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Synthesis and anti-microbial activities of some (aryl)-N’-benzylidene-2-

hydroxybenzohydrazide derivatives

Experiment Findings · February 2019

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 Kenawy et al., 2018, AJMS 1(1): 19-25 DOI:10.5455/ajms.4

Arabian Journal of Medical Sciences

http://www.ajms.tk

Synthesis and anti-microbial activities of some (aryl)-N’-benzylidene-2-hy-

droxybenzohydrazide derivatives

EL-Refaie Kenawy a*, Abd EL-Basset Shokr a, Nayera A.M. Abdel-Wahed b, Tarek M. Zied a
a
Chemistry Department, Faculty of Science, Tanta University, Tanta 31527, Egypt
b
Chemistry of Natural and Microbial Products Department, Pharmaceutical Industries Division, National
Research Centre, Giza, Egypt

Article Info Abstract

In order to study new bioactive compounds, we carried out certain chemical transformations of salicyl-
Keywords:
ic acid hydrazide through reaction with a set of aromatic aldehydes (benzaldehyde, p-chloro-benzalde-
methyl salicylate;
salicylic acid hydrazide; hyde, p-methoxy-benzaldehyde , N , N’di methyl- benzaldehyde) in boiling methanol; and in the pres-
anti-microbial activity;
ence of a catalytic amount of piperidine under reflux conditions to yield the corresponding derivatives in
thiazolidinone;
aromatic aldehydes moderately good yields. The corresponding thiazolidinone derivatives were obtained by the treatment

with thioglycolic acid under reflux conditions. The reactivity of salicyloyl hydrazide towards the reac-
Received Sep 1,
Revised Sep 16, tion with some nucleophiles was investigated by reaction with formamide, urea, acetamide and benzyl.
Published Sep 23, 2018 The produced derivatives were screened for their anti-microbial activities. Salicylic acid hy-

drazide was successfully accommodated subunits of thiazolidine-4-ones or oroxadiazin or py-

rimidin affording a set of derivatives which proved their utility in medicinal chemistry, as they

showed moderate to high antimicrobial properties proving the synthetic utility of salicyl-

ic acid hydrazide in constructing new heterocycles of possible expected therapeutic relevance.

*Corresponding author:
ekenawy@yahoo.com The same molecular hybrid template may afford more potent scaffolds upon the incorporation of

more effective substituents based on the highly biological profile of salicylic acid hydrazide itself.

1. Introduction
activity (Dachineni et al., 2016; Elshaier and Marzouk 2015).
Hydrazides and their derivatives have been described as
Also with acidic moiety, its ester as aspirin or methyl salic-
useful synthons of various heterocyclic systems (Popiołek,
ylate has analgesic activities. The synthesis of salicylic acid
2017). Full therapeutic possibilities of hydrazides were real-
hydrazide (2-hydroxy-benzohydrazide) has been successful-
ized after the discovery of isonicotinic acid hydrazide (INH).
ly done in high yield through the action of hydrazine hydrate
Hydrazides and their derivatives exhibited antifungal, psycho-
on methyl salicylate (Ermann and Henner, 1994). On the
tropic (Popiołek, 2017), anti-tuberculous (Bedia et al., 2006;
other hand, the 4-thiazolidinones have a broad spectrum
Naqvi et al., 2009), anti-parasite (Troeberg et al., 2001), bac-
of biological activities such as: anti-bacterial, anti-fungal
teriostatic (Erman and Henner, 1994; Plech et al., 2015), an-
(Lakhan and Singh, 1991), anti-inflammatory, anti-diarrhoe-
tiviral (Verma et al., 2014), insecticidal (Barbosa et al., 2011)
al, anti-HIV, anti-cancer properties (El-Feky,1993, Bingul et
and anticancer activities (Mansour, 2003 ). Furthermore, they
al., 2016 , Bondock et al., 2007) and hypnotic-sedative, an-
were used in the treatment of inflammatory and autoimmune
algesic, anti-convulsant (Gürsoy et al., 2005), anti-tubercular
diseases, osteoarthritis, respiratory diseases, tumors, cachexia,
activity against M. tuberculosis H37 Rv (Cihan-Üstündağ
cardiovascular diseases, fever, hemorrhage and sepsis (Man-
et al., 2016), and anti-type-2 diabetes (Baihua, 2004).
sour, 2003). Some hydrazides also showed analgesic activity
We reported here a rapid and efficient route for the synthe-
(Koopaei et al., 2013). The replacement of the acidic moiety of
sis of 2-(2-hydrox-benzohydrazide) -oxo -N(substituted phe-
Mefenamic acid (also known as dimethylphenylaminobenzoic
nyl)1,3-thiazolidin-4-ones (4) from its corresponding ben-
acid which is a well-known NSAID drug available worldwide
zylidene salicylic acid hydrazones (3) and also the synthesis
under many brand names) with N-arylidene hydrazides moie-
of some 2-triazine (or oxadiazin or pyrimidin) phenol de-
ty can increase the analgesic activity (Koopaei, 2013). Salicyl-
rivatives (5-9) by reacting with some nucleophiles (Fig. 1).
ic acid is another analgesic agent which also has anti-cancer

