Therapeutic Potential of Hydrazones as Anti-Inflammatory Agents

12 Pages·2015·2.11 MB·English

Hindawi Publishing Corporation
International Journal of Medicinal Chemistry
Volume 2014, Article ID 761030, 11 pages
http://dx.doi.org/10.1155/2014/761030
Review Article
Therapeutic Potential of Hydrazones as
Anti-Inflammatory Agents
AnuKajal,SumanBala,NehaSharma,SunilKamboj,andVipinSaini
M.M.CollegeofPharmacy,MaharishiMarkandeshwarUniversity,Mullana,Ambala,Haryana133207,India
CorrespondenceshouldbeaddressedtoSumanBala;[email protected]
Received8August2013;Accepted20December2013;Published4March2014
AcademicEditor:PaolaFossa
Copyright©2014AnuKajaletal. This is an open access article distributed under the Creative Commons Attribution License,
whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Hydrazones are a special class of organic compounds in the Schiff base family. Hydrazones constitute a versatile compound
of organic class having basic structure (R1R2C=NNR3R4). The active centers of hydrazone, that is, carbon and nitrogen, are
mainly responsible for the physical and chemical properties of the hydrazones and, due to the reactivity toward electrophiles
and nucleophiles, hydrazones are used for the synthesis of organic compound such as heterocyclic compounds with a variety
of biological activities. Hydrazones and their derivatives are known to exhibit a wide range of interesting biological activities
likeantioxidant,anti-inflammatory,anticonvulsant,analgesic,antimicrobial,anticancer,antiprotozoal,antioxidant,antiparasitic,
antiplatelet,cardioprotective,anthelmintic,antidiabetic,antitubercular,trypanocidal,anti-HIV,andsoforth.Thepresentreview
summarizestheefficiencyofhydrazonesaspotentanti-inflammatoryagents.
1.Introduction characters,thatis,nucleophilicandelectrophilic.Theactive
centersofhydrazine,thatis,carbonandnitrogen,aremainly
Inflammation is a physiological reactionwhich involves cel- responsible for the physical and chemical properties of the
lular and biochemical responses, which is not only symp- hydrazones and, due to the reactivity toward electrophiles
tom for common diseases but also known to be an early and nucleophiles, hydrazones are used for the synthesis of
phaseforsomeseriousdiseasessuchasalzheimer’sdisease, organiccompoundsuch as heterocyclic compounds[9, 10].
cancer, heart vascular diseases [1] etc. Nonsteroidal anti- The general method for the synthesis of the hydrazones is
inflammatory drugs (NSAIDs) like ketoprofen, ibuprofen, the reaction of hydrazine with carbonyl compounds such
aceclofenac, and so forth under current clinical usage for as aldehydes or ketones in solvents like ethanol, methanol,
the treatment of inflammation, algesia and pyresis [2] are butanol [11–13], and so forth. Hydrazones and their deriva-
associatedwithmajordrawbacksofgastrointestinaldisorders tives are known to exhibit interesting diverse biological
likedyspepsia,gastriculcers,andsoforth,duetothedirect activities like antioxidant [14], anti-inflammatory [15, 16],
contact of free carboxylic group with the gastric mucosa anticonvulsant[17,18],analgesic[19,20],antimicrobial[21–
[3, 4] and due to decrease in production of prostaglandins 23],anticancer[24,25],antiprotozoal[26],antiparasitic[27],
in tissue [5]. In order to overcome these drawbacks, there cardioprotective[28],antidepressant[29],antitubercular[30,
is an urgent need for design and synthesis of new chem- 31],anti-HIV[32],andtrypanocidaletc.Hydrazonesarealso
ical entities with excellent anti-inflammatory response and emerging as moiety of interest in medical biotechnology.
