Metal complexes of hydrazones and their biological ...Fig. 5. Structures of Salicylaldehyde...

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Main Group Chemistry 13 (2014) 187–218DOI 10.3233/MGC-140133IOS Press

187

Metal complexes of hydrazones and theirbiological, analytical and catalyticapplications: A review

Mohamad M.E. Shakdofaa,b,∗, Majed H. Shtaiwia, Nagy Morsya,c

and Tayseer M.A. Abdel-rasseld,eaChemistry Department, Faculty of Sciences and Arts, Khulais, King Abdulaziz University, Saudi ArabiabInorganic Chemistry Department, National Research Center, Dokki, Cairo, EgyptcChemistry of Natural Compounds, National Research Center, Dokki, Cairo, EgyptdBiology Department, Faculty of Sciences and Arts, Khulais, King Abdulaziz University, Saudi ArabiaeBotany Department, Faculty of Science, Suez canal University, Egypt

Abstract. This is the first comprehensive review of the biological activity of hydrazone-transition metal complexes. Hydrazonecomplexes gained much attention because of their antifugial, antibacterial anticonvulsant, and analgesic, antiinflammatory,antimalarial, antimicrobial, antituberculosis, anticancer, and antiviral activities. Additionally, some of the hydrazone complexeswere used in treatment of iron overload diseases. One application, which reflects the importance of hydrazone complexes, istheir use in detection and determination of metals and some organic constituents in pharmaceutical formulations. This reviewwill provide an overview of the biological, analytical and catalytic applications of this category of complexes.

Keywords: Hydrazones, Transition metal complexes, biological, analytical, catalytic application

1. Introduction

Hydrazones are versatile ligands and considered as azomethine compounds and described by thefollowing general structure R2C = NNR2. They are distinguished from other members of this class (imines,oximes, etc . . . .) by the presence of interlinked nitrogen atoms. The hydrazone group occurs in organiccompounds and can be classified into two types a and b (Fig. 1). The compounds of type a are namedhydrazones whereas compounds of type b are termed azines.

1.1. Nomenclature of hydrazones

Hydrazones are usually named after the carbonyl compounds from which they are derived. Thus,the reaction of benzaldehyde and phenylhydrazine gives benzaldehyde phenylhydrazone. For instance,

∗Corresponding author: Mohamad M.E. Shakdofa, E-mail: [email protected].

ISSN 1024-1221/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

mailto:[email protected]

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188 M.M.E. Shakdofa et al. / Metal complexes of hydrazones and their biological, analytical and catalytic applications

Fig. 1. Two types of compounds with N = C bonding, hydrazones (I) and azines (II). Where R and R\ = H, alkyl, Ar, RC = O,heterocyclic group; Y = H, alkyl, Ar, RC = O, heterocyclic; X and X\ = H, alkyl, Ar, Hal, OR, SR, CN, SO2R, NO3, NHNR1R2,N = NR, COOR, CONR1R2, heterocyclic group.

the name originally used is benzalidenephenylhydrazone. Many authors have recently reverted to thissystem which is, however, cumbersome when applied to more complex hydrazones. Bis-hydrazones of�-diketones are commonly called osazones [1].

1.2. Preparation of hydrazones

Hydrazones, in general, are prepared by refluxing the stoichiometric amounts of the appropriatehydrazine and aldehyde or ketone dissolved in a suitable solvent. The resulting hydrazone usuallycrystallizes out on cooling [1].

1.3. Types of hydrazone ligands

The hydrazone ligands are classified according to the number of hydrazonic groups into monohydra-zone which are characterized by the presence of one hydrazonic group (one interlinked nitrogen atom)(Fig. 2 (a)), dihydrazone ligands, which are characterized by the presence of two hydrazonic groups (twointerlinked nitrogen atoms) (Fig. 2 (b)) and trihydrazone ligands, which are characterized by the presenceof three hydrazonic groups (three interlinked nitrogen atoms) (Fig. 2 (c)). Hydrazone ligands can alsobe classified according to the number of functional groups involved in the complexation process intobidentate, tridentate, tetradentate, pentadentatehexadentate, octadentate, and nonadentate.

Fig. 2. Structure representation of mono-(a), di- (b) and tri- (c) hydrazone ligands.

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M.M.E. Shakdofa et al. / Metal complexes of hydrazones and their biological, analytical and catalytic applications 189

Fig. 3. Mode of bonding of hydrazone ligands with transition metals (a) enolic, (b) ketonic.

1.4. Mode of bonding of hydrazone ligands with transition metals

The bonding of hydrazone ligands with transition metals may proceed according to one of the followingpaths. The first one leads to formation of complexes in which the hydrazone react with transition metalin the ketonic form (Fig. 3 (a)) whereas the second one hydrazone react in the enolic form (Fig. 3 (b)),leading to the formation of two types of complexes. The mode of bonding of hydrazone and molecularstructure of the resulted complexes depends on the nature of the metal ion, anion of the salt and alkalinityof the reaction medium [2].

2. Applications of hydrazone and metal complexes

Hydrazone ligands and their metal complexes have been attracted many authors due to their wideapplications in biological, pharmaceutical, analytical, catalytic and industerial fields.

2.1. Biological applications

Hydrazones and their coordination compounds play important roles in treatment of different diseases.The biological activity of hydrazone may be attributed to the formation of stable chelates with transitionmetals present in the cell, thus many vital enzymatic reaction cannot take place in the presence ofhydrazone. On coordination, the activity of hydrazone increases. This enhancement in the activity maybe rationalized on the basis that their structures mainly possess an additional C = N bond. Moreover,coordination reduces the polarity of the metal ion because of the partial sharing of its positive charge withthe donor atom within the chelate ring system, which formed during the coordination. This process, inturn, increases the lipophilic nature of the central metal atom, which favors its permeation more efficientlythrough the lipid layers of the microorganism, thus destroying them more aggressively. On the other hand,the inhibition of the growth of the microorganisms may be due to the inhibition of the glucose uptake,inhibition of RNA and/or protein synthesis.

2.1.1. Anti-tumour activityCancer is the growth of abnormal cells in the body in an uncontrolled manner. There are many different

kinds of cancer. It can be developed in almost any organ or tissue, such as lung, colon, breast, skin, bones,or nerve tissues. Chemotherapy is the most common way of treatment of different kinds of malignanttumors. The need for new promising antitumor agents is increasing worldwide. Hydrazone ligands andtheir complexes have wide applications as anti-tumour, anti-cancer, anti-neoplastic and anti-proliferativeagents. This activity may be due to one of two mechanisms. The first mechanism depends on the highability of the hydrazone to chelate Fe(III) from cell which is essentially in metabolic pathways that are

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involved in DNA synthesis of neoplastic cells, so that chelation of iron inhibited the proliferation of theneoplastic cell [3].The second mechanism depends on preventing uptake of iron from transferrin of theneoplastic cells. This activity may be ascribed to producing cytotoxic oxygen radicals [3].

