They	 are	
known	for	their	antiplasmodial	properties	and	have	been	used	
as	the	staring	compounds	for	new	antimalarial	agents	[25,26].	

Prompted	 by	 the	 varied	 biological	 activities	 of	 triazole	
derivatives	and	in	continuation	of	our	efforts	for	the	synthesis	
of	 biologically	 active	 heterocycles	 [27‐29],	 the	 present	 work	
describes	 the	 synthesis	 of	 novel	 1,2,4‐triazole	 derivatives	
attached	with	quinoline	moiety	with	the	aim	of	enhancement	of	
their	biological	activity.		
	
2.	Experimental	
	
2.1.	Instrumentation	
	

Melting	 point	 of	 the	 synthesized	 compounds	 was	
determined	 in	 Perkin	 Elmer	 apparatus	 and	 is	 uncorrected.	 IR	

spectra	were	recorded	using	KBr	pellets.	1H	NMR	spectra	were	
recorded	on	Mercury‐300BB	(NMR	200)	 in	CDCl3,	DMSO-d6	as	
solvent.	 Tetramethylsilan	 (TMS)	 served	 as	 an	 internal	
reference	and	chemical	shifts	were	expressed	in	δ	(ppm).	Mass	
spectra	 were	 recorded	 on	 GC‐MS	 Shimadzu	 QP2010.	 All	 the	
microanalysis	 and	 antimicrobial	 activities	were	 performed	 by	
the	Micro	analytical	unit,	Cairo	University.	
	
2.2.	Synthesis	
	
2.2.1.	2‐(Quinolin‐8‐yloxy)acetohydrazide	(1)	

	
The	 titled	 compound	 was	 prepared	 according	 to	 the	

method	described	in	the	literature	[30].	A	mixture	of	hydrazine	
hydrate	(0.01	mol)	and	ethyl	2‐(quinolin‐8‐yl‐oxy)acetate	(0.01	
mol)	 in	ethanol	 (30	mL)	was	heated	under	 reflux	 for	4	hours.	
After	 cooling,	 the	 precipitated	 solid	 was	 collected	 and	
recrystallized	 from	 ethanol.	 Color:	 Yellow.	 Yield:	 70%.	 M.p.:	
218‐220	 oC.	 FT‐IR	 (KBr,	,	 cm‐1):	 3322‐3254	 (NH2,	NH),	 1661	
(C=O),	 1611	 (C=N).	 1H	NMR	 (200	MHz,	 CDCl3,	 δ,	 ppm):	 9.7	 (s,	
1H,	CONH),	8.9	 (s,	 2H,	NH2),	 7.2‐7.5	 (m,	6H,	Ar‐H),	 4.9	 (s,	 2H,	
OCH2).	 MS	 (EI,	m/z	 (%)):	 217	 (M+,	 22.54),	 186	 (54.67),	 145	
(100),	 117	 (50.54),	 91	 (2.25),	 64	 (5.75).	 	 Anal.	 calcd.	 for	
C11H11N3O:	C,	60.82;	H,	5.10;	N,	19.34.	Found:	C,	60.80;	H,	5.08;	
N,	19.32%.	
	
2.2.2.	4‐Amino‐5‐[(quinolin‐8‐yloxy)methyl]‐4H‐1,2,4‐
triazole‐3‐thiol	(2)	
	

Carbon	 disulfide	 (0.015	 mol)	 was	 added	 drop	 wise	 to	 a	
solution	 of	 hydrazide	 1	 (0.01	 mol)	 in	 ethanol	 (30	 mL)	 and	
potassium	hydroxide	 (0.015	mol).	 The	mixture	was	 stirred	 at	
room	 temperature	 for	 14	 h.,	 dry	 diethyl	 ether	 (20	 mL)	 was	
added	and	the	separated	solid	was	filtered	off	and	washed	with	
diethyl	 ether,	 the	 potassium	 salt	 was	 used	 for	 the	 next	 stage	
without	further	purification.		



Behalo	et	al.	/	European	Journal	of	Chemistry	4	(2)	(2013)	92‐97	 93	
 

	

 
	

Scheme	1
	
	

Hydrazine	hydrate	 (0.02	mol)	was	 gradually	 added	 to	 the	
above	 potassium	 salt	 (0.01	 mol)	 dissolved	 in	 water	 (20	 mL)	
and	all	were	refluxed	with	stirring	for	4h.	The	reaction	mixture	
was	 cooled	 and	 acidified	 with	 conc.	 HCl.	 A	 yellow	 solid	
separated	 out	 which	 was	 filtered,	 washed	 with	 water	 and	
purified	 by	 recrystallization	 from	 ethanol	 to	 afford	 triazole	2	
(Scheme	1).	Color:	Yellow.	Yield:	65%.	M.p.:	228‐230	oC.	FT‐IR	
(KBr,	,	 cm‐1):	 3402‐3145	 (NH2),	 2911	 (CH2),	 2668(SH),	 1596	
(C=N).	1H	NMR	(200	MHz,	DMSO-d6,	δ,	ppm):	13.9	(s,	2H,	NH2),	
9.1(s,	1H,	SH),	7.7‐7.9	(m,	6H,	Ar‐H),	5.4	(s,	2H,	OCH2).	MS	(EI,	
m/z	 (%)):	 273	 (M+,	 24.82),	 145	 (100),	 117	 (40.77),	 91	 (2.42),	
64	 (6.41).	 Anal.	 calcd.	 for	 C12H11N5OS:	 C,	 52.73;	 H,	 4.06;	 N,	
25.62.	Found:	C,	52.68;	H,	4.02;	N,	25.66%.	
	