minimum side effects. Hydrazones are a class of organic Hydrazones are also used to couple with certain drugs and
compounds in the Schiff base family [6]. Hydrazones con- the bonds based on hydrazones are stable at the neutral
stitute a versatile compound of organic class having the pH [33]. The hydrazone Schiff bases of aroyl, acyl, and
basicstructureR1R2C=NNR3R4 [7,8].Twonitrogenatoms heteroaroyl compounds are known to have an additional
of hydrazone are nucleophilic but the amino type nitrogen donorsite,thatis,C=O,whichmakethemmoreversatileand
is more reactive, whereas the carbon atom possesses both flexible.Thisversatilityhasleadedthehydrazonestoemerge
2 InternationalJournalofMedicinalChemistry
1 Ar
OH O
a Phenyl
N Ar b 2-Pyridinyl
N c 4-Isopropylphenyl
H
d 4-Dimethylaminophenyl
N
S CH3 e 2-Thiophenyl
O O f 2-Thiazolyl
g 2-Biphenyl
1
h 3,5-Diterbutyl-4-hydroxyphenyl
Figure1
O 2 R R
H a 3-Chlorophenyl H
H2C C N N C R1 b 4-Chlorophenyl H
H
c 2-Pyridyl H
N N d 3-Chlorophenyl CH3
O N NR e 4-Chlorophenyl CH3
f 2-Pyridyl CH3
g 3-Chlorophenyl OCH3
2 h 4-Chlorophenyl OCH3
i 2-Pyridyl OCH3
Figure2
3 R
N
N a H
b 4-Methyl
R
N O c 4-Methoxy
d 3,4-Dimethoxy
N e 2-Chloro
f 4-Chloro
HC NHNOC g 4-Dimethylamino
h 4-Hydroxy
3 i 3-Nitro
j 4-Nitro
Figure3
N HNO2S
N
H
4
Figure4
InternationalJournalofMedicinalChemistry 3
O
N N Ar 5 R
N
H o 4-oxo-4H-2-chromene
H
N 5
Figure5
R1 6 R R1 R2
a H H H
S N R2 b H Cl H
c H N(CH ) H
N 3 2
d H OH OCH
3
N NH e 5-CH Cl OH
3
f 5-CH3 OH OCH
g 5-CH H OH
R O 3
h 5-Cl OH OCH
N 3
H i 5-Cl Cl OH
6
j 5-NO OH OCH
2 3
Figure6
H Ar 2.Anti-InflammatoryActivity
N N
A series of benzothiazine N-acylhydrazones 1(a–h) was
NH O designedbystructuralmodificationofpiroxicamandsynthe-
N sizedandevaluatedfortheanti-inflammatoryandantinoci-
N
ceptive activities (Figure1). The pharmacological screening
revealedthatcompounds1(a–h)haveexhibitedbetteractivity
than standard drug piroxicam. Compounds 1f and 1g were
7 identified as new anti-inflammatory and antinociceptive
agents which were capable of inhibiting cell recruitment by
70% and 80%, respectively, at dose of 100𝜇mol/kg, p.o in
Figure7
zymosan-andcarrageenan-inducedperitonitis[36].
A novel series of 6-substituted-3(2H)-pyridazinone-
H C
3 2-acetyl-2(p-substituted/nonsubstituted benzal)hydrazine
2(a–i) was synthesized and evaluated for their analgesic
Ar
N N and anti-inflammatory activity (Figure2). The activity was
evaluated by using carrageenan-induced paw oedema assay
andindomethacinwasemployedasstandardforcomparison
NH O
N of results. The results revealed that 6-substituted-3(2H)-
N
pyridazinone-2-acetyl-2(nonsubstitutedbenzal)hydrazones,
that is, 2a, 2b, and 2c, were found to be most potent
anti-inflammatory agents. Compound 2a, 6-[4-(3-chloro-
phenyl)piperazine]-3(2H)-pyridazinone-2-acetyl-2(p-sub-
8
stituted/nonsubstituted benzal)hydrazine, was found to be
slightlybetterthanstandarddrugindomethacin[37].
Figure8
A novel series of N-(substituted benzylidene)-2-(N-
(4H-1,2,4-triazole-4-yl) benzamido)acetohydrazide deri-
asgoodchelatingagentsthatcanformavarietyofcomplexes vatives 3(a–j) was synthesized and evaluated for the anti-
with different transition metals [6]. Some hydrazones have inflammatory and antimicrobial activity (Figure3). Indo-
beenintroducedbytheresearchersaspotentdrugs,suchas methacin was used as standard drug and carrageenan-
nifuroxazide, an intestinal antiseptic [34, 35], dihydralazine induced paw oedema method was employed for the anti-
ashypertensive,andgyromitrin,atoxin. inflammatoryscreeningofthetestcompounds.Itwasfound
4 InternationalJournalofMedicinalChemistry
H
O C N N CH 9 R󳰀 Ar
Ar c 4-Cl 4-NO2C6H4
d 4-Cl 4-CH C H
3 6 4
e 4-Cl 2-OHC H
10 6
9
R󳰀
Figure9
O
N
C N 10 R
BT
CH
3 a H
b 2-Nitro-4-methyl
O
c 2,5-Dichloro
N
N d 4-Chloro-2-methyl
H R e 2,5-Dimethyl
10
Figure10
that compounds 3f, 3g, and 3j substituted with 4-chloro, Carrageenan-induced rat paw oedema model was
4-dimethylamino,and4-nitroexhibited66.7,61.7,and63.2% used for evaluation of anti-inflammatory activity and
inhibition, respectively, at 50mg/kg, oral dose, whereas indomethacinwasemployedasstandarddrug.Itwasfound
standarddrugindomethacinhadshown64.2%inhibitionat that the compounds 6f, 6h, and 6j substituted at fifith
10mg/kg,oraldose[38]. positionwithmethyl,chloro,andnitrogroups,respectively,
Synthesis of a novel series of some amidine and hydra- exhibitedsignificantanti-inflammatoryactivity[41].