Examples of hydrazones and their complexes which have antitumor activity are the pyridoxal isonicoti-noyl hydrazone ligands and their iron(III), gallium(III) and copper(II) complexes. These class of ligandshave distinct activity against certain mammary tumors and leukemias in mice. Since they have affinityand selectivity for iron in the cell [3]. The activity of these ligands are similar to the deferiprone drug(DFO) but it is orally effective, economical to synthesize and has high Fe chelation efficiency in a widevariety of biological models. Moreover, DFO does not have anti-proliferation property due to its poorefficiency for pentration of cell membranes and short half-life time in plasma [4].

An important example of effective anti-tumour hydrazone is isonicotinoyl hydrazone derivatives as 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone and its iron complexes [5–7], and di-2-pyridyl ketoneisonicotinoyl hydrazone and its analogues [8, 9]. These ligands have iron chelation efficiency, are anti-proliferative agents, and have potential for the treatment of cancer. Several isothiazolehydrazones foundto be inactive against viruses, but showed cytotoxicity at micromolar concentration against the humanlymphocytes that support HIV-1 growth. They possess anti-retroviral activity and anti-proliferation activ-ities against panal of human cell lines such as haematological tumour, skin melanoma, lung squamous,carcinoma, breast adeno carcinoma, hepato cellular and prostate carcinoma [10]. Aroyl hydrazones ofpyridoxal and salicylaldehyde hydrazone classes are potent inhibitors of DNA synthesis and cell growthin a number of human and rodent cell lines growth in culture and inhibit in vitro lymphoprolifera-tion [11, 12]. 2-Benzoxazolyl and 2-benzimidazolyl hydrazones derived from 2-acetyl pyridine inhibitcell proliferation and colon cancers [13]. Cyano acetic acid hydrazones of 3- and 4-acetylpyridine alsoact as potential anti-tumor and capable of inhibiting the replication of hepatitis-C virus [14]. Hydra-zone derivatives of 2,6-dimethylimidazo[2,1-b]-[1,3,4]thiazole-5-carbohydrazide and the derivatives ofhydrazine primidines have anti-cancer against lung, breast, renal, leukemia, colon, and overian cancers[15, 16]. Organotin(IV) complexes of 2-hydroxy-1-naphthaldehyde 5-chloro-2-hydroxy benzoylhydra-zone (Fig. 4) have been synthesized and structurally characterized. Structural analyses reveals thatcomplexes show similar monomeric structure, in which the tin center is coordinated with the enolictridentate ligand (L) in the ONO chelate mode and exhibits five-coordinated trigonal bipyramidal geom-etry. All compounds exhibit in-vitro antitumor activity toward human colon cancer cells (HCT-8), lungcancer cells (A549) and human promyelocyticfina leukemic cells (HL-60). The results indicate that both

Fig. 4. Structures of tin complexes 2-hydroxy-1-naphthaldehyde 5-chloro-2-hydroxy benzoylhydrazone derivatives.

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Fig. 5. Structures of Salicylaldehyde isonicotinoyl hydrazone (SIH) and its analogues.

alkyl groups bound with tin centers and the structural of organotin compounds have significant effect ontheir in-vitro antitumor activities [17].

Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic, orally active tridentate iron chelatorproviding both effective protection against various types of oxidative stress-induced cellular injury andanticancer action. However, its labile hydrazone bond that makes it prone to plasma hydrolysis representsthe major limitation of SIH as anticancer. Recently, nine new SIH analogues (Fig. 5) derived fromaromatic ketones with improved hydrolytic stability were developed. Their antiproliferative potentialevalution in MCF-7 breast adenocarcinoma and HL-60 promyelocytic leukemia cell lines. Seven of thetested substances showed selectivity greater than parent agent towards the latter cancer cell lines comparedto non-cancerous H9c2 cardiomyoblast-derived cells [18].

A series of trisubstituted 3,5-triazine-2,4,6-triyltris(oxy)tris(benzene-4,1-diyl)tris(meth-anylylidene))tri(benzohydrazide) derivatives (Fig. 6) have in-vitro antiproliferative activity. The activities of thesehydrazone ligands against human liver carcinoma (HepG2) and human cervix carcinoma (HeLa) cell linesshowed that these compounds exhibited lower activity against HeLa cell lines but reasonably moderatein-vitro cytotoxicity against HepG2 cell lines [19].

Copper(II) complex of 2-hydroxy naphthaldehyde-2-pyridylhydrazone ligand (Fig. 7) was preparedand characterized. The cytotoxic activity of the ligand and its complex were measured in-vitro against theHeLa cells and showed that, the complex has cytotoxic effect with HeLa cells (LD50 = 4.97 �M) [20].

In-vitro antioxidant and cytotoxicity effect of three organoruthenium(II) carbonyl complexes withbenzoic acid pyridine-2-ylmethylenehydrazide, benzoic acid (1-pyridin-2-yl-ethylidene)hydrazide andbenzoic acid (phenyl-pyridin-2-yl-methylene)hydrazide (Fig. 8) have been studied. The resultsshowedthat these metal complexes could serve as potential antioxidants where as the cytotoxicity experimentsrevealed that the complexes possess selective activity against both human cervical cancer cell line HeLa,human skin cancer cell line A431 with a preference to inhibit the proliferation of the later, therebyproved that the selected compounds could serve as promising candidates in anti-tumour applications.The significant result of this work showed that the activities of ruthenium organometallic hydrazonecomplexes increase withinserting substitutents of the phenyl ring at the azomethine carbon of the ligandwhich led to an increased interaction with biomolecules such as free radicals and tumour cell lines thanthe rest of the complexes without such a phenyl ring in that position [21].

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Fig. 6. Structures of tri-substituted 3,5-triazine-2,4,6-triyltris(oxy)tris(benzene-4,1-diyl)tris (meth-anylylidene))tri(benzo-hydrazide) derivatives (X = H, Br, Cl, F, OH, OCH3, CH3, NO2 or NH2).

Fig. 7. Geometry of Cu(II) complex of 2-hydroxy naphthaldehyde-2-pyridylhydrazone ligand.

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Fig. 8. Structures of organoruthenium(II) carbonyl complexes of benzoic acid, (phenyl-, pyridine-2-ylmethylene,hydrazide,benzoic acid (1-pyridin-2-yl-ethylidene)hydrazide.

Fig. 9. Trans palladium complexes of benzaldehyde, 2,3-dimethoxybenzaldehyde, 4-chlorobenzaldehyde, and 4-hydroxybenzaldehyde (1,3-dimethyl-4-nitro-1H-pyrazol-5-yl) hydrazone.