19
 Kenawy et al., 2018, AJMS 1(1): 19-25 DOI:10.5455/ajms.4
O
O
H N
N Ar
OH
O
[4a-e] Ar=Ph,p- MePh,O-OHPh, p-OMePh , p-ClPh
NHNH2
OH
N N
[2 ] Salicylic acid hydrazide
X R
OH
[5-9] ;X=O,NH,CHAr and R=S or Ph or NH2 or CH3 or H
Figure 1
Fig. 1. The preparative chemical transformations of salicylic acid hydrazide
into 4- thiazolidinones, triazine- , oxadiazin- or pyrimidin- phenol analogous.
2. Experimental
2.1. Materials
Methyl salicylate (2-Hydroxy-benzoic acid methyl es-
ter) was acquired from (Sigma chemical Co.) and was
used without purification. Thioglycolic acid [TGA] was
purchased from ( ULTIMA CHEMICALS Mumbai, In-
dia ) and hydrazine hydrate was purchased from (Innova
Corporate India ). Dimethyl formamide (DMF) was dis-
tilled prior use. MeOH and ethanol (EtOH), were bought as
spectroscopic grade materials and were used without fur-
ther purification. Carbon disulphide and the aromatic al-
dehydes were purchased from Sigma-Aldrich (St. Louis,
MO) and Acros (Geel, Belgium) Concoction Companies.
2.2. Characterization
Melting points (uncorrected) were recorded on an elec-
tro-thermal melting apparatus. IR spectra were recorded on
a Perkin-Elmer spectrometer, at Faculty of Science, Tan-
ta University. 1HNMR were recorded in DMSO-d6 on a
Bruker 400 MHz instrument using TMS as internal stand-
ard (chemical shifts in δ ppm), at Faculty of Science, Kaf-
relshiekh University. TGA analysis was recorded on Shi-
madzu 50, at Faculty of Science , Kafrelshiekh University.
Microanalytical data (C, H, N) were performed on Perkin
Elmer 240 B analyzer, at the center of micro analysis , Fac-
ulty of Science , Cairo University. Solvent evaporation was
performed under reduced pressure using Buchi Rotatory
Evaporatory unless otherwise stated. TLC 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 de-
tect the UV absorbing compounds (CHCl3, acetone 5:2).
2.3. Synthesis of 2-hydroxybenzohydrazide (salicylic acid
hydrazide ) 2
A mixture of methyl salicylate (0.01 mole ; 0.89 ml) and
hydrazine hydrate (1 ml; 0.02 mol ; 99 %) was refluxed in 50
ml methanol for about 13-15 hours. The resultant mixture
was concentrated, cooled and poured into crushed ice. The sol-
id product was separated, filtered, washed with ethanol and
recrystallized from methanol ( Pattan et al., 2009 ). White solid
, m p 142 – 145 °C as reported , yield = 77 % , IR (KBr Disc):1640
(C =O) ,1089 ( C- O ) ,1821 ( C=N) , 1244 (C-N ) ,1588
(C=C) ,3047 (C-H) aromatic ,755 (aromatic C-H); O-disub-
stituted phenyl ring, 3133 (NH),3313 (NH2), 3266 (OH).
2.4. General procedure for the Synthesis of N’-ben-
S zylidene-2-hydroxybenzohydrazides 3 a- e
A mixture of salicylic acid hydrazide 2 (1.5 g , 0.01
mol) and substituted benzaldehydes (0.015 mol) in etha-
nol (15 mL) were refluxed in boiling methanol (50 ml) for
about 2- 3 hours in the presence of a few drops of piperi-
dine. The reaction proceeding was monitored by TLC. The
solid product was separated, filtered, washed with ethanol ,
and was purified by recrystallization from suitable solvents.
N’-benzylidene-2-hydroxybenzohydrazide 3 a
Pale yellow solid, m p 249 – 252 °C, yield = 75 % , MeOH ,
IR (KBr Disc):1626 (C=O amide) ,1311 ( C-O ) ,1944 ( C=N )
, 2855 (N=C-H), 1565 (C–N amide), 1311 (C-N benzylidene),
1453 (C=C) ,3035 (C sp2-H) aromatic ,725 (aromatic C-H);
P-mono substituted phenyl ring, 3441 (NH ) , 3240 (OH).
N’-(4-methylbenzylidene)-2-hydroxybenzohydrazide 3 b
Yellowish-white solid, m p 285– 290 °C , yield =
73 % , MeOH, 1HNMR [d6-DMSO]; δ 3.35 ppm (brS,1H,
OH ), 2.5 (S,3H, CH3 ) ,6.9 –7.8 ppm (complex spectra ,
8H , aromatic protons), 8.43 ppm (S,1H , -CH) , 11.83 ppm
(S,1H , NH) 13C NMR: 165.28 ,159.68,149.32,140.7,134.32
,131.96, 129.08, 127.82,119.44,117.85, 116.44,21.6.
N’(2-hydroxybenzylidene)-2hydroxybenzohydrazide 3 c
Yellowish-white solid , m p 285– 290 °C, yield = 73 % ,
MeOH , IR(KBr Disc) :1627 (C=O amide) ,1373 (C- O) ,1940
(C=N) , 2844 (N= C-H), 1560 (C-N amide), 1303 (C-N ben-
zylidene), 1487 (C=C) ,3051(C sp2-H) aromatic ,754 (aromatic
C-H); P-mono substituted phenyl ring, 3198 (NH ) , 3443 (OH).
N’-(4-methoxybenzylidene)-2-hydroxybenzohydrazide 3 d
Pale yellowish-white solid, m p 285– 290 °C, yield = 73
% , MeOH , IR (KBr Disc) :1615 (C =O amide),1376 ( C-O
amide ),1544(C=N ) , 2845 (N= C-H) , 1560 (C-N amide),
1308 (C-N benzylidene), 1455 (C=C),3063(C sp2-H) aromat-
ic, 827 (aromatic C -H); P-mono substituted phenyl ring, 3256
(NH) , 3456 (OH ) 1HNMR [d6-DMSO]: δ2.5ppm (S,1H, OH
) , 3.80 (S,3H, CH3) ,6.95 – 7.91 ppm (complex spectra , 8H ,
aromatic protons), 8.42 ppm (S,1H , -CH) , 11.78 ppm (S,1H
, -NH) . 13C NMR: 165.28, 161.57, 159.78, 149.26, 134.32,
129.46, 128.96, 127.18, 119.44, 117.86, 116.29,114.9,55.83.
N’-(4-chlorobenzylidene)-2-hydroxybenzohydrazide 3 e
White solid ,m p 225– 229 °C, yield = 73 % , MeOH
, IR (KBr Disc):1641 (C =O amide) , 1384 ( C-O amide)
,1913 (C = N ) , 2857 (N= C-H), 1606 (C -N amide), 1298
(C - Nbenzylidene), 1455 (C = C), 3065 (C sp2-H) aromat-
ic, 748 (aromatic C -H); P-di substituted phenyl ring, 3441 (
-NH ) , 3235 (OH ). 1HNMR [d6-DMSO];δ 2.5ppm (S,1H,
OH ) ,6.9 – 7.8 ppm (complex spectra , 6H , aromatic pro-
tons), 8.46 ppm (S,1H , -CH) , 11.78 ppm (SS,1H , -NH)
2.5. Synthesis of 2-(2-Hydrox-benzohydrazide) -oxo
–N-(substituted phenyl)1,3-thiazolidin-4-ones 4a-e
N’-benzylidene-2-hydroxybenzo hydrazides 3 a-e (0.001
mole) were refluxed with thioglycolic acid [TGA] (0.001 mole
, 0.3 ml) in DMF (15 ml ) in the presence of anhydrous ZnCl2
(1.36 gm ; 0.01 mole) for 8 h. The reaction proceeding was mon-
itored by TLC. After completion of the reaction, the mixture
was cooled and poured into crushed ice, the solid product sep-
arated was filtered ,washed with water, and recrystallize from
suitable solvents (Ganesh et al., 2010; Sekhar et.al., 2010).
20
 Kenawy et al., 2018, AJMS 1(1): 19-25 DOI:10.5455/ajms.4