zonederivatives4 wasreported(Figure4). Thesynthesized
SynthesisofanovelseriesoforallyactiveN-phenylpyra-
compounds were further subjected to evaluation of anti-
zolyl-N-glycinyl-hydrazone derivatives, 7a–g (Figure7)
inflammatory and analgesic activities. Anti-inflammatory
and 8 (Figure8), was carried out. Synthesized com-
activity evaluation was carried out using carrageenan-
pounds were evaluated for their in vivo analgesic and anti-
inducedratpawoedemaassayandcompound4awasfound
inflammatory activities and in vitro inhibition of TNF-
tohavegoodanti-inflammatoryactivity[39]. 𝛼 (tumor necrosis factor). Compounds 7a, (E)-2-(3-
A series of nineteen pyrazine N-acylhydrazone (NAH) tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-𝑁󸀠-((4-(2-mor-
derivatives 5(a–s) was (Figure5) designed by molecular
pholinoethoxy)naphthalen-1-yl)methylene)acetohydrazide,
simplification of the prototype (LASSBio-1018), a nonselec-
and7f,(E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-
tive cyclooxygenase inhibitor. Synthesis of the designed 󸀠
N -(4-chlorobenzylidene)acetohydrazide, were known to
compounds was carried out and they were evaluated for
possess anti-inflammatory activities when compared to the
their anti-inflammatory and analgesic activities in several
standarddrugused,thatis,SB-203580[42].
animalmodels ofpain and inflammationlike writhingtest, Synthesis of a novel series of substituted-𝑁󸀠-[(1E)-sub-
formalin test, hot plate test, zymosan-induced peritonitis,
stitutedphenylmethylidene]benzohydrazideanalogs,9(a–n)
capsaicin-induced ear edema, and Freund’s adjuvant-
induced arthritis model. Thalidomide (TNF-𝛼 inhibitor), (Figure9) was reported and evaluated for their in vitro
anti-inflammatory, antimicrobial and antioxidant activities.
celecoxib (COX-2) inhibitor, and indomethacin (selective
Albumin denaturation studies were carried out in order
COX-1inhibitor)wereemployedasstandarddrugs.Results
enlightened that compound 5o (2-𝑁󸀠-[(E)-(3,4,5-trim- to evaluate the anti-inflammatory activity by employing
diclofenac sodium as standard. Compounds 9c, 9d, and 9e
ethoxyphenyl)methylidene]-2-pyrazinecarbohydrazide, LA-
were reported to have good anti-inflammatory activity due
SSBio-1181,hadbetterpharmacologicalactivitiesandcanbe
to presence of 4-nitro, 4-methyl, and 2-hydroxy groups,
usedasaleadcompoundfordevelopmentofnewanalgesic
andanti-inflammatoryagents[40]. respectively,whereas9ewasfoundtobethemostactiveanti-
Anovelseriesofisatinderivatives,thatis,isatin-3-[N2- inflammatoryagent[43].
(2-benzalaminothiazol-4-yl)]hydrazones6(a–j),wassynthe- Synthesisandbiologicalevaluationofsomenewbenz[b]-
sized and evaluated for anti-inflammatory, analgesic, and thiophene derivatives like thiadiazole, pyrazoline, oxadia-
1
antipyreticactivities(Figure6)[41]. zole and diaryl pyrazoles was carried out. N -(3- chlo-
InternationalJournalofMedicinalChemistry 5
Br
HN N C CN
CH
3
O O
13
Figure11
O
R
N N C 14 R
H H
a 3-NO2
b 2-NO2
N 14
Figure12
R O
H 15 R
C N N C NH
2 a −C H
6 5
b −CH3
15
Figure13
N
R N O
O 16 R R󳰀 R R󳰀
S
N OH a H 4-NO g 2.4-Cl 4-NO
2 2
N b H 4-OCH3 h 2.4-Cl 4-OCH3
c H 2-OH i 2.4-Cl 2-OH
d H 2,4-Cl j 2.4-Cl 2,4-Cl
R󳰀 e H 4-Cl k 2.4-Cl 4-Cl
16 f H 4-CH l 2.4-Cl 4-CH
3 3
Figure14
O R
R 17 R Ar
NH
NH HN a 4-MeC6H4 4-ClC6H4
O HN b 4-NO2C6H4 4-ClC6H4
c 4-NO2C6H4 4-BrC6H4
H d Benzothiazol-2-yl 4-ClC6H4
17 Ar
Figure15
6 InternationalJournalofMedicinalChemistry
18 R
O
a H
N b NO2
N
H c CH3
d Br
e F
f OH
g OCH
3
18 h Cl
R i CH(CH )
3 2
j N(CH )
3 2
Figure16
Ph
N
O
O
N
O N
N
H
O
O
19
Figure17
robenzo[b]thiophene-2-carbonyl)-3-methyl-4-9 substituted revealed that naphthalen-1-yloxy)-acetic acid [1-(2-bromo-
phenylhydrazonopyrazolin-5-one10(a-e)weresubjectedto 4-cyano-phenyl)-ethylidene]-hydrazide 13 (Figure11) has
anti-inflammatoryandantimicrobialevaluation(Figure10). shown percent inhibition of 20.90% at a dose of 50mg/kg
Compound10bsubstitutedwith2-nitro-4-methylwasfound [50].