2.2.3.	General	procedure	for	preparation	of	3a‐b		
	

A	mixture	of	triazole	2	(0.01	mol)	and	urea/thiourea	(0.015	
mol)	was	 fused	 at	 232	 oC	 for	 2h.	 After	 cooling,	 the	 solid	was	
triturated	with	water	and	 filtered	off,	washed	and	crystallized	
from	ethanol.		

Alternative	 method	 for	 synthesis	 of	 3b:	 A	 mixture	 of	 an	
equimolar	 amount	of	 compound	2	and	CS2	 (0.02	mol)	 in	DMF	
(50	mL)	was	 refluxed	 for	6	h.	 then	 it	 cooled	and	poured	onto	
ice.	 The	 product	 was	 filtered	 off	 and	 crystallized	 from	 acetic	
acid	(Scheme	1).	

3‐((Quinolin‐8‐yloxy)methyl)‐[1,2,4]triazolo[3,4‐b][1,3,4]	
thiadiazol‐6(5H)‐one	(3a):	Color:	Pale	yellow.	Yield:	52%.	M.p.:	
248‐250	oC.	FT‐IR	(KBr,	,	cm‐1):	3409‐3165	(NH),	2917	(CH2),	
1685	(C=O),	1618	(C=N),	1310	cm‐1	(NCS).	 1H	NMR	(200	MHz,	
DMSO-d6,	δ,	ppm):	13.6	(s,	1H,	NH),	8.6‐7.2	(m,	6H,	Ar‐H),	5.1	(s,	
2H,	OCH2).	MS	(EI,	m/z	(%)):	298	(M+1,	25.05),	273	(31.69),	257	
(46.78),	 157	 (1.62),	 145	 (100).	 Anal.	 calcd.	 for	 C13H9N5O2S:	 C,	
52.17;	H,	3.03;	N,	23.40.	Found:	C,	52.07;	H,	2.99;	N,	23.30%.	

3‐((Quinolin‐8‐yloxy)methyl)‐[1,2,4]triazolo[3,4‐b][1,3,4]	
thiadiazol‐6(5H)‐thione	 (3b):	 Color:	 Yellow.	 Yield:	 55%.	 M.p.:	
218‐220	oC.	FT‐IR	(KBr,	,	cm‐1):	3406	(NH),	2918	(CH2),	1622	
(C=N),	1375	(NCS),	1279	(C=S).	1H	NMR	(200	MHz,	DMSO-d6,	δ,	
ppm):	8.8	(s,	1H,	NH),	8.2‐7.3	(m,	6H,	Ar‐H),	5.2	(s,	2H,	OCH2).	
MS	(EI,	m/z	(%)):	315	(M+,	15.87),	257	(3.85),	225	(12.50),	184	
(3.13),	145	(100).	Anal.	calcd.	for	C13H9N5OS2:	C,	49.51;	H,	2.88;	
N,	22.21.	Found:	C,	49.45;	H,	2.75;	N,	22.15%.	
	

2.2.4.	8‐((6‐	Methyl‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazol‐3‐
yl)methoxy)quinoline	(4)	
	

A	mixture	of	triazole	2	(0.01	mol)	and	acetyl	chloride	(0.01	
mol)	in	dry	pyridine	(25	mL)	was	heated	for	2	h	on	steam	bath.	
The	 reaction	 mixture	 was	 poured	 into	 crushed	 ice,	 the	 solid	
product	 obtained	 by	 filtration	 was	 purified	 by	 crystallization	
from	ethanol	(Scheme	1).	Color:	Yellow.	Yield:	58%.	M.p.:	203‐
205	 oC.	 FT‐IR	 (KBr,	 ,	 cm‐1):	 2921	 (CH2),	 1626	 (C=N),	 1380	
(NCS).	1H	NMR	(200	MHz,	DMSO-d6,	δ,	ppm):	8.2‐7.5	(m,	6H,	Ar‐
H),	 5.6	 (s,	 2H,	 OCH2),	 2.4	 (s,	 3H,	 CH3).	MS	 (EI,	m/z	 (%)):	 299	
(M+2,	 12.05),	 258	 (8.89),	 145(100),	 56	 (0.95).	 Anal.	 calcd.	 for	
C14H11N5OS:	C,	56.55;	H,	3.73;	N,	23.55.	Found:	C,	56.49;	H,	3.68;	
N,	23.50%.	
	
2.2.5.	General	procedure	for	preparation	of	5a‐c	
	

A	 mixture	 of	 triazole	 2	 (0.01	 mol)	 and	 aromatic	 acids	
namely	 (p‐nitrobenzoic	 acid,	 p‐aminobenzoic	 acid,	 p‐hydroxy	
benzoic	acid)	(0.01	mol)	in	the	presence	of	POCl3	(15	mL)	was	
refluxed	 for	 3	 h.	 After	 removal	 of	 the	 excess	 of	 POCl3	 under	
reduced	 pressure,	 the	 residue	 was	 added	 to	 crushed	 ice	 and	
stirred	 at	 room	 temperature	 for	 1	 h.	 during	 this	 time	 the	
solution	 was	 gradually	 neutralized	 with	 Na2CO3,	 the	 solid	
product	 was	 filtered	 off,	 washed	 with	 water,	 dried	 and	
crystallized	from	DMF	(Scheme	1).	