The cytotoxic effect of trans palladium complexes of benzaldehyde (1,3-dimethyl-4-nitro-1H-pyrazol-5-yl) hydrazone, 2,3-dimethoxybenzaldehyde (1,3-dimethyl-4-nitro-1H-pyrazol-5-yl) hydrazone, 4-chlo-robenzaldehyde (1,3-dimethyl-4-nitro-1H-pyrazol-5-yl) hydrazone, and 4-hydroxybenzaldehyde (1,3-dimethyl-4-nitro-1H-pyrazol-5-yl) hydrazone (Fig. 9) against the fast growing head and neck squamouscarcinoma cells SQ20B and SCC-25 have been studied. The influence is dose dependent and varies bycell type. Some complexes had higher clonogenic cytotoxic effect than cisplatin when tested on SQ20Bcell line [22].

Comparative cytotoxic activities of three 2-oxo-quinoline-3-carbaldehyde hydrazone ligands (Fig. 10)and their Cu(II) complexes were studied. The results showed that the three Cu(II) complexes exhibitedmore effective cytotoxic activities against HL60 cells and HeLa cells than corresponding ligands. More-over, the most active compound is copper complex of the thrid ligand which may be explained on the basisof the difference in the terminal functional group (3,4-dimethylpyrryl heterocycle) relative to othergroup[23].

Anti-cancer activities of the N-(1-phenyl-3-methyl-4-propyl-pyrazolone-5)-salicylidene hydrazone(Fig. 11) and its copper(II) complex showed that both ligand and its copper complex are potent anti-

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Fig. 10. Structure 2-oxo-quinoline-3-carbaldehyde hydrazone ligands.

Fig. 11. Structure N-(1-phenyl-3-methyl-4-propyl-pyrazolone-5)-salicylidene hydrazine.

cancer agent against ovarian cancer cells (OVCAR3) and liver cancer cells (Hep-G2). The results of theeffect on the resistant of Hep-G2 revealed that the copper complex was an active compound with lethalconcentration (IC50) value 5.0 �g/ml. An IC50 of 35.1 �g/ml found for ligand, which was not as goodas the complex. This enhansment of activity of complex may indicate that the coordination improvethe anti-cancer activity of the compound. Meanwhile, the anti-cancer activities of the tested compoundson Hep-G2 were better than that on OVCAR3. Besides, the efficacy on resisting to cancer cell of thecopper complex is more powerful than that of the ligand, which shows that the coordination improvesthe anti-tumor activity of the compound [24].

Several biological activities of 6-acetyl-cyclohex-3-enecarboxylic acid [1-pyridin-2-yl-1-(pyridyn-2-yloamin)methylidene] hydrazide (Fig. 12) were examined in-vitro.They were suppression ofphytohemagglutinin A (PHA)- induced proliferation of human peripheral blood mononuclear cells(PBMC) and their effects on tumor necrosis factor alpha (TNF-�) and interleukin 6 (IL-6) production.The cytotoxic activity of Cu(II) complex was determined with respect to the four carcinoma cell lines(SW 984, CX-1, L-1210, A-431). The studied complex exhibited significant cytotoxic effects (particularlyagainst CX-1 colon carcinoma), comparable to those reported for cisplatin [25].

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Fig. 12. Structure of 6-acetyl-cyclohex-3-enecarboxylic acid [1-pyridin-2-yl-1-(pyridyn-2-yloamin) methylidene] hydrazide.

Fig. 13. Structure of N’-(1-(pyridin-2-yl) ethylidene)acetohydrazide ligand.

The inhibitory effects of end-to-end thiocyanato-bridged zig-zag polymers of Cu(II), Co(II) and Ni(II)complexes of N’-(1-(pyridin-2-yl)ethylidene)acetohydrazideligand (Fig. 13) on human cell canser. Suchas lung carcinoma cells (A549 cells), human colorectal carcinoma cells (COLO 205 cells and HT-29cells), and human hepatocellular carcinoma cells (PLC5 cells) reveled that the Cu(II) complex had thestrongest population growth inhibition of human colorectal carcinoma cells (COLO 205 cells and HT-29cells). Moreover, the 50% inhibitory concentration (IC50) showed the highest activity for this complexwith IC50 value of 22.7 ± 0.5 �M (COLO 205 cells) and 24.7 ± 2.5 �M (HT-29 cells), respectively. TheCu(II) complex could be further tested by an in-vivo model to justify if it is effective for prevention ofhuman cancer and showed the highest inhibitory activity in human colorectal carcinoma cells (COLO205 cells and HT-29 cells) [26].

Hydrazones also play an important role in improving the anti-tumor selectivity and toxicity profile ofanti-tumour agents by forming drug carrier systems employing suitable carrier proteins [27].

2.1.2. Anti-mycobacterial activityTuberculosis (TB) is one of the most common infectious diseases known to population. Nearly

one-third of the world’s population is infected with Mycobacterium tuberculosis with new infectionsoccurring at a rate of about one per second [28]. In that respect the World Health Organization (WHO)

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estimates that about 30 million persons will be infected within the next 20 years. Every year, approx-imately 8 millions of those infected people develop active TB, and almost 2 millions of them diefrom the disease [29–32]. The distribution of tuberculosis is not uniform across the globe; about80% of the population in many Asian and African countries test positive in tuberculin tests, whileonly 5–10% of the United States population tests positive [33]. So that developing of new drugs fortreatments of these diseases is considered as a challenge to scientists. One of the most important com-pounds that play a significant part in therapy of these diseases isthe hydrazones [29–32]. For example,isonicontinoyl hydrazone derivatives and their nickel and copper complexes have anti-mycobacterialactivity in-vitro and/or in-vivo against M. tuberculosis H37 Rv [34–37]. Whereas the copper com-plexes of isonicontinoyl hydrazide is the most effective frist-line antitubercular compound used inthe DOT program advocated by WHO [38–40]. The second example is the diclofenac acid hydra-zones derivatives, which were found to be more active than parent drug declofenac. The most effectivehydrazones is derived from 1-cyclopropyl-6-fluoro-8-methoxy-7-[[N4-(2-(2-(2,6-dichlorophenylamino)phenyl) acetyl)-3-methyl]-N1-piperazinyl]-4-oxo-1,4-dihydro-3-quinoline carboxylic acid which is moreactive than fluoroquinolones, ciprofloxacin or gatifloxacin [41].