tohave50.25%inhibitionwhichisnearaboutthestandard The nicotinic acid hydrazide derivatives, 14a and 14b,
drugdiclofenacsodiumi.e.51.88%[44]. substituted with nitro group at meta and ortho posi-
Synthesisofzinccomplexes11,[Zn(LASSBio-466)H2O]2 tions, respectively, were found to be the most active anti-
ofsalicylaldehyde2-chlorobenzoylhydrazone(H2LASSBio- inflammatory agents (Figure12). The percent inhibition of
466), and 12, [Zn(HLASSBio-1064)Cl]2 salicylaldehyde 4- compounds14aand14bwasfoundtobe37.29%and35.73%,
chlorobenzoyl hydrazone (H2LASSBio-1064), was carried respectively,atthedoseof20mg/kgand34.17%and25.12%,
out.Thecomplexeswerefurthersubjectedtoevaluationfor respectively, at the dose of 50mg/kg, whereas percent inhi-
peripheral and central nociception and acute inflammation bition of diclofenac sodium was found to be 38.85%. The
in animal models. Both of the complexes exhibited anti- conclusiondrawnfromtheresultswasthatthesubstitutionof
inflammatoryactivity.Complex11hasshownactivityinboth nitro group and halogens contributed to anti-inflammatory
phases of formalin test like indomethacin and indicated its activity[50].
abilitytoinhibitnociceptionassociatedwiththeinflamma- Synthesis of benzophenone semicarbazone (BSC) 15a
tory response, whereas H2LASSBio-466 was active only in andacetophenonesemicarbazone(ASC)15bwascarriedout
firstphaseofformalintest.H2LASSBio-1064inhibitedboth (Figure13). The anti-inflammatory activity was determined
phases but no improvement was indicated by the complex on Swiss albino mice by using carrageenan-induced mice
[45]. paw oedema model. Bothof the compoundswere screened
Synthesis of some new hydrazide derivatives of 2- attwodifferentdoses,thatis,25mg/kgand50mg/kg(p.o.).
napthoxy acetic acid [46], nicotinic acid [47, 48] and nap- Compound 15a showed 36.6% and 46.6% of inhibition at
thlene-1-acetic acid [49] has been reported. Out of these 25mg/kg and 50mg/kg, respectively, whereas compound
hydrazidederivativesmostactiveantimicrobialcompounds 15bshowed34.6%and41.5%inhibition.Diclofenacsodium
were selected and subjected to evaluation of the anti- wasusedasstandarddrugwhichshowed70.29%inhibition
inflammatoryactivity.Carrageenaninducedratpawoedema at 10mg/kg (p.o.). From the above observations, it was
modelwasemployedfortheevaluationofthesesactivecom- concluded that both of the test compounds possessed anti-
pounds using diclofenac sodium as standard drug. Results inflammatoryactivity[51].