8‐((6‐(4‐Nitrophenyl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadi‐	
azole‐3‐yl)methoxy)quinoline	 (5a):	 Color:	 Yellow.	 Yield:	 72%.	
M.p.:	150‐152	oC.	FT‐IR	(KBr,	,	cm‐1):	2924	(CH2),	1606	(C=N),	
1496	(NO2),	1344	(NCS).	1H	NMR	(200	MHz,	DMSO-d6,	δ,	ppm):	
6.5‐8.3	(m,	10H,	Ar‐H),	5.7	(s,	2H,	OCH2).	MS	(EI,	m/z	(%)):	404	
(M+,	85.23),	257	(9.01),	225	(5.08),	145	(100),	117	(50.89),	91	
(30.45),	 64	 (0.05).	 Anal.	 calcd.	 for	 C19H12N6O3S:	 C,	 56.43;	 H,	
2.99;	N,	20.78	%.	Found:	C,	56.35;	H,	2.90;	N,	20.68	%.		

4‐(3‐((Quinolin‐8‐yloxy)methyl)‐[1,2,4]triazolo[3,4‐b][1,3,4]	
thiadiazol‐6‐yl)aniline	 (5b):	 Color:	 Yellow.	 Yield:	 74%.	 M.p.:	
208‐210	oC.	FT‐IR	(KBr,	,	cm‐1):	3410	(NH2),	2925	(CH2),	1600	
(C=N),	1316	(NCS).	1H	NMR	(200	MHz,	DMSO-d6,	δ,	ppm):	11.9	
(s,	2H,	NH2),	6.9‐8.2	 (m,	10H,	Ar‐H),	5.2	 (s,	2H,	OCH2).	MS	(EI,	
m/z	 (%)):	 375	 (M+,	 10.89),	 256	 (9.10),	 145	 (20.89),	 117	
(50.66),	 91	 (30.78),	 64	 (100).	 	 Anal.	 calcd.	 for	 C19H14N6OS:	 C,	
60.95;	H,	3.77;	N,	22.45.	Found:	C,	60.93;	H,	3.75;	N,	22.42%.	



94	 Behalo	et	al.	/	European	Journal	of	Chemistry	4	(2)	(2013)	92‐97	
	

	

 
	

Scheme	2	
	
	
4‐(3‐((Quinolin‐8‐yloxy)methyl)‐[1,2,4]triazolo[3,4‐b]	

[1,3,4]thiadiazol‐6‐yl)phenol	 (5c):	 Color:	 Yellow.	 Yield:	 66%.	
M.p.:	233‐235	oC.	FT‐IR	(KBr,	,	 cm‐1):	3387	(OH),	2925	(CH2),	
1598	(C=N),	1377	(NCS).	1H	NMR	(200	MHz,	DMSO-d6,	δ,	ppm):	
13.8	(s,	1H,	OH),	7.4‐8.3	(m,	10H,	Ar‐H),	5.3	(s,	2H,	OCH2).	Anal.	
calcd.	 for	 C19H13N5O2S:	 C,	 60.79;	 H,	 3.49;	 N,	 18.66.	 Found:	 C,	
60.75;	H,	3.50;	N,	18.68%.	
	
2.2.6.	General	procedure	for	preparation	of	6a,b	
	

Triazole	2	 (0.01	mol)	was	fused	with	phthalic	anhydrid	or	
maleic	anhydride	(0.01	mol)	 for	3h.,	 the	reaction	mixture	was	
cooled,	 triturated	with	water,	 the	separated	solid	was	filtered,	
washed	with	water	and	crystallized	from	ethanol	(Scheme	2).	

2‐(3‐Mercapto‐5‐((quinolin‐8‐yloxy)methyl)‐4H‐1,2,4‐
triazol‐4‐yl)isoindoline‐1,3‐dione	 (6a):	 Color:	 Yellow.	 Yield:	
75%.	M..p.:	126‐128	oC.	FT‐IR	(KBr,	,	cm‐1):	2923	(CH2),	2660	
(SH),	1749,	1649	(C=O),	1598	(C=N).	1H	NMR	(200	MHz,	DMSO -
d6,	 δ,	ppm):	8.8	 (s,	1H,	SH),	7.8‐8.1	 (m,	10H,	Ar‐H),	4.9	 (s,	2H,	
OCH2).	 MS	 (EI,	 m/z	 (%)):	 403	 (M+,	 2.85).	 Anal.	 calcd.	 for	
C20H13N5O3S:	 C,	 59.55;	 H,	 3.25;	 N,	 17.36.	 Found:	 C,	 59.50;	 H,	
3.35;	N,	17.40	%.	

1‐(3‐Mercapto‐5‐((quinolin‐8‐yloxy)methyl)‐4H‐1,2,4‐
triazol‐4‐yl)‐1H‐pyrrole‐2,5‐dione	 (6b):	 Color:	 Pale	 yellow.	
Yield:	73%.	M.p.:	143‐145	oC.	FT‐IR	(KBr,	,	cm‐1):	2922	(CH2),	
2668	 (SH),	1706,1680	 (C=O),	1597	 (C=N).	 1H	NMR	 (200	MHz,	
DMSO-d6,	δ,	ppm):	10.1	(s,	1H,	SH),	8.6‐7.7	(m,	8H,	Ar‐H),	5.1	(s,	
2H,	OCH2).	MS	(EI,	m/z	 (%)):	355	(M+2,	4.77),	257	(1.95),	158	
(48.25),	 145	 (100),	 117	 (9.05),	 91	 (10.23),	 64	 (6.59).	 	 Anal.	
calcd.	 for	 C16H11N5O3S:	 C,	 54.38;	 H,	 3.14;	 N,	 19.82.	 Found:	 C,	
54.40;	H,	3.12;	N,	19.89%.	