2-hydroxy-N-((4-oxo-2-phenylthiazolidin-3-l) methyl) Table (1). The physical properties of the synthesized prod-
benzamide 4a ucts 2-4.
Yellowish-white solid, m p 240-242 °C , yield = 65 % IR Code Molecular formula Melting Yield % Solvent
(KBr Disc):1626 , 1560 (C=O) ,1309 ( C-O) , 1232 (C-N) ,1491 (Molecular weight) Point
(C=C) , 3061 (C-H) aromatic ,752(aromatic C-H); P-mono sub- 2 C7H8N2O2 143-145 80 MeOH
stituted phenyl ring , 3239 ( -NH ) , 2415 (-OH ) ,752 ( C–S ). (152)
2-hydroxy-N-((4-oxo-2-p-tolylthiazolidin-3- yl) methyl) 3a C14H12N2O2 249 -252 75 n-Butanol
benzamide 4 b (240)
Yellowish-white solid, m p 250-252 °C , yield = 65 % 3b C14H12N2O3 285 -290 73
IR (KBr Disc):1620 , 1563 (C=O),1311 (C-O) , 1240 (C-N (256)
) ,1504 (C=C),3042 (C-H) aromatic ,809 (aromatic C-H); 3c C15H14N2O2 255 -258 68
(254)
P- di substituted phenyl ring, 3423 ( NH) , 2721 (OH ) ,745
(C–S), 2857 (CH3), 1HNMR [d6-DMSO]: δ2.504 ppm (S,1H, 3d C15H14N2O3 178 -182 68
(270)
OH), 2.35 (S,3H, CH3) ,6.9 –7.8 ppm (complex spectra , 8H
, aromatic protons), 3.34 ppm (S,1H , CH2) , 11.81 ppm 3e C14H11N2O2Cl 249 -252 75
(274.5)
(S,1H , NH). 13C NMR: 165.2 ,159.65 ,149.3 ,140.7,134.
4a C18H16N2O3S 240-242 65
35,131.95,130.04,129.04,127.7,119.4,117.8,116.4. (340)
2-hydroxy-N-((2-(2-hydroxyphenyl)-4-oxothiazolidin-3-yl)
4b C16H14N2O4S 250-252 65
methyl) benzamide 4 c (330)
Yellowish-white solid, m p 258-260 °C , yield = 65 % , 4c C17H16N2O4S 258-260 65
IR (KBr Disc):1619 , 1562 (C=O) ,1309 (C-O) ,1229 (C-N ) (344)
,1503 (C=C) ,3033 (C-H) aromatic ,807(aromatic C-H); O- di 4d C17H16N2O4S 238-240 65
substituted phenyl ring,3262 (NH) , 3440 (OH ) ,741 (C–S ). (344)
2-hydroxy-N-((2-(4-methoxyphenyl)-4-oxothiazoli- 4e C16H13N2O3SCl 255-258 65
din-3-yl)methyl)benzamide 4 d (348.5)
Yellowish-white solid, m p 238-240 °C, yield = 65 % ,
IR (KBr Disc) :1616 , 1555 (C=O) ,1308 (C- O) ,1249 (C-N ) then recrystallized from methanol. Yellowish-white solid ,
,1509 (C= C) ,3069 (C-H) aromatic ,828(aromatic C-H); P- di m p 232 -234°C , yield = 73 %, IR(KBr disc) : 1009( C- O
substituted phenyl ring, 3441 (NH), 2728 (OH ),747 (C–S ), ),1750(C=N),1230 (C-N),1607 (C = C) ,3067 (C-H) aromatic
2854 (CH3 ). 1H NMR[d6-DMSO]: δ2.504 ppm (S,1H, OH ), , 752 (aromatic C-H) ; O- di substituted phenyl ring,1481( the
3.81 (S,3H, CH3) ,6.9 –7.7 ppm (complex spectra , 8H , aromat- triazine ring ),3125 ( -NH ) , 3296 (OH ) , 2858 (-CH3). 1HNMR
ic protons), 3.36 ppm (S,1H , CH2) , 11.75 ppm (S,1H , -NH) [d6-DMSO]: δ 10.2( S , 1H,NH), 6.9 – 7.9 ppm (complex spec-
2-hydroxy N-((2-(4-chlorophenyl)-4-oxothiazolidin-3-yl) tra , 4H, aromatic protons) ,1.96 (S,3H,-CH3) ,2.5(S,1H,OH).
methyl)-2-hydroxybenzamide 4e 2.8. Synthesis of 2-(6-amino-1,4-dihydro-1,3,5-triazin-2-yl)