InternationalJournalofMedicinalChemistry 7
N
Me O
O
N
N
HN N
H
N O
20
Figure18
O R
N 21 R
N
H
Me a COOH
CH
3
N b N
CH
N 3
O
21
O
Figure19
Ar O 22 R󳰀 Ar
a 4-CH 2-C H -CH -5-thiazolyl-CO-
3 6 5 3
b 3-CF3 2-C6H5-CH3-5-thiazolyl-CO-
c 4-CH3 2-C6H5-CH3-5-thiazolyl-4-yl
H N R󳰀 d 3-CF3 2-C6H5-CH3-5-thiazolyl-4-yl
N
N e 4-CH3 2-(4-Br-C6H5)-thiazolyl-4-yl
S f 3-CF3 2-(4-Br-C6H5)-thiazolyl-4-yl
O
22
Figure20
Ar O
O R󳰀 Ar
23
N
N N R󳰀 a 4-CH3 2-C6H5-thiazol-4-yl
H b 3-CF3 2-C6H5-thiazol-4-yl
S c 3-CF3 2-(4-Br-C6H5)-thiazolyl-4-yl
23
Figure21
Ar O 24 R󳰀 Ar
H
N N
N a 4-CH3 2-(4-Br-C6H5)-thiazol-4-yl
b 3-CF3 2-(4-Br-C6H5)-thiazol-4-yl
O S
24
Figure22
8 InternationalJournalofMedicinalChemistry
Ar O
O
H
N
N
O
O
O
25
Ar=2-C H -thiazol-4-yl
6 5
Figure23
A novel series of 2-[4-(substituted benzylideneamino)- 7.7,and6.4𝜇g/mL,respectively(Figure17).Thisobservation
5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] correlatedthatmethylandchlorogroupshaveaconsiderable
aceticacid,16(a–l),wassynthesized(Figure14).Allthenewly influenceontheinhibitionofNF-𝜅Bmediatedtranscription.
synthesized compounds were evaluated for in vivo anti- Theothercompounds18d,18e,18g,and18iinhibitedtheNF-
inflammatoryandanalgesicactivities.Amongtheseries16d, 𝜅BactivitytoalesserextentwithIC50 valuesintherangeof
16e, 16j, and 16k showed significant activity with 63.4%, 10–14𝜇g/mL.Compounds18b,18d,and18jwerefoundtobe
62.0%, 64.1%, and 62.5% edema inhibition, respectively, as comparatively less active than other compounds. From the
compared to standard drug diclofenac 67.0% after the third results,itwasconcludedthatsubstitutionsatparapositionof
hour.Compounds16g,16h,16i,and16lshowedgoodanti- phenyl ring had significant influence on anti-inflammatory
inflammatory activity, whereas compounds 16a–c and 16f activity[54].
werefoundtobetheleastactive.Theresultsenlightenedthe By application of molecular hybridization approach
effectofelectronwithdrawingmoiety,thatis,chlorogroupon design, and synthesis of thirty two furoxanyl N-acylhydra-
theanti-inflammatoryactivity[52]. zones(furoxanyl-NAH) was carried out. Synthesized com-
󸀠 󸀠󸀠
Aseriesofbis-hydrazonederivatives,thatis,(Z)-N ,N - pounds were evaluated for their in vitro as well as in-
(1-(4-substituted phenyl)ethene-1,2-diyl)bis(4-substituted vivoanalgesicandanti-inflammatoryactivities.Theinvitro
benzhydrazide), 17(a–d), was synthesized by reaction of anti-inflammatory activity was evaluated by decrease in
2-chloro-1-(4-chlorophenyl)ethanoneor2-bromo-1-(4-bro- NF-𝜅B activation and interleukin-8 inhibition by using
mophenyl)ethanonewithacidhydrazides(Figure15).Allthe a human pathway-specific reporter cell system (HT-29-
synthesized compounds were evaluated for the anti-infla- NF-𝜅B-hrGFP) whereas carrageenan induced paw oedema
mmatory, analgesic, and ulcerogenic activities. Formalin- was used for in vivo evaluation of anti-inflammatory
inducedratpawoedemamodelwasselectedandketoprofen activity.Furoxanyl-NAH19(Figure17)andbenzofuroxanyl-
wasemployedasstandarddrug.Allcompoundswerefound derivative 20 (Figure18) were reported to have orally anti-
to exhibit good anti-inflammatory activity with percent inflammatory and analgesic activities without interleukin-
inhibition of 68.4% and 61.4% of compounds 17b and 17c, 8 inhibition. Furoxanyl-NAH derivative 21a (Figure19)was
respectively,afterthreehours[53]. emerged as a structural lead to develop new lipoxygenase
Synthesis of a series of hydrazone derivatives, that (LOX)inhibitors.Theactivederivatives19,21aand21bwere
is, N-(substituted benzylidene)-3-cyclohexylpropionic acid foundtobelessmutagenicandwereproposedascandidates
hydrazide, 18(a–j), was carried out (Figure16). The syn- forthefurtherclinicalstudies[55].
thesized compounds were evaluated for anti-inflammatory Synthesisofaseriesofnovelacyl-hydrazonesbearing2-
activity and cytotoxicity. Inducible nitric oxide synthase aryl-thiazole moiety was carried out. The synthesized com-
(iNOS)andNF-𝜅Bwereselectedfordeterminationofanti- pounds were screened for invivo anti-inflammatory activity
inflammatory activity. Inhibition of iNOS activity was also byevaluatingthreeparameters,thatis,nitricoxidesynthesis,
observedinLPS-inducedRAW264.7cells.Compounds18c, phagocytesactivity,andacutephasebonemarrowresponse,
18e, and 18i were more active than the other synthesized inacuteexperimentalinflammation[56].