2.2.7.	8‐((6‐Methyl‐	[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazol‐3‐
yl)methoxy	quinoline	(7)	
	

A	solution	of	 triazole	2	 (0.01	mol)	 in	acetic	anhydride	(20	
mL)	 was	 heated	 under	 reflux	 for	 14	 h,	 after	 cooling;	 the	
reaction	mixture	was	poured	 into	 ice.	 The	obtained	 solid	was	
crystallized	from	ethanol	(Scheme	2).	Color:	Yellow.	Yield:	57%.	
M.p.:	200‐202	oC.	FT‐IR	(KBr,	,	cm‐1):	2921	(CH2),	1599	(C=N),	
1373	(NCS).	 1H	NMR	(200	MHz,	DMSO-d6,	δ,	ppm):	8.1‐7.9	(m,	
6H,	Ar‐H),	4.8	(s,	2H,	OCH2),	2.8	(s,	3H,	CH3).	MS	(EI,	m/z	(%)):	
299	(M+2,	20.89),	259	(10.50),	179	(30.89),	92	(8.09),	56	(100).		
Anal.	calcd.	for	C14H11N5OS:	C,	56.55;	H,	3.73;	N,	23.55.	Found:	C,	
56.75;	H,	3.60;	N,	23.45%.	
	
2.2.8.	4‐([3‐Mercapto‐5‐(quinolin‐8‐yloxymethyl)‐[1,2,4]	
triazol‐4‐ylimino]‐methyl)‐phenol	(8)	
	

A	solution	of	triazole	2	(0.01	mol)	in	glacial	acetic	acid	(10	
mL)	 reacted	 with	 p‐hydroxy	 benzaldehyde	 (0.01	 mol)	 under	
reflux	 for	 1	 h.,	 the	 reaction	mixture	was	 then	 cooled	 and	 the	
precipitated	 solid	 was	 filtered	 off,	 washed	 with	 water,	 dried	
and	crystallized	from	ethanol	(Scheme	2).	Color:	Yellow.	Yield:	
65%.	M.p.:	 148‐150	 oC.	 FT‐IR	 (KBr,	,	 cm‐1):	 3416	 (OH),	 2923	
(CH2),	2695	(SH),	1597	(C=N).	 1H	NMR	(200	MHz,	DMSO-d6,	δ,	
ppm):	13.8	(s,	1H,	OH),	8.8	(s,	1H,	SH),	8.3	(s,	1H,	CH=N),	7.4‐8.1	
(m,	10H,	Ar‐H),	4.9	(s,	2H,	OCH2).	MS	(EI,	m/z	 (%)):	379	(M+2,	
36.28).	Anal.	calcd.	for	C19H15N5O2S:	C,	60.46;	H,	4.01;	N,	18.56.	
Found:	C,	60.55;	H,	4.10;	N,	18.65%.	
	
	
	



Behalo	et	al.	/	European	Journal	of	Chemistry	4	(2)	(2013)	92‐97	 95	
 

	
N

N

N

HN

S

O
10

Ar
CH3COONa

13

CH3NCS

DMF

N

N

N

N
S

Ar

R
11a-c

POCl3

Amino acid

N

N

N

N
S

Ar

HN
12

N

N

N
Ar

SH
NHCHO

HCO2H

N

N

N

N
S

Ar

CH2COCH3
14

Etylacaetoacetate

DMF

Ar =

N

O

ClCH2COOH

11 a

R

H
C

NH2

CH

CH3

CH3

b CH2NH2

c

H2N

N

N

N

HS

NH2

Ar

2

	
	

Scheme	3
	
	
2.2.9.	8‐(([1,2,4]Triazolo[4,3‐d][1,2,3,4]thiatriazol‐6‐yl)	
methoxy)quinoline	(9)	
	

A	 solution	 of	 triazole	 2	 (0.01	 mol)	 in	 HCl	 (50	 mL)	 was	
cooled	to	0	oC	and	a	cold	solution	of	sodium	nitrite	(0.01	mol)	
in	water	 (10	mL)	was	 gradually	 added.	 The	 reaction	mixture	
was	 kept	 at	 0‐5	 oC	 with	 stirring	 for	 2h,	 the	mixture	 was	 left	
overnight	 and	 diluted	 with	 water	 where	 upon	 precipitation	
took	 place,	 the	 solid	 that	 precipitated	 was	 collected	 and	
crystallized	from	ethanol	(Scheme	2).	Color:	Yellow.	Yield:	50%.	
M.p.:	128‐130	oC.	FT‐IR	(KBr,	,	cm‐1):	2920	(CH2),	1627	(C=N),	
1500	(N=N),	1385	(NCS).	1H	NMR	(200	MHz,	DMSO-d6,	δ,	ppm):	
8.2‐7.5	(m,	6H,	Ar‐H),	5.1	(s,	2H,	OCH2).	MS	(EI,	m/z	(%)):	284	
(M+,	71.33),	257	(1.4),	225	(12.50),	198	(17.48),	184	(3.13),	145	
(100),	 117	 (85.72),	 91	 (18.54),	 64	 (61.80).	 Anal.	 calcd.	 for	
C12H8N6OS:	C,	50.70;	H,	2.84;	N,	29.56.	Found:	C,	50.65;	H,	2.75;	
N,	29.77%.	
	