Anti-microbial and anti-tubercular activities of trigonal bipyramidal and tetrahedral Co(II),Ni(II), Cu(II) and Zn(II) complexes of N’-(1-(2-oxo-2H-chromen-3-yl)ethylidene)isonicotinohydrazidescreened using serial broth dilution method and Minimum Inhibitory Concentration (MIC). Zn(II) com-plex has shown significant antifungal activity with an MIC of 6.25�g/mL while Cu(II) complex isnoticeable for antibacterial activity at the same concentration. Anti-TB activity of the ligand has enhancedon complexation with Co(II) and Ni(II) ions [42].

Anti-tubercular and anti-microbial activities of synthesised and characterized distorted square planartransition metal complexes of salicylhydrazone of anthranilhydrazide investigated. Metal complexesin general have exhibited better antibacterial and antifungal activity than the free ligand and in fewcases better than the standard used. Among the bacterial strains used, the complexes are highly potentagainst Gram-positive strains compared to Gram-negative. Anti-tubercular activity exhibited by the Co(II)complex is comparable with the standard used [43].

Series of benzofuran-3-carbohydrazide and its analogs screened for in-vitro anti-tuberculosis (anti-TB) activity against M. tuberculosis H37Rv strains by using resazurin assay utilizing microtiterplatemethod (REMA). These compounds also showed good anti-fungal activity against Candida albicans.The synthesized N-benzylidene benzofuran-3-carbohydrazide and its analogs show promising activityagainst M.tuberculosis. The inhibition of M.tuberculosis at concentrations as low as 2 and 8 �g/mLindicates that these compounds can act as leads for development of newer anti-TB compounds [44].

Hydrazone derived from 3-(4-chlorophenyl)-4-substituted pyrazoles have been synthesised and weretested for anti-tubercular activity in-vitro against M.tuberculosis H37Rv strain, anti-fungal activity againsta pathogenic strain of fungi and antibacterial activity against gram positive and gram-negative organisms.Among them tested, many compounds showed good to excellent antimicrobial and antitubercular activity.The results suggest that hydrazones, 2-azetidinones and 4-thiazolidinones bearing a core pyrazole scaffoldwould be potent antimicrobial and antitubercular agents [45].

Anti-tubercular activities against M. tuberculosis H37Rv of synthetic five coordinate square-pyramidalcopper(II) complexes of 2-(2-benzoylhydrazono)-, 2-(2-(2-hydroxy benzoyl) hydrazono)-2-(2-isonicotinoyl hydrazono) and 2-(2-nicotinoyl hydrazono) propanoic acid (Fig. 15) were investigated.The result of antibacterial activity against M. tuberculosis H37Rv strain indicates percent inhibitionranging from 6% to 92%. Compounds containing isonicotinoyl group are the most active among thegroup [46].

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Fig. 14. Structure representation of (a) Trigonal bipyramidal and (b) tetrahedral Co(II), Ni(II), Cu(II) and Zn(II) complexes ofN’-(1-(2-oxo-2H-chromen-3-yl)ethylidene)isonicotinohydrazide.

Fig. 15. Structure of square-pyramidal Cu(II) complexes of (a) 2-(2-benzoylhydrazono)-, (b)2-(2-(2-hydroxy ben-zoyl)hydrazono), (c) 2-(2-isonicotinoyl hydrazono) and (d) 2-(2-nicotinoyl hydrazono) propanoic acid.

Fig. 16. Metal conjugation of the carboxamidrazone ligands with copper and iron ions.

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Fig. 17. Structure of 4-(((3-hydroxynaphthalen-2-yl)methylene) amino)-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one ligand.

Some metal ions are essential for biological functions, other metal ions are poisons to our bodies and alarge number of them and their complexes are used as drugs or diagnostic agents for treatment of a varietyof diseases [45]. Metal conjugation of the carboxamidrazone ligands with copper and iron ions resultsin significant enhancement in their anti tubercular activities against M. tuberculosis. Copper was moreactive rather than iron ion. It may be due to the increase in liposolubilities of metal conjugates contributeto their easy permeability through the mycobacterial cell wall. On the other hand, the carboxamidrazonemoiety may interfere with the copper transport by chaperone proteins through up regulation of oxidativestress [47].

2.1.3. Anti-microbial activityHydrazone ligands and their complexes act as anti-microbial agents against gram negative, gram pos-

itive bacteria, fungi and yeast [48–50]. The biological activities of the metal complexes are governed bythe following factors: (i) the chelate effect of the ligands, (ii) the nature of the donor atoms, (iii) the totalcharge on the complex ion, (iv) the nature of the metal ion, (v) the nature of the counter ions that neutralizethe complex, and (vi) the geometrical structure of the complex [51]. Furthermore, chelation reduces thepolarity of the metal ion because of partial sharing of its positive charge with the donor groups and possiblythe π-electron delocalization within the completely chelate ring system that is formed during coordina-tion [52]. These factors increase the lypophilic nature of the central metal atom and hence increasingthe hydrophobic character and liposolubility of the molecule favoring its permeation through the lipidlayer of the bacterial membrane. This enhances the rate of uptake/entrance and thus the anti-bacterialactivity of the testing compounds. The metal complexes of some hydrazones showed higher activity thanthe parent hydrazones such as gadolinium complexes of N-(2-propionic acid) salicyloyl hydrazone andmanganese(III), cobalt(III), iron(III) and chromium(III) complexes of benzyl �-monooxime substitutedbenzoyl hydrazones [53, 54]. Sometimes the activity of the complexes is less than the parent ligandsuch as hafnium(IV) complexes of acetyl ferrocenyl hydrazone derivatives. Some ligands showed higheractivity towards fungi whereas thecomplexes showed higher toxicity toward some types of bacteria thanthe parent ligands [55]. The anti-microbialactivity of some hydrazone ligands and their correspondingcomplexes may be close or equal to the standard durg which used as reference, such as the thiozolyl

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Fig. 18. Structure of Ni(II), Pd(II), Pt(II) complexes of methanesulfonylhydrazone derivatives.

hydrazone derivatives [56], hydrazone of 4-fluorobenzoic acid hydrazide and 3-acetyl- 2,5-disubstituted-1,3,4-oxadiazolines [57], diflunisal hydrazide-hydrazone [31] as well as copper(II) and cadmium(II)complexes of amino acid (N-benzoyl) hydrazide and amino acid (N-nicotinoyl) hydrazide [58] have activ-ities are equal or close to fluconazole, ceftriaxone, cefepime and ampiciline drugs respectively. The typeof the metal has a pronounced effect on the anti-microbial activity of the complexes, for example the activ-ity of copper(II), nickel(II), cobalt(II) and zinc(II) complexes of 3-salicylidenehydrazono-2-indolinonewas found to be decreased in the order Zn(II)>Cu(II)>Co(II)>Ni(II) [59]. 4-(((3-hydroxy naphthalen-2-yl)methylene)amino)-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (Fig. 17) and its Cu(II),Ni(II), Co(II), Zn(II), Cd(II), VO(IV) and UO2(VI) complexes. Antimicrobial screening of the free lig-and and its complexes in vitro towards Staphylococcus aureus and Bacillus subtilis as Gram-positivebacteria, E. coli and Salmonella typhimurium as Gram-negative bacteria and Candida albicans showedhigh activity for Cd(II) complex, however the rest complexes exhibit moderate activity, in contrary to thelower activity of the free ligand [60].