Yellowish-white solid, m p 255-258 °C, yield = 65 % , phenol 7
IR (KBr Disc):1620 , 1555 (C=O), 1308 (C-O),1234 (C-N) A mixture of salicylic acid hydrazide 2 (1.52 g, 0.01
, 1489 (C= C), 3060 (C-H) aromatic, 822 (aromatic C-H); mole) and Urea (0.72 g, 0.012 mole) were heated at 180 °C
P- di substituted phenyl ring,3423 (NH), 3247 (-OH), 702 in an oil bath for 2 h followed by cooling and the solid prod-
(C–S), 651 (C-Cl). 1HNMR [d6-DMSO]: δ2.504 ppm (S,1H, uct obtained was filtered, washed with ethanol and dried then
OH ), 6.9 – 7.8 ppm (complex spectra , 8H , aromatic pro- recrystallized from methanol (Shaban et al., 1990 and Yous-
tons), 3.39 ppm (S,1H , CH2), 11.92 ppm (S,1H , -NH). sif et al., 2003) light beige solid, m p 243-246°C , yield =
2.6. Synthesis of 2-(1,4-dihydro-1,3,5-triazin-2-yl) phenol 68 % , IR(KBr disc) : 1043( C- O ),1703(C=N),1243 ( C-N
5 ) ,1552 (C=C) ,3071 (C-H) aromatic ,750(aromatic C-H) ;
A mixture of salicylic acid hydrazide 2 (1.52 g, 0.01 O- di substituted phenyl ring,1490( the triazine ring ),3311
mole) and formamide (0.47 ml, 0.012 mole) were heated at (NH ) , 3206 (OH ) , 3427 (-NH2) , 1HNMR [d6-DM-
180 °C in an oil bath for 2 h followed by cooling, the solid SO]: δ 10.33( S , 1H,NH),6.11 – 7.9ppm(complex spectra
product separated was filtered, washed with ethanol, dried , 4H, aromatic protons) ,3.3(S,1H,OH) ,2.5(S,2H,NH2).
and crystallizied from methanol white solid, m p 249 -252 2.9. Synthesis of 2-(2,5-dihydro-5,6-diphenylpyrimi-
°C, yield = 75 %, IR (KBr disc) : 1041 (C- O),1673(C=N), din-4-yl)phenol 8
1231 (C-N),1607 (C = C), 2955 (C-H) aromatic, 749 (ar- A mixture of salicylic acid hydrazide 2 (1.52 g, 0.01
omatic C-H) ; O- di substituted phenyl ring,1555 (the tri- mole) and Benzil (2.52 g, 0.012 mole) in absolute ethanol and
azine ring), 3125 ( -NH ) , 32290 (OH ). 1HNMR [d6-DM- triethylamine (5 ml) were heated under reflux for 2 h fol-
SO]: δ 11.82 (S, 1H,NH),7.94 (d,1H,CH), 6.95 – 7.4 ppm lowed by cooling and the solid product obtained was filtered
(complex spectra, 4H, aromatic protons), 3.3 (S,1H,OH). ,washed with ethanol, dried and recrystallizied from metha-
2.7. Synthesis of 2-(1,4-dihydro-6-methyl-1,3,5-triazin-2- nol (Shaban et al., 1990 and Youssif et al., 2003) buff solid
yl)phenol 6 , m p198 - 200°C, yield = 68 % , IR(KBr disc) : 1090( C- O
A mixture of salicylic acid hydrazide 2 (1.52 g, 0.01 ),1673(C=N),1231 ( C-N ),1543 (C=C) ,3056 (C-H) aromatic
mole) and acetamide (0.70 g, 0.012 mole) were heated at 180 ,748(aromatic C-H) ; O- di substituted phenyl ring,1543(the
°C in an oil bath for 2 h followed by cooling , the solid triazine ring ) , 2925 (-NH ) , 3219 (OH ) , 685 (phenyl
product obtained was filtered, washed with ethanol and dried
21
 Kenawy et al., 2018, AJMS 1(1): 19-25 DOI:10.5455/ajms.4