2.2.10.	3‐((Quinolin‐8‐yloxy)methyl)‐5H‐[1,2,4]triazolo[3,4‐
b][1,3,4]thiadiazin‐6‐(7H)‐one	(10)	
	

To	a	solution	of	triazole	(0.01	mol)	 in	acetic	acid	(50	mL),	
chloroacetic	 acid	 (0.01	 mol)	 and	 fused	 sodium	 acetate	 (0.01	
mol)	were	added.	The	reaction	mixture	was	refluxed	for	6h,	the	
separated	 solid	 was	 filtered	 and	 recrystallized	 from	 ethanol	
(Scheme	 3).	 Color:	 Pale	 yellow.	 Yield:	 48%.	M.p.:	 159‐161	 oC.	
FT‐IR	(KBr,	,	cm‐1):	3423	(NH),	2922	(CH2),	1659	(C=O),	1635	
(C=N),	1390	(NCS).	1H	NMR	(200	MHz,	DMSO-d6,	δ,	ppm):	8.9	(s,	

1H,	 NH),	 7.6‐8.3	 (m,	 6H,	 Ar‐H),	 5.4	 (s,	 2H,	 CH2),	 4.1	 (s,	 2H,	
OCH2).	 MS	 (EI,	 m/z	 (%)):	 313	 (M+2,	 3.56).	 Anal.	 calcd.	 for	
C14H11N5O2S:	 C,	 53.66;	 H,	 3.54;	 N,	 22.35.	 Found:	 C,	 53.75;	 H,	
3.45;	N,	22.29%.	
	
2.2.11.	General	procedure	for	preparation	of	11a‐c	
	

To	 a	mixture	 of	 triazole	2	 (0.01	mol)	 and	different	 amino	
acids	namely	(anthranilic	acid,	glycine,	and	valine)	(0.01	mol),	
POCl3	was	added	and	 the	content	was	heated	under	reflux	 for	
2h	on	 an	oil	 bath.	Excess	 of	POCl3	was	 then	 removed	 and	 the	
residue	was	 poured	 onto	 crushed	 ice	 and	 stirred	well.	 These	
were	then	washed	with	NaHCO3	(5%)	and	the	resulting	solids	
were	 then,	 filtered,	 washed	with	 water	 and	 crystallized	 from	
DMF	(Scheme	3).		

2‐Methyl‐1‐[3‐(quinolin‐8‐yloxymethyl)‐[1,2,4]triazolo[3,4‐b]	
[1,3,4]thiadiazol‐6‐yl]‐propylamine	 (11a):	 Color:	 Yellow.	 Yield:	
70%.	M.p.:	132‐135	oC.	FT‐IR	(KBr,	,	cm‐1):	3417	(NH2),	2962	
(CH2),	1656	(C=N),	1381	(NCS).	1H	NMR	(200	MHz,	DMSO-d6,	δ,	
ppm):	10.1	(s,	2H,	NH2),	7.3‐8.1	(m,	6H,	Ar‐H),	5.0	(s,	2H,	OCH2),	
2.9	(m,	2H,	CH),	1.6	(d,	6H,	2CH3).	Anal.	calcd.	for	C17H18N6OS:	C,	
57.61;	H,	5.12;	N,	23.71.	Found:	C,	57.50;	H,	4.99;	N,	23.80%.		

(3‐((Quinolin‐8‐yloxy)methyl)‐[1,2,4]triazolo[3,4‐b][1,3,4]	
thiadiazol‐6‐yl)methanamine	 (11b):	 Color:	 Yellow.	 Yield:	 62%.	
M.p.:	188‐190	oC.	FT‐IR	(KBr,	,	cm‐1):	3421	(NH2),	2926	(CH2),	
1606	(C=N),	1382	(NCS).	1H	NMR	(200	MHz,	DMSO-d6,	δ,	ppm):	
9.9	(s,	2H,	NH2),	7.6‐8.3	(m,	6H,	Ar‐H),	4.7	(s,	2H,	OCH2),	2.9	(s,	
2H,	CH2).	MS	 (EI,	m/z	 (%)):	313	 (M+1,	10.25),	160	 (0.05),	 145	



96	 Behalo	et	al.	/	European	Journal	of	Chemistry	4	(2)	(2013)	92‐97	
	
(5.05),	 91	 (10.09),	 64	 (100).	 Anal.	 calcd.	 for	 C14H12N6OS:	 C,	
53.83;	H,	3.87;	N,	26.91.	Found:	C,	53.92;	H,	3.77;	N,	26.82%.	

2‐(3‐((Quinolin‐8‐yloxy)methyl)‐[1,2,4]triazolo[3,4‐b][1,3,4]	
thiadiazole‐6‐yl)benzenamine	 (11c):	Color:	Yellow.	Yield:	68%.	
M.p.:	98‐100	 oC.	FT‐IR	 (KBr,	,	 cm‐1):	3432	 (NH2),	2927	 (CH2),	
1611	(C=N),	1376(NCS).	1H	NMR	(200	MHz,	DMSO-d6,	δ,	ppm):	
8.8	 (s,	2H,	NH2),	 6.6‐8.3	 (m,	11H,	Ar‐H),	5.8	 (s,	2H,	OCH2).	MS	
(EI,	m/z	 (%)):	 374	 (M+,	 4.27),	 257	 (2.10),	 145	 (58.72),	 117	
(100),	 91	 (18.54),	 64	 (61.80).	 Anal.	 calcd.	 for	 C19H14N6OS:	 C,	
60.90;	H,	3.77;	N,	22.45.	Found:	C,	60.85;	H,	3.65;	N,	22.35%.	
	