compoundswhichprovedthatthereisapositivecorrelation Compounds 22c, 22e, 22f, 24b, and 26b were found
between the inhibitions of iNOS activity and functional to have a good inhibitory effect on the acute phase mar-
groups,thatis,methyl,fluoro,andisopropyl,onphenylring row response by reducing the absolute leukocytes count
[54]. due to the lower neutrophils percentage. Compound 22c
InhibitionofNF-𝜅Bmediatedtranscriptionwasseenin (Figure20)with2-phenyl-thiazoleand[2-(4-methylphenyl)-
humanchondrosarcoma(SW1353)cellsandcompounds18a, 4-methylen]-thiazole hydrazine moieties was proved to be
18c,and18hhaveshowninhibitionwithIC50 valuesof6.9, a more potent inhibitor of the acute phase bone marrow
InternationalJournalofMedicinalChemistry 9
Ar O O
26 Ar
O
a 2-C H -thiazol-4-yl
6 5
N O
N O b 2-(4-Br-C6H5)-thiazol-4-yl
H
26
Figure24
O
O
H2 H 27 R
N C C N N R
d 4-Cl
e 3-OCH3
O h 3-OCH3,4-OH
27
Figure25
response than meloxicam, the anti-inflammatory standard 3.Conclusion
drug[56].
Phagocytic activity was assessed by calculating phago- Hydrazonederivativesarewellknowntohavevariousimpor-
cytic index (PI) and the phagocytic activity (PA). All tantpharmacologicalactivitiesandareusedforsynthesisof
the newly synthesized compounds reduced PI significantly awidevarietyofmedicinallyactivecompounds.Thisreview
and compounds 22a (Figure20), 22b (Figure20), 22d papersummarizestheanti-inflammatorypotentialofhydra-
(Figure20),23b(Figure21),24b(Figure22),25(Figure23) zone derivatives and the effect of substitutions of different
and26b(Figure24)wereobservedasmorepotentinhibitors groups on the anti-inflammatory activity. This summarized
than meloxicam. PA was significantly reduced by the com- study is an attempt to bring about the anti-inflammatory
pounds22a,22d,23b,24b,23c,25and26bfromwhich22a, activityforawakingthesafeuseofthisimportantchemical
22d,20and26bwerefoundtobemorepotentinhibitorsthan moietywithminimalornoulcerogeniceffectsinfuture.
meloxicam[56].
Synthesis of NO increases significantly in acute inflam- ConflictofInterests
mationduetotheexpressionofiNOS.TheNOsynthesiswas
significantlyreducedby22a,22b,23c,26a,and26bandthey The authors declare that there is no conflict of interests
all, except for 26a, displayed a stronger inhibitory activity regardingthepublicationofthispaper.
thanmeloxicam[56].
Synthesis of a novel series of phthalic anhydride based References
substituted benzylidene-hydrazide derivatives, 27a–i, was
carried out. All the synthesized derivatives were screened [1] N.Ingale,V.Maddi,M.Palkaretal.,“Synthesisandevaluation
for in vivo anti-inflammatory and analgesic activities by ofanti-inflammatoryandanalgesicactivityof3-[(5-substituted-
carrageenan-induced rat paw oedema and tail immersion 1,3,4-oxadiazol-2-yl-thio)acetyl]-2H-chromen-2-ones,” Medic-
inalChemistryResearch,vol.21,no.1,pp.16–26,2012.
methods, respectively, using diclofenac sodium as stan-
dard drug. The results revealed that derivatives 27d, 27e, [2] B.Rigas,“Theuseofnitricoxide-donatingnonsteroidalanti-
inflammatory drugs in the chemoprevention of colorectal
and 27h (Figure25) have shown potent anti-inflammatory
neoplasia,”CurrentOpinioninGastroenterology,vol.23,no.1,
activity with percentage inhibition of 58.6%, 61.4%, and
pp.55–59,2007.
64.0%,respectively,whichiscomparablewithstandarddrug
[3] M.Venerito,T.Wex,andP.Malfertheiner,“Nonsteroidalanti-
diclofenac sodium, that is, 68.0%. The reaction time of
inflammatorydrug-inducedgastroduodenalbleeding:riskfac-
derivatives27dand27hthatwasfoundtobe8.91±0.21and
torsandpreventionstrategies,”Pharmaceuticals,vol.3,no.7,pp.