group). 1HNMR [d6-DMSO]: δ 11.2(S, 1H,NH),6.9 –7.9 ppm hyde , p-chloro- benzaldehyde ) in boiling methanol and in the
(complex spectra , 11H, aromatic protons), 3.36 (S,1H,OH). presence of a catalytic amount of piperidine, to afford the corre-
2.10. Synthesis of 3,4-dihydro-6-(2-hydroxyphe- sponding benzylidene salicylic acid hydrazides 3a- e in good
nyl)-1,3,5-oxadiazine-2-thione 9 isolated yields. Thiazolidinones are synthesized via variety of
A solution of a mixture of salicylic acid hydrazide routes such as reaction between benzylidene-amines and mer-
2 (1.52 g, 0.01 mole) in methanol (30 ml) and carbon di- captoacetic acid (Bolognese et al., 2004) or by condensation of
sulfide (2 mL, 0.033mol), and dry DMF (2 ml) was refluxed either aliphatic or aromatic moieties containing a formyl group
for about 5 h on a water bath , a solid separated , carbon with different aminothiols (Sattigeri et al., 2005) or by reflux-
disulfide was boiled off, the mixture was cooled, filtered and ing a solution of arylhydrazones and thioglycolic acid in DMF
rinsed with small amounts of DMF and absolute ethanol, in the presence of anhydrous ZnCl2 (Cacic et al., 2009, Singh
dried then recrystallized from methanol (Smakula and Bak- et al., 1981, Troeberg et al., 2001). On the basis of such proce-
er, 1984) white solid , m p 248 – 250 °C , yield = 70 % dure, the reaction was performed and the corresponding deriv-
, IR(KBr disc) : 1057( C- O) ,1777(C=N),1253 (C-N) ,1629 atives 2-(2-Hydrox-benzohydrazide) -oxo -N(substituted phe-
(C=C) ,3072 (C-H) aromatic ,743(aromatic C-H) ; O- di sub- nyl)1,3-thiazolidin-4-one 4 (a-e) were formed (Schemes 1 and 2).
stituted phenyl ring,1594( the triazine ring ),3273 (NH) , 3240
(OH ). 1HNMR [d6-DMSO]: δ 10.73( S , 1H,NH), 6.8 – 7.3 O
O O
ppm(complex spectra , 4H, aromatic protons),3.3(S,1H,OH). OCH3
N2H4 NHNH2 Ar - C H
OH MeOH MeOH / piperidine
OH
Table (2). The physical properties of the synthesized prod- [2]
ucts 5-9.
Code Molecular formula Melting Yield % Solvent O
O Ar
(Molecular weight) Point H NH
SHCH2COOH R
N N S reflux N
5 C8H6N3O 249 -252 75 MeOH OH C
OH H
(160) O
6 C9H9N3O 232 -234 73 [ 3 a -e ] ; a ; R =H , b ;R = p- Me
(175)
[4 a - e ] ; a ; R =H , b ;R = p- Me
c ; R =O-OH ,d ;R = p-OMe
c ; R =O-OH ,d ;R = p-OMe
e ; R = p-Cl
e ; R = p-Cl
7 C8H8N4O 243-246 68
(176)
Scheme 1
8 C21H16N2O 198 - 200 68
(312)
9 C8H6N2O2S 248 - 250 70 O
O
(194) OCH3
(a) N2H4 NH N H
OH H
MeOH O H
OH + C
2.11. Antimicrobial assessment [2]