2.2.12.	N‐methyl‐3‐((quinolin‐8‐yloxy)methyl)‐[1,2,4]	
triazolo[3,4‐b][1,3,4]thiadiazol‐6‐amine	(12)		
	

An	 equimolar	 amount	 of	 triazole	 2	 and	 methyl	
isothiocyanate	(0.01mol)	 in	DMF	(30	mL)	was	refluxed	for	4h,	
cooled,	and	then	poured	onto	ice.	The	product	solid	was	filtered	
off	 and	 crystallized	 from	 ethanol	 (Scheme	 3).	 Color:	 Yellow.	
Yield:	63%.	M.p.:	250‐252	 oC.	FT‐IR	 (KBr,	,	 cm‐1):	3323	 (NH),	
2845	(CH2),	1620	(C=N),	1374	(NCS).	1H	NMR	(200	MHz,	DMSO-
d6,	 δ,	 ppm):	 9.1	 (s,	 1H,	NH),	 7.7‐8.1	 (m,	 6H,	 Ar‐H),	 4.9	 (s,	 2H,	
OCH2),	2.4	(s,	3H,	CH3).	MS	(EI,	m/z	(%)):	313	(M+1,	30.03),	257	
(20.43),	 184	 (0.73),	 158	 (7.44),	 145	 (100),	 117	 (35.78),	 64	
(5.05).	Anal.	 calcd.	 for	C14H12N6OS:	C,	 53.83;	H,	3.87;	N,	26.91.	
Found:	C,	53.75;	H,	3.95;	N,	26.85%.	
	
2.2.13.	N‐(3‐Mercapto‐5‐((quinolin‐8‐yloxy)methyl)‐4H‐
1,2,4‐triazol‐4‐yl)	formamide	(13)	
	

Triazole	2	 (0.01	mol)	 in	 formic	 acid	 (10	mL)	was	 heated	
under	 reflux	 for	 3	 h.	 The	 solid	 formed	 was	 collected	 by	
filtration	 and	 crystallized	 from	 ethanol	 (Scheme	 3).	 Color:	
Yellow.	Yield:	60%.	M.p.:	254‐256	oC.	FT‐IR	(KBr,	,	cm‐1):	3410	
(NH),	2857	(CH2),	2729	(SH),	1713	(C=O),	1599	(C=N).	1H	NMR	
(200	MHz,	DMSO-d6,	δ,	ppm):	12.3	(s,	1H,	SH),	9.7	(s,	1H,	NH),	
8.9	(s,	1H,	CHO),	7.2‐8.2	(m,	6H,	Ar‐H),	4.8	(s,	2H,	OCH2).	MS	(EI,	
m/z	(%)):	301	(M+,	20.67),	257	(10.78),	145	(100),	117	(45.56),	
91	(30.54),	64	(35.89).	Anal.	calcd.	for	C13H11N5O2S:	C,	51.82;	H,	
3.68;	N,	23.24.	Found:	C,	51.99;	H,	3.65;	N,	23.19%.		
	
2.2.14.	1‐(3‐((Quinolin‐8‐yloxy)methyl)‐[1,2,4]triazolo[3,4‐
b][1,3,4]thiadiazol‐6‐yl)propan‐2‐one	(14)	
	

A	mixture	of	 triazole	2	 (0.01	mol),	ethylacetoacetate	(0.02	
mol)	and	triethylamine	(0.02	mol)	in	DMF	(20	mL)	was	heated	
under	 reflux	 for	 12	h.	 The	precipitated	 solid	was	 collected	by	
filtration	 and	 crystallized	 from	 ethanol	 (Scheme	 3).	 Color:	
Yellow.	Yield:	60%.	M.p.	256‐258	oC.	FT‐IR	(KBr,	,	cm‐1):	2919	
(CH2),	1679	(C=O),	1599	(C=N),	1379	(NCS).	1H	NMR	(200	MHz,	
DMSO-d6,	 δ,	 ppm):	 δ	 ppm:	 6.9‐8.1	 (m,	 6H,	 Ar‐H),	 4.9	 (s,	 2H,	
OCH2),	 4.2	 (s,	 2H,	 CH2),	 2.3	 (s,	 3H,	 CH3).	 Anal.	 calcd.	 for	
C16H13N5O2S:	 C,	 56.63;	 H,	 3.86;	 N,	 20.64.	 Found:	 C,	 56.55;	 H,	
3.80;	N,	20.59%.	
	
2.3.	Antimicrobial	activity	test	
	

The	 tested	 microorganisms	 were	 Gram‐positive	 bacteria	
(Staphylococcus	 aureus)	 and	 Gram‐negative	 bacteria	
(Escherichia	coli).	In	addition,	some	fungi	(Candida	albicans	and	
Aspergillus	 flavus)	 were	 also	 tested.	 On	 the	 other	 hand,	
Tetracycline	 and	 Amphotericin	 B	 were	 used	 as	 standard	
antibacterial	and	antifungal	agents,	respectively.	The	observed	
data	 on	 the	 antimicrobial	 activity	 of	 the	 compounds	 and	 the	
standard	drugs	are	given	in	Table	1.	

Agar	 diffusion	method	was	 used	 for	 the	 determination	 of	
the	 preliminary	 antibacterial	 and	 antifungal	 activity	 [31]	 and	
the	 results	 were	 recorded	 for	 each	 tested	 compound	 as	 the	
average	diameter	of	 inhibition	zones	 (r)	of	bacterial	or	 fungal	
growth	 around	 the	 disks	 in	 millimeters	 at	 100	 μg	
concentrations	in	dimethylsulfoxide.	