9.09±0.03,respectively,after90minuteswhichiscomparable
2225–2237,2010.
withreactiontimeofdiclofenacsodium(10.93±0.01)after
[4] A.Lanas,L.A.Garc´ıa-Rodr´ıguez,M.T.Arroyoetal.,“Effect
90minuteshasshownanalgesicpotencyofthesederivatives of antisecretory drugs and nitrates on the risk of ulcer
[57]. bleedingassociatedwithnonsteroidalanti-inflammatorydrugs,
10 InternationalJournalofMedicinalChemistry
antiplateletagents,andanticoagulants,”TheAmericanJournalof drugcandidates,”Mini-ReviewsinMedicinalChemistry,vol.7,
Gastroenterology,vol.102,no.3,pp.507–515,2007. no.11,pp.1108–1119,2007.
[5] S. Prakash, B. N. Gupta, and N. S. H. Moorthy, “Synthesis [20] U.Salgin-Go¨k¸sen,N.Go¨khan-Kelekc¸i,O¨.Go¨kta¸setal.,“1-Acy-
and physicochemical characterization ofmutual prodrug of lthiosemicarbazides, 1,2,4-triazole-5(4H)-thiones, 1,3,4-thia-
indomethacin,”TrendsinAppliedScienceResearch,vol.2,no. diazoles and hydrazones containing 5-methyl-2-benzoxazo-
2,pp.165–169,2007. linones:synthesis,analgesic-anti-inflammatoryandantimicro-
[6] J. P. Cornelissen, J. H. Van Diemen, L. R. Groeneveld, bialactivities,”Bioorganic&MedicinalChemistry,vol.15,no.17,
J. G. Haasnoot, A. L. Spek, and J. Reedijk, “Synthesis pp.5738–5751,2007.
and properties of isostructural transition-metal (copper,
[21] A.Deeb,F.El-Mariah,andM.Hosny,“Pyridazinederivatives
󸀠 󸀠
nickel, cobalt, and iron) compounds with 7,7,8,8-tetracya-
and related compounds—part 13: synthesis and antimicro-
noquinodimethanide(1-) in an unusual monodentate coordi- 󸀠 󸀠
bialactivityofsomepyridazino[3,4:3,4]pyrazolo[5,1-c]-1,2,4-
nation mode. Crystal structure of bis(3,5-bis(pyridin-2-yl)-
triazines,”Bioorganic&MedicinalChemistryLetters,vol.14,no.
󸀠 󸀠
4-amino-1,2,4-triazole)bis(7,7,8,8-tetracyanoquinodimetha-
19,pp.5013–5017,2004.
nido)copper(II),” Inorganic Chemistry, vol. 31, no. 2, pp.
[22] A. J. M. Rasras, T. H. Al-Tel, A. F. Al-Aboudi, and R. A.
198–202,1992.
Al-Qawasmeh,“Synthesisandantimicrobialactivityofcholic
[7] M.B.SmithandM.Jerry,March’sAdvancedOrganicChemistry:
acid hydrazone analogues,” European Journal of Medicinal
Reactions, Mechanisms, and Structure, John Wiley & Sons,
Chemistry,vol.45,no.6,pp.2307–2313,2010.
Milton,Australia,6thedition,2007.
[23] Y.O¨zkay,Y.Tunali,H.Karaca,andI.I¸sikdagˇ,“Antimicrobial
[8] R. Lazny and A. Nodzewska, “N,N-dialkylhydrazones in
activityandaSARstudyofsomenovelbenzimidazolederiva-
organic synthesis. From simple N,N-dimethylhydrazones to
tivesbearinghydrazonemoiety,”EuropeanJournalofMedicinal
supportedchiralauxiliaries,”ChemicalReviews,vol.110,no.3,
Chemistry,vol.45,no.8,pp.3293–3298,2010.
pp.1386–1434,2010.
[9] S. N. P. Belskaya, W. Dehaen, and V. A. Bakuleva, “Synthesis [24] D. Kumar, N. M. Kumar, S. Ghosh, and K. Shah, “Novel
and properties of hydrazones bearing amide, thioamide and bis(indolyl)hydrazide-hydrazones as potent cytotoxic agents,”
amidinefunctions,”Arkivoc,vol.2010,no.1,pp.275–332,2010. Bioorganic&MedicinalChemistryLetters,vol.22,no.1,pp.212–
[10] R.Brehme,D.Enders,R.Fernandez,andJ.M.Lassaletta,“Alde- 215,2012.
hydeN,N-dialkylhydrazonesasneutralacylanionequivalents: [25] K. Effenberger, S. Breyer, and R. Schobert, “Modulation of
umpolungoftheiminereactivity,”EuropeanJournalofOrganic doxorubicin activity in cancer cells by conjugation with fatty
Chemistry,vol.2007,no.34,pp.5629–5660,2007. acylandterpenylhydrazones,”EuropeanJournalofMedicinal
[11] I. S. Berdinskii, “The chemistry of hydrazones,” Chemistry of Chemistry,vol.45,no.5,pp.1947–1954,2010.