The anti-bacterial activities of Nickel(II), palladium(II), platinum(II) complexes of salicylaldehydemethanesulfonylhydrazone, 2-hydroxyacetophenonemethanesulfonyl hydrazone and 2-hydroxy-3-etoxybenzaldehydemethanesulfonylhydrazone have been determined in vitro against gram positive bac-teria; S.aureus ATCC 25923, Bacillus cereus RSKK 709, and gram negative bacteria; Pseudomonosaeruginosa ATCC 27853, E. coli ATCC 35268 by paper disc diffusion and microdilution broth methods.The biological activity screening showed that metal complexes have more activity than their ligandsagainst the tested bacteria [61].

The anti-microbial activity of copper(II), nickel(II), platinum(II) and palladium(II) complexes with2-hydroxy-1-naphthaldehyde-N-methylpropanesulfonylhydrazone compounds (Fig. 19) was screenedagainst three Gram-positive B. subtilis, S. aureus and B. cereus and three Gram-negative bacteria E.coli, P. aeruginosa, Y. enterocolitica. The results of anti-microbial studies indicate that Pt(II) and Pd(II)complexes showed the most activity against all bacteria [62].

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Fig. 19. Structure of Cu(II), Ni(II), Pt(II) and Pd(II) complexes of 2-hydroxy-1-naphthaldehyde-N-methyl propane sulfonylhydrazone compounds.

Fig. 20. Structure representation of Ni(II), Co(II) and Cu(II) complexes of 2-((2-phthalazin-1-yl)hydrazono) methyl)phenolligand.

2-((2-phthalazin-1-yl)hydrazono)methyl)phenol ligand and its Ni(II), Co(II) and Cu(II) complexes(Fig. 20) were screened for their anti-microbial activities using the disc diffusion method against Grampositive (S. aureus, B. subtillis) and two Gram negative (E. coli, P. aeruginosa) bacteria at concentrationof 20 mg/ml in DMSO as solvent using ampicillin as standard material and fungi: Aspergills flavusand C. albicans using amphotericin as standard material. The hydrazone ligand is biologically activeand its activity may be arise from the hydroxyl groups which may play an important role in the anti-bacterial activity, as well as the presence of imine group which imports in elucidating the mechanism oftransformation reaction in biological systems. The synthesized compounds were found to be more toxiccompared with their parent hydrazone ligand against them same microorganism and under the identicalexperimental conditions. The increase in biological activity of the metal chelates may be due to the effectof the metal ion on the normal cell process [63].

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Fig. 21. Structure representation of (a) Ni(II) and Cu(II), (b) tetragonal Co(II) complexes of benzil bis(carbohydarzone).

The square planar Ni(II) and Cu(II) and tetragonal Co(II) complexes derived from benzilbis(carbohydarzone) (Fig. 21) were structurally and pharmaceutically studied. Anti-fugial activity of thesecompounds was examined against the opportunistic pathogens, i.e., Alternaria brassicae, Aspergillusniger and Fusarium oxysporum and led to the conclusion that the free ligand has growth inhibition capac-ity against the tested fungal strains and this efficacy is positively affected by the complex formation[64].

Hydrazone complexes of Co(II), Ni(II), Cu(II), Pd(II), Cd(II), Zn(II) and U(VI)O2 with 3-(2-(1-(2-hydroxyphenyl)hydrazinyl)-3-oxo-N-(thiazol-2yl)propanamide (Fig. 22) have been synthesized. Theligand and its complexes have been screened for their antibacterial (E. coli and Clostridium sp.) and anti-fungal activities (Aspergillus sp. and Stemphylium sp.) by MIC method. from the results, the Ni(II), Co(II),Cu(II), Cd(II), Zn(II), Pd(II) and U(VI)O2 metal complexes shown potential antimicrobial activitiesagainst all the bacterial and fungal strains. Amongst all the compounds tested, Pd complex demonstratedthe most potent antibacterial and antifungal activity (90%) at the higher concentration of 1.5 mg/ml. Ingeneral, all the metal complexes possess higher antimicrobial activity than the ligand. This inhansmentof activity may be due to the change in structure due to coordination and chelating tends to make metalcomplexes act as more powerful and potent bactereostatic agents [65].

2.1.4. Anti-malarialTropical diseases constitute a major world health problem and offer an extraordinary challenge for drug

discovery [66, 67]. Malaria is the most widespread, and one of the most severe, tropical parasitic diseasesand it continues to be a major cause of mortality and morbidity in poor regions in the developing world. It isendemic in most of the tropical regions of the planet causing 1–3 million deaths annually, mostly childrenunder 5 years. The disease is caused by protozoa of the genus Plasmodium and it is transmitted throughthe byte of female Anopheles mosquito.Mortality from malaria has doubled in the last 20 years mainly dueto the development of resistance of malarial parasites to anti-malarial drugs, particularly to the first-line

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Fig. 22. Geometries of Co(II), Ni(II), Cu(II), Pd(II), Cd(II), Zn(II) and UO2 (VI) complexes of 3-(2-(1-(2-hydroxy-phenyl)hydrazinyl)-3-oxo-N-(thiazol-2yl)propanamide.

Fig. 23. Structure representation of acylhydrazone derivatives.

drug chloroquine [68, 69]. Several organic compounds have been used as antimalarial drugs, includingquinine, chloroquine, hydroxychloroquine, mefloquine, primaquine, proguanil, cotrifazid, doxycycline,sulfadoxine, pyrimethamine, artemether, lumefantrine, artesunate and amodiaquine.

Some hydrazones ligands showed a pronounced anti-malarial activity more than the desferrioxaminedrug. Acylhydrazone deravatives (Fig. 23) showed the ability to inhibit the growth of a chloroquine resis-tant strain of Plasmodium falciparum. Some of these new compounds are significantly more active thandesferrioxamine DFO [70]. N1-arylidene-N2-quinolyl- and N2-acrydinylhydrazones deravatives weresynthesized and tested for their anti-malarial properties. These compounds showed remarkable anti-plasmodial activity in-vitro especially against chloroquine-resistant strains. This potent biological activitymakes them promising lead structures for the development of new antimalarial drugs [71].