R
The activities of all synthesized compounds were tested
MeOH / piperidine
O
in vitro against the Gram-positive bacteria Bacillus subtilis,
and Staphylococcus aureus, and the Gram-negative bacteria NH
R
N
Escherichia coli using nutrient agar medium, as well as against OH C
H
Candida albicans and Aspergillus niger using Sabouraud dex- [3 a -e ]
trose agar medium. All compounds activities were screened Ar
O O O
by agar diffusion method (Cruickshank et al., 1975). In brief, N Ar
SH DMF/reflux
N
H2
N C + HO C N C
a suspension of the organisms was added to sterile nutrient (b) H C
H2 ZnCl2 H C
C H
OH H OH S
agar media at 45 °C and the mixture was transferred to ster- - H2O O
ile Petri dishes and allowed to solidify. Holes (10 mm) were [ 3 a -e]
Ar
made using a cork borer and the synthesized compounds (0.1 CH
ml) and DMSO (control) were poured inside them. The plates O
S
O
Ar
N N
were pre-incubated for 1 h at room temperature and then N CH2
C
OH
HC N
incubated at 37 °C for 24 h. The zone of inhibition diame- OH
H
H
H C
O OH
ters were measured and compared with that of the standard. S CH2

Ar
3. Results and discussion O
H
CH
3.1. Chemistry N N S
The reaction sequence leading to the formation of com- OH C
CH2
pounds 3 and its further reaction to form compounds 4 is O
[4 a - e ]
outlined in Scheme 1. Compound 2 was prepared by the ac-
tion of hydrazine hydrate on methyl salicylate 1 and as pre- Scheme 2
viously described (Vidya et al., 2014). It reacted with a set of
aromatic aldehydes (including: benzaldehyde , p-methyl-ben-
zaldehyde ,o-hydroxy- benzaldehyde, p-methoxy-benzalde-
22
 Kenawy et al., 2018, AJMS 1(1): 19-25 DOI:10.5455/ajms.4

The IR spectrum of salicylic acid hydrazide 2 showed an
absorption band at 1640 cm-1 corresponding to C=O and at
1244 cm-1due to C-N stretching vibration of the amide group
, two bands at 3266 and 3313 cm-1 appeared due to the pres-
ence of -OH and -NH2 groups respectively. The IR spectra
for compounds 3 a-e showed the characteristic bands for
such derivatives; they were all characterized by strong absorp-
tion bands at region 1680 – 1610 cm-1 due to the carbonyl
group , they showed strong absorption bands ranging from
2700 – 2600 cm-1 due to the –OH group. All compounds
showed a characteristic absorption bands at 3450 cm-1 due
to the stretching vibration of N – H bond , the disappearance
of the NH2 peak at 3313 cm-1 and the appearance of C=N
stretching vibration band for benzylidine ring at 1944 cm-1
provide an evidence for the formation of such derivatives.
The 1HNMR spectra for compounds 3 a-e showed a sig-
nificant peaks at δ (11.6 – 12.0) ppm due to the -NH proton
and a sharp singlet peaks at δ (2.5) ppm for the proton
of the OH group , and a complex spectra were noticed at
the aromatic region in the range δ (6.9 – 8.0) ppm due to
the aromatic protons. The IR spectra for compounds 4
a-e were characterized by strong absorption bands at region
1620 cm-1 due to the carbonyl group , they showed absorption
bands ranging from 3440 – 3420 cm-1 due to the –OH group,
all compounds showed a characteristic absorption bands at
3230 - 3260 cm-1 due to the stretching vibration of N – H bond
, the disappearance of the C=N stretching vibration peak and
the appearance of bands at region 1562 - 1550 cm-1 due to the
carbonyl group of the thiazolidin-4-one ring which provide an
evidence for the formation of such derivatives. The 1HNMR
spectrum of compounds 4b,d,e showed a sharp singlet peaks
at δ 2.5 ,2.97 ppm due to the OH proton . Compounds 4b,e
showed a sharp singlet peaks at δ 2.35, 3.81 ppm, respectively
due to the three protons of CH3 group . A complex spectra
appeared at δ (6.9 - 7.8) ppm due to 8 aromatic ring protons.
The sharp singlet appeared at δ 11.81 ppm due to the –NH
proton. The disappearance of the singlet peak of –N-CH and
the presence of singlet peaks at δ 3.34,3.36,3.39 ppm re-
spectively were due to the –CH2 proton of the thiazolidinone
ring, confirming the formation of the desired compounds.
Our attention was directed to extent the application of sali-
cyloyl hydrazide 2 by tethering salicylic acid with heterocyclic
ring by reacting it with some reagents to yield the correspond-
ing derivatives 5 – 8, (Scheme 3).