The	 Gr(+)	 test	 organism	 and	 Gr(‐)	 test	 organism	 were	
applied	 using	 8	 pore	 suspension	 of	 each	 test	 organism	
separately	 spreaded	 over	 a	 petri	 dish	 containing	 a	 solid	
nutrient	agar	medium	of	the	following	composition	(g/L).	

Beef	 extract,	 3.0;	 tryptone,	 5.0;	 Agar,	 15.0;	 and	 distilled	
water,	1000.0.	After	immediately	fresh	inoculation	of	the	tested	
organism,	a	well	per	each	Petri	dish	was	made,	and	the	0.1	g	of	
the	 tested	 compound	 was	 filled	 the	 6	 mm	 in	 diameter	 well	
respectively	 then	 incubated	at	37	 oC	 for	48	h,	 the	diameter	of	
the	 inhibition	 zone	was	measured	 in	mm.	 Also	 the	 antifungal	
activities	 were	 tested	 using	 spore	 suspension	 of	 each	 tested	
organism	separately,	spreaded	over	Petri	dish	containing	solid	
Czapeks	Dox	agar	of	the	following	composition	(g/L).	

Sucrose,	30.0;	MgSO4,	0.5;	KCl,	0.5;	FeSO4,	0.01;	NaNO3	3.0;	
K2HPO4	 1.0;	 Agar,	 20.0;	 and	 distilled	 water,	 1000.0.	 After	
immediately	fresh	inoculation	of	the	test	organism,	a	6	mm	well	
per	each	Petri	dish	was	made,	and	the	tested	compounds	were	
added	to	fill	wells	respectively,	and	then	incubated	at	28	°C	for	
7	days.		

	
3.	Results	and	discussion	
	
3.1.	Synthesis	
	

Scheme	 1‐3	 show	 the	 synthetic	 pathways	 to	 prepare	 the	
target	 compounds	 2‐14.	 The	 starting	 material	 4‐amino‐5‐
[(quinolin‐8‐yloxy)	 methyl]‐4H‐1,2,4‐triazole‐3‐thiole	 (2)	 was	
synthesized	 from	 the	 reaction	 of	 acid	 hydrazide	 1	 [30]	 with	
carbon	 disulfide	 in	 ethanol	 containing	 potassium	 hydroxide	
followed	by	treatment	with	hydrazine	hydrate.	The	structure	of	
triazole	 2	 was	 elucidated	 by	 1H	 NMR	 spectrum	 that	 showed	
signals	 at	 δ	 13.9	 and	 10.5	ppm	 corresponding	 to	NH2	 and	 SH	
protons	 respectively.	 Also,	 IR	 spectrum	 displays	 absorption	
bands	 at	 3263‐3145	 and	 2668	 cm‐1	 due	 to	 NH2	 and	 SH	
absorption	(Scheme	1).		

Triazole	2	with	the	reactive	amino	and	thio	groups	proved	
to	 be	 versatile	 key	 precursor	 for	 constructing	 wide	 range	 of	
fused	 triazole	 derivatives.	 Thus,	 the	 reactivity	 of	 triazole	 2	
towards	variety	of	chemical	reagents	with	the	aim	of	synthesis	
of	 fused	 heterocyclic	 systems	 of	 expected	 biological	 activity	
was	 investigated.	 The	 reaction	 of	 compound	 2	 with	 urea	 or	
thiourea	afforded	[1,2,4]‐triazolo‐[3,4‐b][1,3,4]‐thiadiazoles	3a	
and	3b	respectively.	Compound	3b	was	prepared	also	from	the	
reaction	 of	 1,2,4‐triazole	2	with	 carbon	disulfide	 in	DMF.	 The	
structures	of	 the	products	were	assigned	on	 the	basis	of	 their	
spectral	 data	 and	 elemental	 analysis.	 Treatment	 of	 triazole	 2	
with	acetyl	chloride	in	dry	pyridine	afforded	product	4.	On	the	
other	hand,	 reaction	of	 triazole	2	with	 aromatic	 acids	namely	
(p‐nitrobenzoic	 acid,	 p‐aminobenzoic	 acid	 and	 p‐hydroxy	
benzoic	 acid	 in	 the	 presence	 of	 POCl3	 gave	 5a‐c	 respectively	
(Scheme	1).	

Furthermore,	 heating	 of	 triazole	 2	 with	 acid	 anhydride	
namely	 phthalic	 anhydride	 or	 maleic	 anhydride	 afforded	
triazole	derivatives	6a	and	6b	respectively	where	as	refluxing	
of	triazole	2	in	acetic	anhydride	due	to	ring	closure	to	afford	8‐
((6‐methyl‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazole	 7.	 However,	
triazole	 derivative	 8	 can	 be	 synthesized	 from	 reaction	 of	
triazole	2	with	p‐hydroxybenzaldhyde	in	the	glacial	acetic	acid.	
Treatment	 of	 triazole	 2	 with	 sodium	 nitrite	 gave	 product	 9	
(Scheme	2).		

Furthermore,	 the	 reaction	 of	 triazole	 2	 with	 chloroacetic	
acid	 in	 the	presence	of	 sodium	acetate	 furnished	 triazolo[3,4‐
b][1,3,4]thiadiazin	derivative	10.	