The anti-malarial activity of novel aroylhydrazones (Fig. 24) and thiosemicarbazone Fe chelatorsinvestigated using the chloroquine-sensitive, 3D7, and chloroquine-resistant, 7G8, strains of Plasmodiumfalciparum in vitro. The newligands were significantly more active in both strains than the Fe chelatorwas in widespread clinical use, desferrioxamine (DFO). The most effective chelators examined were2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone and 2-hydroxy-1-naphthylaldehyde-4-phenyl-3-thiosemicarbazone. These result indicated that, these class of lipophilic chelators might have potentialas useful agents for the treatment of malaria [72].

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Fig. 24. Structure representation of novel aroylhydrazones derivatives.

Fig. 25. Structures of hydrazones derived from (2-oxobenzoxazoline-3-yl)acetohydrazide.

2.1.5. Anti-convulsantEpilepsy is most common neurological disorder, second to stroke. The number of drugs useful

for the treatment of epilepsy is remarkably small. New epileptic drugs have been developed thatmay constitute novel and effective therapies for epilepsies [73]. It was found that both 2-oxoben-zoxazoline and 2-oxobenzothiazoline hydrazone derivatives exhibited remarkable anticonvulsant activity.5-chloro-2(3H)-benzoxazolinone-3-acetyl-2-(o-methoxybenzaldehyde) hydrazone, 5-chloro-2(3H)-ben-zoxazolinone-3-acetyl-2-(o-methylbenzaldehyde)hydrazone, 5-chloro-2(3H)benzoxazolinone-3-acetyl-2-(p-methyl-benzaldehyde)hydrazone, 5-chloro-2(3H)-benzoxaz-olinone-3-acetyl-2-(p-nitrobenzaldeh-yde) hydrazone, and 5-chloro-2(3H)-benzoxazo-linone-3-acetyl-2-(p-dimethylaminobenz-aldehyde)hydrazone were significantly active than phenytoin (a commercial antiepileptic drug) in the tests [73,74].Ingeneral The biological results revealed that, the acetylhydrazones provided a good protection againstconvulsions while the oxamoylhydrazones were significantly less active [75, 76]. Fifteen new hydrazonesof (2-oxobenzoxazoline-3-yl)acetohydrazide (Fig. 25) were synthesised and their antiepileptic activitywas tested in scPTZ test. The 4-fluoro derivative was found to be more active than the others [75, 77].

4-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian brain.GABA hydrazones (Fig. 26) were designed and synthesized and evaluated for their anticonvulsant prop-erties in different animal models of epilepsy such as MES, scPTZ, subcutaneous strychine (ScSTY) andintraperitonal picrotoxin (IpPIC) induced seizure tests. Some of the compounds were effective in thesemodels [75, 78].

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Fig. 26. Structures of GABA hydrazones.

The hydrazones along with semicarbazones and thiosemicarbazones which are derived from pyridylketones have been found to be nonneurotoxic antiepileptic drugs and are potent orally active. Their usehas been proposed in the treatment of convulsive disorders such as epilepsy, in the treatment of strokeand other neurological disorders such as Parkinson’s disease [79]. They act as excitatory amino acidantagonists and inhibitors of L-glutamate neurotransmission. These compounds afford protection in themaximal electroshock seizure (MES) model in both mice and rats, by either route, intraperitoneal andoral. The study represents them as glutamate antagonists. Hydrazones in addition to Schiff and Mannichbases of isatin were evaluated for anticonvulsant activity by maximal electroshock method (MES) andmetrazol-induced convulsions (MET) at different dose levels [80]. Neurotoxicity of the compounds wasalso noticed at the same dose levels. Eight compounds of the series denoted significant anticonvulsantactivity at 30 mg/kg dose level. 3-(4-chloro-phenylimino)-5-methyl-1,3-dihydro-indol-2-one showed tobe the most potent compound of the series with 87% protection at 100 mg/kg and an ED(50) of 53.61 mg/kg(MET).

2.1.6. Antiviral activityHIV infection and AIDS represent one of the first diseases for which the discovery of drugs was

performed entirely via a rational drug design approach. Current treatment regimens are based on the useof two or more drugs that belong to group of inhibitors termed as highly active antiretroviral therapy(HAART). Some thiourea compounds were reported to be non-nucleoside inhibitors (NNIs) ofthe reversetranscriptase (RT) enzyme of the human immunodeficiency virus (HIV). Hydrazoneshave been reportedto be the potent inhibitors of ribonucleotide reductase activity. N-Arylaminoacetylhydrazones and O-acetylated derivatives of sugar N-arylaminoacetyl hydrazones were synthesized and evaluated for theirantiviral activity against Herpes simplex virus-1 (HSV-1) and hepatitis-A virus (HAV). Some compoundsrevealed the highest antiviral activity against HAV-27 and HSV-1 [75, 81].

2.2. Pharmaceutical applications

2.2.1. Anti-inflammatory activityHydrazones and their complexes showed an activity as anti-inflammatory and analgesic activity. The

tellurium complexes of phenyl and acetyl hydrazone have mild anti-inflamatory activity compared to

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Fig. 27. Geometries of metal complexes of pyridine-2-ethyl-(3-carboxylideneamino)-3-(2-phenyl)-1,2-dihydroquinazolin-4(3H)-one.

Fig. 28. Structure of 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(p-substituted benzal) hydrazone derivatives.

phenylbutazone [82]. The hydrazone derived from sulphonylhydrazide and 2-acetyl-, 4-acetylpyridineor indol aldehyde have anti-inflammatory and analgesic activity equals or close to that of aspirin [83].inflammatory and analgesic activity of Cu(II), Ni(II), Zn(II), Mn(II), Co(II), Cd(II) complexes of pyridine-2-ethyl-(3-carboxylideneamino)-3-(2-phenyl)-1,2-dihydroquinazolin-4(3H)-one (Fig. 27) showed thatthe synthesized complexes were found to be more active than free ligand [84].

6-substituted-3(2H)-pyridazinone-2-acetyl-2-(p-substituted benzal) hydrazone derivatives (Fig. 28)were synthesized as analgesic and anti-inflammatory agents. Compounds in which R1 is hydrogen wereexhibited more potent analgesic activity than ASA. Also these derivatives demonstrated anti-inflammatoryactivity as well as standard compound indomethacin. Side effects of the compounds were examined ongastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with referencenonsteroidal anti-inflammatory drugs (NSAIDs) [85].

2.2.2. Hydrazones in treatment of iron overload diseasesAll living cells, whether prokaryotic or eukaryotic, need a supply of iron for reduction of oxygen

(respiration), reduction of carbon dioxide (photosynthesis), reduction of dinitrogen or other fundamentalbiological processes. Excessive amounts of iron may become very toxic to the human body and, eventually,

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Fig. 29. Structure representation of (a) pyridoxal isonicotinoyl hydrazone, (b) salicylaldehyde benzoyl hydrazone derivatives.