Table (3). Band Assignments of the IR spectrum of compounds 2 – 4.

Code C=O C-O C=N C-N C=C C-H -NH -OH Other
arm
2 1640 3266 3133 3047 1588 1244 1821 1089

3a 1626 3441 3240 3035 1453 1565 1944 1379 2855 N=C-H
1311 C-N benzylidene
3b 1627 3468 3242 3037 1457 1555 1910 1315 2854 N=C-H
1311 C-N benzylidene
3c 1627 3443 3198 3051 1487 1560 1940 1373 2844 N=C-H
1303 C-N benzylidene
3d 1615 3456 3256 3063 1455 1554 1830 1376 2845 N=C-H
1308 C-N benzylidene
2926 CH3
3e 1641 3441 3235 3065 1546 1606 1913 1384 2857 N=C-H
1298 C-N benzylidene
815 C-Cl
4a 1626,1560 3415 3239 3061 1491 1232 - 1309 752 C-S

4b 1620,1563 3423 3261 3042 1504 1240 - 1311 745 C-S

2857 CH3
4c 1619,1562 3440 3262 3033 1503 1229 - 1309 741 C-S

4d 1616,1555 3441 3256 3069 1509 1249 - 1308 747 C-S

4e 1620,1555 3423 3247 3060
The structural characteristic features for the prepared
derivatives 5–9 were confirmed by IR and 1HNMR spec-
tra, that indicates the presence of the main groups as were
proposed. The IR spectrum was characterized by the pres-
ence of absorption bands at 1560 -1510 cm-1 corresponding
to the triazole ring and bands at 1600-1700 cm-1 region due
to stretching vibration of C=N. bands at 3100-3500 cm-1
region for the stretching vibration of NH , the stretching vi-
bration of OH was located within the range 3290 -3100
cm-1 region. The 1H NMR spectrum for these derivatives
were characterized by the presence of peaks at 10.5 -12.0
2854 CH3
1489 1234 - 1308 702 C-S
651 C-Cl
ppm due to the –NH proton , the OH proton resonated at 2.5-
3.5 ppm, aromatic protons resonated at the aromatic protons
region in the range of 6.5-8.00 ppm. The IR of compound
5 is characterized by the appearance of absorption bands at
1673cm-1 due to (C=N) , 1607 ccm-1 due to (C=C) , 2955
cm-1 due to the stretching frequency of (C-H aromatic), 1555
cm-1 due to the stretching frequency of (C-H aromatic of tri-
azine ring), 142 cm-1 due to (-NH), 3290 cm-1 due to (-OH).
The 1HNMR spectrum of compound 5 showed a sharp singlet
peak at δ 3.3 ppm due to the OH proton and complex spectra
appeared at δ (6.95 - 7.4) ppm due to 4 aromatic ring protons
23
 Kenawy et al., 2018, AJMS 1(1): 19-25 DOI:10.5455/ajms.4

O
and a singlet peak was appeared at δ 11.82 ppm due to the N N

–NH proton. The IR of compound 6 is characterized by the H - C - NH2 N

H
appearance of absorption bands at 1750 cm-1 due to (C=N ), fusion OH
1607 cm-1 due to (C=C ) , 3067 cm-1 due to the stretching fre- [5]
quency of (C-H aromatic) and 1481 cm-1 due to the stretching
O
frequency of (C-H aromatic of triazine ring), 3125 cm-1 due N N
to (-NH), 3296 cm-1 due to (-OH), 2858 cm-1 due to (-CH3). CH3 - C - NH2 N CH3
The 1HNMR spectrum of compound 6 showed a sharp singlet O fusion
OH
H

peak at δ 1.96 ppm due to 3 protons of the CH3 group , δ 2.5 NHNH2 [ 6]
ppm due to the OH proton . complex spectra appeared at δ
OH
(6.9 - 7.9) ppm due to 4 aromatic ring protons and a singlet [2]
O
N N
peak was appeared at δ 10.2 ppm due to the –NH proton. H2N - C - NH2
N NH2
The IR of compound 7 is characterized by the appearance of fusion H
absorption bands at 1703 cm-1 due to (C=N ),1552 cm-1 due OH
[7]
to (C=C ), 3071 cm-1 due to the stretching frequency of (C-H N N
aromatic). 1490 cm-1 due to the stretching frequency of (C-H Ph Ph
C C
aromatic of triazine ring ), 3311 cm-1 due to (-NH), 3206 cm-1 O O
Ph
Ph

due to (-OH), 3472 cm-1 due to (-NH2). The 1HNMR spectrum EtOH/Et3N reflux OH
of compound 7 showed a sharp singlet peak at δ 2.5 ppm due [8]
to 2 protons of the amino group. and δ 3.3 ppm due to the N NH
OH proton , a complex spectra appeared at δ (6.11 - 7.44) ppm CS2 / KOH O
due to 4 aromatic ring protons, and the peak appeared at δ reflux / DMF
S