HeterocyclicCompounds,vol.15,no.2,p.238,1979. [26] M. E. Caputto, L. E. Fabian, D. Ben´ıtez et al., “Thiosemicar-
[12] P.A.S.Smith,“Hydrazones,”inDerivativesofHydrazineand bazones derived from 1-indanones as new anti-Trypanosoma
Other Hydronitrogens Having N-N Bonds, pp. 43–74, Ben- cruziagents,”Bioorganic&MedicinalChemistry,vol.19,no.22,
jamin/Cummings,Reading,Mass,USA,1983. pp.6818–6826,2011.
[13] V. Polshettiwar and R. S. Varma, “Polystyrene sulfonic acid [27] M. A. S. Aslam, S.-U. Mahmood, M. Shahid, A. Saeed, and
catalyzedgreenersynthesisofhydrazonesinaqueousmedium J. Iqbal, “Synthesis, biological assay in vitro and molecular
using microwaves,” Tetrahedron Letters, vol. 48, no. 32, pp. docking studies of new Schiff base derivatives as potential
5649–5652,2007. ureaseinhibitors,”EuropeanJournalofMedicinalChemistry,vol.
[14] N. Belkheiri, B. Bouguerne, F. Bedos-Belval et al., “Synthesis 46,no.11,pp.5473–5479,2011.
and antioxidant activity evaluation of a syringic hydrazones
[28] O. I. El-Sabbagh, M. A. Shabaan, H. H. Kadry, and E. S.
family,”EuropeanJournalofMedicinalChemistry,vol.45,no.
Al-Din,“Newoctahydroquinazolinederivatives:synthesisand
7,pp.3019–3026,2010.
hypotensiveactivity,”EuropeanJournalofMedicinalChemistry,
[15] M. A. A. Radwan, E. A. Ragab, N. M. Sabry, and S. M.
vol.45,no.11,pp.5390–5396,2010.
El-Shenawy, “Synthesis and biological evaluation of new 3-
[29] M. Catto, R. Aliano, A. Carotti et al., “Design, synthesis and
substituted indole derivatives as potential anti-inflammatory
biological evaluation of indane-2-arylhydrazinylmethylene-
andanalgesicagents,” Bioorganic & Medicinal Chemistry,vol.
1,3-diones and indol-2-aryldiazenylmethylene-3-ones as 𝛽-
15,no.11,pp.3832–3841,2007.
amyloidaggregationinhibitors,”EuropeanJournalofMedicinal
[16] A. Almasirad, M. Tajik, D. Bakhtiari et al., “Synthesis and
Chemistry,vol.45,no.4,pp.1359–1366,2010.
analgesicactivityofN-arylhydrazonederivativesofmefenamic
acid,”JournalofPharmacy&PharmaceuticalSciences,vol.8,no. [30] A. K. Jorda˜o, P. C. Sathler, V. F. Ferreira et al., “Synthesis,
3,pp.419–425,2005. antitubercular activity, and SAR study of N-substituted-
phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides,”
[17] S. K. Sridhar, S. N. Pandeya, J. P. Stables, and A. Ramesh,
Bioorganic&MedicinalChemistry,vol.19,no.18,pp.5605–5611,
“Anticonvulsant activity of hydrazones, Schiff and Mannich
2011.
basesofisatinderivatives,”EuropeanJournalofPharmaceutical
Sciences,vol.16,no.3,pp.129–132,2002. [31] A.Mahajan,L.Kremer,S.Louw,Y.Gue´radel,K.Chibale,andC.
[18] D. Kaushik, S. A. Khan, G. Chawla, and S. Kumar, “N’- Biot,“Synthesisandinvitroantitubercularactivityofferrocene-
[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene] basedhydrazones,”Bioorganic&MedicinalChemistryLetters,
2/4-substituted hydrazides: synthesis and anticonvulsant vol.21,no.10,pp.2866–2868,2011.
activity,”EuropeanJournalofMedicinalChemistry,vol.45,no. [32] C.A.Y.Jin,Z.Tan,M.Heetal.,“SARandmolecularmechanism
9,pp.3943–3949,2010. studyofnovelacylhydrazonecompoundstargetingHIV-1CA,”
[19] C. D. Duarte, E. J. Barreiro, and C. A. M. Fraga, “Privileged Bioorganic&MedicinalChemistry,vol.18,no.6,pp.2135–2140,
structures:ausefulconceptfortherationaldesignofnewlead 2010.