The	 reactivity	 of	 triazole	 2	 towards	 amino	 acids	 to	 give	
triazolo[3,4‐b][1,3,4]thiadiazole	 derivatives	 was	 investigated.	
Thus,	 the	 reaction	 of	 triazole	 2	 with	 valine,	 glycine	 and	
anthranilic	 acid	 in	 the	 presence	 of	 POCl3	 due	 to	 formation	 of	
triazoles	11a‐c,	respectively	(Scheme	3).	The	structures	of	the	
products	were	confirmed	on	the	basis	of	their	spectral	data.		

	
	



Behalo	et	al.	/	European	Journal	of	Chemistry	4	(2)	(2013)	92‐97	 97	
 

	
Table	1.	Antimicrobial	activities	of	the	synthesized	compound	*.	
Compound	No.	 Escherichia	coli	 Staphylococcus	aureus Aspergillus	flavus Candida	albicans
3a	 ‐	 ‐ ‐ ‐	
3b	 21	 20	 ‐	 12	
4	 14	 12	 ‐	 12	
5a	 ‐	 ‐	 ‐	 11	
5b	 12	 11	 ‐	 ‐	
5c	 13	 11 ‐ 12	
6a	 17	 17 12 12	
6b	 21	 20 11 12	
7	 ‐	 ‐ ‐ ‐	
8	 14	 14 ‐ 13	
9	 14	 12 ‐ ‐	
10	 14	 12 ‐ ‐	
11a	 15	 13	 ‐	 ‐	
11b	 13	 10 ‐ ‐	
11c	 15	 11	 ‐	 ‐	
12	 15	 13	 ‐	 13	
Tetracycline	 24	 22 ‐ ‐	
Amphotericin	B	 ‐	 ‐ 13 14	
*	Numbers	in	table	represent	the	extent	of	the	zone	diameter	(r,	mm)	inhibition	of	either	fungal	growth	or	bacterial	cells	for	each	compound;	(‐)	no	inhibition	was	
observed,	i.e.	compound	not	active;	(r)	>	10	mm,	slightly	active;	(r)	>	13	mm,	moderately	active	and	(r)	>	20	mm,	high	active.	

	
Reaction	of	compound	2	with	methyl	isothiocyanate	in	the	

presence	 of	 DMF	 gave	 heterocycle	 12.	 On	 the	 other	 hand,	
heating	 of	 triazole	 2	 with	 formic	 acid	 afforded	 triazole	 13.	
When	 triazole	 2	 was	 allowed	 to	 react	 with	 1,3‐dicarbonyl	
compounds	 like	 ethylacetoacetate,	 triazole	 14	 was	 formed	
(Scheme	3).	
	
3.2.	Antimicrobial	activity	
	

1,2,4‐Triazole	derivatives	were	reported	to	have	biological	
activity.	 In	 this	 study,	 some	 of	 the	 synthesized	 compounds	
containing	 1,2,4‐triazole	 moiety	 appear	 to	 be	 promising	 as	
potential	 bio	 responses	 which	 increase	 their	 importance	
towards	 application	 in	 pharmacological,	 industrial	 and	
agriculture	 fields.	 Therefore,	 their	 effectiveness	 against	 a	
number	of	microorganisms	was	tested	(Table	1).	

The	 results	 revealed	 that	 majority	 of	 the	 synthesized	
compounds	 showed	 varying	 degrees	 of	 inhibition	 against	 the	
tested	 microorganisms.	 In	 general,	 the	 inhibitory	 activity	
against	the	Gram‐positive	bacteria	and	Gram‐negative	bacteria	
was	higher	than	that	of	the	tested	fungi.	The	tested	compounds	
showed	 moderate	 (6a,	 11	 and	 12)	 to	 high	 (3b	 and	 6b)	
inhibitory	effect	towards	tested	bacteria	(Table	1).	Introduction	
of	thiadiazolethione	and	pyrrolidindione	moiety	to	triazole	ring	
to	 give	 mixed	 heterocyclic	 systems	 3b	 and	 6b	 enhance	
antibacterial	activities	when	compared	with	Tetracycline.	It	has	
been	 observed	 through	 the	 results	 in	 Table	 1	 that	6a	 and	6b	
derivatives	showed	both	antifungal	and	antibacterial	activities	
towards	 the	 tested	 organisms.	 On	 the	 other	 hand,	 triazoles	8	
and	 12	 showed	 moderate	 activity	 towards	 the	 most	 tested	
microorganisms,	while	it	 is	 inactive	towards	Aspergillus	 flavus.	
In	 summary,	 the	 presence	 of	 thiadiazole	 moiety	 attached	 to	
fused	 triazole	 system	 enhances	 the	 inhibition	 zones	 of	 the	
tested	microorganisms.		
	
4.	Conclusion	
	

In	 the	 present	 paper,	 we	 have	 described	 the	 synthesis	 of	
1,2,4‐triazole	derivatives	fused	to	five	and	six	membered	rings	
from	 4‐amino‐5‐[(quinolin‐8‐yloxy)methyl]‐4H‐1,2,4‐triazole‐
3‐thiole	 (2).	 It	 was	 observed	 that	 some	 of	 the	 synthesized	
compounds	 behave	 as	 efficient	 antibacterial	 and	 antifungal	
agents	when	 compared	with	 standard	drugs.	 The	 structure	 of	
all	 derivatives	was	 confirmed	 and	 characterized	 by	 elemental	
analysis	and	spectroscopic	studies.	
		
Acknowledgement	

	
The	authors	wish	 to	 thank	Chemistry	Department,	Faculty	

of	 Science,	 Benha	 University,	 Egypt	 for	 providing	 required	
chemicals	to	complete	this	work.		

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