Fig. 30. Structure representation of 2-pyridylcarboxaldehyde, 2- thiophenecarboxyl hydrazone derivatives.

is fatal for vital cell structure. Iron overload may be defined as an excess in total body iron stores. Thenormal iron concentration in the human body ranges between 40 and 50 mg/kg of body weight. Mostof this iron is present in hemoglobin and in myoglobin. All the rest is stored as ferritin or as its lessaccessible form, hemosiderin. Only a few hundred milligrams of iron are stored in enzymes such ascytochrome c oxidase that, however, are essential to human life. Humans have very limited capacityfor excretion of excess iron; in particular, they lack any effective means to protect cells and tissuesagainst iron overload. Consequently, any increase in iron intake may cause in a short time an increase inbody iron stores. Iron balance is normally regulated by controlling iron absorption in the proximal smallintestine. In the category of patients affected by chronic anaemia, who need regular blood transfusionsin order to sustain their normal growth and development during childhood, �-thalassemia major (BTM)constitutes one of the most serious public health problems in the Mediterranean area, in the Middle East,in the Indian subcontinent, in Southeast Asia and, in particular, in the island of Sardinia. BTM is anautosomal recessive disease, characterized by absent or decreased synthesis of the �-globin gene.Thenumber of thalassemic children requiring regular blood transfusions and a program of iron chelationhas been estimated to be100 000 world-wide. Although desferrioxamine has been demonstrated to be

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Fig. 31. Structure representation of Di-2-pyridyl ketone isonicotinoyl hydrazone and its analogues.

Fig. 32. Geometry of oxovanadium(V) complexes of tridentate hydrazone ligands.

a safe drug when administered in the presence of an elevated body iron burden, serious complicationsmay arise because of long-term chelation, mainly in young patients with low body iron stores. At thebasis of desferrioxamine, toxicity is the fact that, like other chelators, desferrioxamine is not completelyiron-selective. It may due to depletion of other trace elements, such as zinc, copper, manganese, cobalt; adirect toxic effect of free desferrioxamine; depletion of iron from critical iron-dependent enzymes, suchas cytochrome c oxidase. So chemist need to develop a new selective iron chelator [86]. One of the mosteffective compounds is hydrazone chelators such as pyridoxal isonicotinoyl hydrazone, salicylaldehydebenzoyl hydrazone deravatives which are effective iron chelators in vivo and in vitro, and are of interestfor the treatment of secondary iron overload (Fig. 29) [87–90].

Desferrioxamine (DFO), is expensive and cumbersome since the drug requires long subcutaneous infu-sions and it is not orally active. So chelator, 2-pyridylcarboxaldehyde, 2- thiophenecarboxyl hydrazonederavatives (Fig. 30) were designed and shown to have high Fe chelation efficacy in vitro [91, 92].

Di-2-pyridyl ketone isonicotinoyl hydrazone and a range of its analogues comprise a series of monobasicacids that are capable of binding iron (Fe) as tridentate (N,N,O) ligands (Fig. 31) [93].

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Fig. 33. Structure of bis(2-hydroxybenzylidene)oxalohydrazide.

The diaroylhydrazone (N,Nbis-picolinoyl, N-4-aminobenzoyl-Npicolinoyl, N-3-bromo-benzoyl-N-picolinoyl and N-(4-bromobenzoyl)-Npicolinoylhydrazone) are considered as a good chelator for iron(III)so that they act as orally effective drugs for treatment of iron overload or genetic diseases �-thalassemia.They have been demonstrated a greater iron chelation efficacy than deferiprone (DFO) [94, 95].

2.3. Catalytic applications

Coordination chemistry of hydrazones has been a subject of competitive research since they exhibita wide range of catalytic activities in some polymerization as well as oxidation processes. For exam-ple, the palladium complexes of 2-acetylpyridine or 2-formylpyridine benzoyl hydrazones as well astitanium complexes of hydrazone catalyze the polymerization of phenylacetylene [96] and olefine [97]respectively. The nickel(II) complexes of benzoyl hydrazone derivatives catalyze the oligmerization ofethylene with methylaluminoxane [98]. Manganese(II), cobalt(II), nickel(II) and copper(II) complexesof bis(salicylaldiminato) hydrazone catalyze the oxidation of cyclohexene with tert-butylhydroperoxide[99]. Another example is the catalytic activity of copper(II) complexes of picolyl hydrazone derivativestoward ascorbic oxidation of vitamin C [100].

The catalytic potential of oxovanadium(V) complexes of tridentate hydrazone ligands, 3-hydroxy-N-(2-hydroxy-3-methoxybenzylidene)-2-naphthohydrazide, 3-hydroxy-N-(2-hydroxy benzylidene)-2-naphthohydrazide and N-(5-bromo-2-hydroxybenzylidene)-3-hydroxy-2-naphthohydr-azide (Fig. 32)has been tested for the oxidation of cyclooctene using H2O2 as the terminal oxidant. The complex of3-hydroxy-N-(2-hydroxy benzylidene)-2-naphthohydrazide showed the most powerful catalytic activityin oxidation of various terminal, cyclic and phenyl substituted olefins. Excellent conversions have beenobtained for the oxidation of cyclic and bicyclic olefins [101].

The catalytic potential of dinuclear vanadium, copper, manganese and titanium complexes ofdichelating ligands,bis(2-hydroxybenzylidene)oxalo- and bis(2-hydroxybenzylidene) terephthalohy-drazide (Fig. 33) were evaluated for oxidation of hydrocarbons including cycloalkenes, cyclic alkanesand benzylalcohol using H2O2 as terminal oxidant. Of the studied aroylhydrazone complexes, titaniumcomplex of bis(2-hydroxy benzylidene)oxalohydrazide showed the best selectivity and activity as catalyst(Fig. 34) [102].

Molybdenum complexes of salicylidene 2-picoloyl hydrazone ligand (Fig. 35) have been synthesizedand characterized. The complexes were evaluated for epoxidation catalysis with tert-butyl hydroperoxide(tert-BuOOH). The molybdenum complex exhibited high catalytic activity for the epoxidation of olefins,whereas the peroxo analogue is inert to reaction with olefins, thus ruling out the peroxide compound asthe intermediate responsible in the molybdenum complex catalyzed epoxidation with tert-BuOOH [103].

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Fig. 34. Structure of bis(2-hydroxybenzylidene)terephthalohydrazide.

Fig. 35. Geometry of molybdenum complexes of salicylidene 2-picoloyl hydrazone ligand.

Fig. 36. Structure of distorted square-planar palladium complexes of substituted pyridoxal hydrazone ligands.

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Fig. 37. The structure of pseudo-octahedral nickel complexes of N-(1-(thiophen-2-yl)ethylidene) benzohydrazide ligand.