10.33 ppm is due to the NH proton. The IR of compound 8 OH

[9]
is characterized by the appearance of absorption bands at 1637 Scheme 3
cm-1 due to (C=N ) , 1543 cm-1 due to (C=C ), 3056 cm-1 due
to the stretching frequency of (C-H aromatic), 1543 cm-1 due Table (4). Band assignments of the IR spectrum of compounds 5-9.
to the stretching frequency of (C-H aromatic of triazine ring )
, 2925 cm-1 due to (NH), 3219 cm-1 due to (OH) and 685 cm-1 Code C-O C=N C-N C=C C-H -NH -OH Other
arm
due to phenyl group. The 1HNMR spectrum of compound 8
showed a sharp singlet peak at δ 3.36 ppm due to the OH 5 3290 3124 2955 1607 1231 1673 1041 1481 TR
proton, a complex spectra appeared at δ (6.9 - 7.9) ppm due
to 11 aromatic ring protons , and a singlet peak appeared at 6 3296 3125 3067 1607 1230 1750 1009 1481 TR
2858 CH3
δ 11.2 ppm due to the NH proton. The IR of compound 9 is
characterized by the appearance of absorption bands at 1777 7 3206 3311 3071 1552 1243 1703 1043 1490 TR
3427 NH2
cm-1 due to (C=N ) , 1629 cm-1 due to (C=C ) , 3072 cm-1 due
to the stretching frequency of (C-H aromatic), 1594 cm-1due 8 3219 2925 3056 1543 1231 1673 1090 1543 TR
to the stretching frequency of (C-H aromatic of triazine ring), 685 PR
3273 cm-1 due to (NH) group , 3240 cm-1 due to (OH). The 9 3240 3273 3072 1629 1253 1777 1057 1151
1HNMR spectrum of compound 9 showed a sharp singlet peak C=S
at δ 3.3 ppm due to the OH proton a complex spectra appeared TR: triazine ring; PR: phenyl ring
at δ (6.8 - 7.3) ppm are due to 4 aromatic ring protons and
the peak appeared at δ 10.73 ppm due to the NH proton . Table (5). Inhibition zone diameters (mm) of compounds 2 - 9.

Code Bacillus Staph. E. coli Candida Aspergillus

3.2. Antimicrobial assessment subtilis aureus albicans niger
Inhibition zone diameters (highly active = inhibition zone 2 21 - 21 21 18
≥ 19 mm, moderately active = inhibition zone 14 - 18 mm;
slightly active = inhibition zone 7 - 13 mm; and inactive (-ve) 3a - 13 18 - -
= no inhibition zone ( Khalil et al., 2003) of the compounds 3b - - 13 - -
against some selected microorganisms are shown in Table 5. 3c 13 13 - 13 -
Most compounds showed decreased activities than salicylic
3d - - 18 - -
acid hydrazide 2 which showed high activity profile ; that may
be due to the presence of the hydrazino group. Compounds 3e 13 15 13 11 -
3b,d and 4 d were inactive against Gram +ve bacteria strains 4a 17 13 16 16 11
,while the other derivatives showed moderate activities. Com-
pounds 3c, 4 c were inactive against Gram -ve bacteria strains. 4b 18 21 21 18 13
All compounds were inactive against Candida albicans and As- 4c 13 13 - 13 -
pergillus niger except compounds 4 a,b. The presence of chlo- 4d - - 18 - -
rine atom in the aldehydic moiety in addition to the thiazolidine
ring has not enhanced the activity as expected [compound 4 4e 15 21 11 5 -
e]. Compound 5 was inactive against Gram +ve and Gram 5 13 - - 13 -
-ve bacteria strains, while the other derivatives were slightly 6 18 13 13 13 -
active. The presence of free amino group in compound 7 may
7 18 12 18 12 -
enhance the anti-bacterial properties. Compound 9 showed the
highest activity which may be due to the presence of the mer- 8 13 13 12 11 -
capto group. 9 23 20 19 20 -

24
 Kenawy et al., 2018, AJMS 1(1): 19-25 DOI:10.5455/ajms.4
Conclusion
Salicylic acid hydrazide was successfully accommodated
subunits of thiazolidine-4-ones or oroxadiazin or pyrimi-
din affording a set of derivatives which prove their utility
in medicinal chemistry ; as they showed a moderate to high
antimicrobial properties proving the synthetic utility of sal-
icylic acid hydrazide in constructing new heterocycles of
possible expected therapeutic relevance. The same molec-
ular hybrid template may afford more potent scaffolds upon
the incorporation of more effective substituents based on the
highly biological profile of salicylic acid hydrazide itself.
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