The synthetic distorted square-planar palladium complexes of substituted pyridoxal hydrazone ligands[36]. The catalytic efficiency of the one of the palladium(II) hydrazone complexes was determined inSuzukieMiyaura cross-coupling reaction and was found to be excellent. This facile, mild and generalprotocol represents, to a certain extent, a new advance in Suzukie Miyaura cross-coupling reactions (arylbromides with phenylboronic acid) [104].

The aquasoluble Fe(III) complexes of 5-chloro-3-(2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl)-2-hydroxy-benzenesulfonic acid and 3-(2-(2,4-dioxopentan-3-ylidene)hydrazinyl)-2-hydroxy-5-nitrobenzenesulfonic acid, were synthesized and fully characterized including by X-raycrystal structural analysis. In the channels of the water-soluble 3D networks of 3 and 4, the uncoordinatedwater molecules are held by oxygen atoms of the carbonyl and sulfonyl groups, and by the water ligands.The Fe(III) coordination environment resembles that in the active sites of some mononuclear non-hemeiron-containing enzymes. The complexes show a high catalytic activity for the peroxidative oxidation(with aqueous H2O2) of C5–C8 cycloalkanes to the corresponding alcohols and ketones under mildconditions [105].

The pseudo-octahedral nickel complexes of N-(1-(thiophen-2-yl)ethylidene) benzohydrazide ligand(Fig. 37) is reported and discussed. The catalytic activity of this complex for the oligomerization ofethylene indicate that it provide ethylene dimers and trimers as primary products with a turnover frequency(TOF) of 31200 mol of C2H4 per mol. of Ni and per hour [106].

2.4. Analytical applications

In the field of analytical chemistry, hydrazones were used in detection, determination and iso-lation of compounds containing carbonyl group. Recently, they have been extensively used indetection and determination of several metals [107], such as the micro determination of gold byN-cyanoacylacetaldehyde hydrazone [108], lanthanides by aryl hydrazones [109], molybdenum by2,4-dihyroxy acetophenone benzoyl hydrazone [110]. They are used in sensitive determination of ura-nium(VI) by o-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone[111] or o-hydroxy propiophenoneisonicotinoyl hydrazone [112]. Hydrazones are also used in the spectrophotometric determination of

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titanium in mineral or rock using 1,2 cyclohexanedione bis-benzoyl hydrazone [113], and determinationof copper and iron in ores, alloys and in their mixture in pharmaceutical formulation by biacetyl(2-pyridyl) hydrazone thiosemi-carbazone [114]. Hydrazones are also used in photometric determinationof sub-nanograms level of cobalt(II), chromium(III) Iron(III) by oxidative coupling reaction of 3-methyl-2-benzothiazolinone hydrazone with N-ethyl-N-(2-hydroxy-3-sulfopropyl)-3,5-dimethoxanilineor N,N-dimethylaniline respectively [115–117]. 2,4-Dihydroxybenz-aldehyde isonicotinoyl hydrazoneis used in direct, rapid and derivative spectrophotometric deremination of thorium, titanium and zincin potable water or pharmaceutical formulations [118–120]. 3,5-Dimethyl-4-hydroxy-2-aminoaceto-phenone isonicotinoyl hydrazone is used in facile flow injection spectrophotometric detection of gold(III)in water or pharmaceutical sample [121]. Substituted quinolyl and benzothiazolyl hydrazones used as met-allochromic indicators in the EDTA titration of copper(II) [122]. Complexes of hydrazones are used alsoin radiometric determination of metals such as determination of copper and iron by labeled cobalt (60Co)complexes of o-hydroxybanzaldehyde isonicotinoyl hydrazine [123, 124]. Some hydrazone ligands areused in the extraction of metals, such as substituted 2-thiophenealdehyde-2-benzothiazolyl hydrazones,which used as analytical reagent for extraction of trace of copper [125]. 2,2pyridyl mono-2-quniolylhydrazone are used in liquid-liquid extraction of copper(II), nickel(II) and cobalt(II) [126]. Benzilmono-(2-quinolyl) hydrazone and diacetyl bis-(2-pyridyl) hydrazone are used in the extraction of copper(II),nickel(II) and cobalt(II) [127–129]. It is used in the highperformance chromatographic separations ofsome complexes [130]. Poly acrolein isonicotinic acid hydrazone resin was used for separation and con-centration of palladium and platinum in the road dust [131]. The hydrazone derivatives of dialdehydecellulose were used in sewage wastewater treatment. They act as good and active coagulants for removingthe total suspended solids (TSS), chlorine, iron and chromium [132].

2.4.1. Spectrophotometric determination of some active species in pharmaceutical formulationsSome hydrazones are considered as analytical reagents used in spectrophotometric determination

of some organic constituents in pharmaceutical formulations such as spectrophotometric determina-tion of acetaminophen and phenobarbital [133], acyclovir [134], antidepressant [135], nortriptylinehydrochloride [136], propranolol [137], labetalol hydrochloride [138] and clozapine [139] using3-methylbenzothiazolin-2-one-hydrazone. In that respect 2-hydroxybenzaldehyde hydrazone and p-diethylaminosalicylaldehyde hydrazone are used in determination of iron(II) in antianaemic formulations[140, 141].Nimesulide either in pure form or in pharmaceutical formulations is determined using of3-methyl-2-benzothiazolinone hydrazone hydrochloride in presence of FeCl3 [142].

3. Conclusions

Development of new metal complexes suitable for therapeutic, analytical and catalytic applications isa recent research priority. One of the most significant compounds catogry is the hydrazone ligands and itsmetal complexes, which represent a resource of probabilities for new design due to its peerless structureof hydrazone itself and its mode of bonding with metal ions.

This article review reveals that the hydrazone ligands are extremely needed because of theirproperties such as anti-tumor, anti-malarial, anti-bacterial, anti-fungal anti-mycobacterial, antiviral, anti-inflammatory, anti-convulsant and in treatment of iron overload diseases due to their selective chelatingability to iron or other transition metal necessary for enzymatic reaction in the cell. In addition to hydra-zone, metal complexes of it are also strongly required because of the coordination reduces the polarity ofthe metal ion mainly because of the partial sharing of its positive charge with the donor atom within the

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chelate ring system, which formed during the coordination. This process, in turn, increases the lipophilicnature of the central metal atom, which favors its permeation more efficiently through the lipid layer of themicroorganism thus destroying them more aggressively. However, hydrazone and its complexes exhibita wide range of catalytic activities in some polymerization as well as oxidation processes and are used indetection, determination and isolation of compounds containing carbonyl group, metal and as analyticalreagents used in spectrophotometric determination of some species in pharmaceutical formulations.

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Metal complexes of hydrazones and their biological ...Fig. 5. Structures of Salicylaldehyde...

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