Analgesic , Anti-Inflammatory , and Antiplatelet Profile of Hydrazones Containing Synthetic Molecules

Hydrazones are present in many of the bioactive compounds with wide interest because of their diverse pharmacological applications. Hydrazones possess wide variety of biological activities such as anticonvulsant, antidepressant, analgesic, anti-inflammatory, antiplatelet, antimicrobial, anticancer, antihypertensive, anthelmintic, antidiabetic, antiparasitic, and other anticipated activities. This created an interest for researchers towards synthesized variety of hydrazone derivatives for different biological activities. Therefore many researchers have synthesized hydrazone derivatives as target structures for their biological activities. This is paper focuses on the analgesic, anti-inflammatory, and antiplatelet activities of hydrazones.


Introduction
Hydrazones constitute an important class of biologically active drug molecules which has attracted the attention of medicinal chemists due to their wide range of pharmacological properties.These compounds are being synthesized as drugs by many researchers in order to combat diseases with minimal toxicity and maximal effects.These predictions have provided a therapeutic pathway to develop new effective biologically active hydrazones.A number of hydrazone derivatives have been reported to exert notably biological activities [1,2].
The hydrazones are used as hole transporting agents in organic layer photoconductors, as quantitative analytical reagents, especially in colorimetric and fluorometric determination of metal ions [11][12][13].Furthermore, some hydrazones have also been used as herbicides, insecticides, nematocides, rodenticides, and plant growth regulators as well as plasticizers and stabilizers for polymers.The metal complexes of hydrazones have potential applications as catalysts, luminescent probes, and molecular sensors [1,14,15].A class of N-arylsulfonyl hydrazones has been developed as novel inhibitors of IMP-1, a metallo--lactamase.As a requirement for bulky aromatic substituents on each side of the sulfonyl hydrazone backbone, these compounds may serve as efficient inhibitors of IMP-1.Molecular modeling has provided structural basis for the anti-metallo--lactamase activity of hydrazonone compounds [16].A series of hydrazones were evaluated as potential inhibitors of anthrax lethal factor.There were significant differences in the types of inhibition observed with the different assays [17].Kinetic analysis of the dipeptidyl disulfides and dipeptidyl benzoylhydrazones indicated that these inhibitors act as irreversible inhibitors of Cathepsin S, and benzoylhydrazones were shown to be potent inhibitors of Cathepsin S [18].Hydrazones and phenyl hydrazones of different aryl aldehydes showed an effect on endogenous proteolysis in liver.It was observed that p-nitro benzaldehyde hydrazone exhibited maximum inhibitory effect [19].The effect of hydrazones and phenyl hydrazones of simple aryl aldehydes along with their semicarbazones and thiosemicarbazones on the activity of liver alkaline and acid phosphatase [20,21].
Hydrazones are an important class of compounds for new drug development.This created an interest to researchers who have synthesized variety of hydrazone derivatives and screened them for their various biological activities.In the present study, we have made an attempt to collect analgesic, anti-inflammatory, and antiplatelet properties of hydrazone derivatives.Hydrazones are not only intermediates but also very effective organic compounds when they are used as intermediates and coupling products that can be synthesized by using the active hydrozen component of -CONHN=CHazomethine group.Many effective compounds, such as iproniazid and isocarboxazid, are synthesized by the reduction of hydrazide-hydrazones. Iproniazid, like INH, is used in the treatment of tuberculosis.It has also displayed an antidepressant effect, and patients appear to have a better mood during the treatment.Another clinically effective hydrazidehydrazones is nifuroxazide, which is used as an intestinal antiseptic [22][23][24][25].Hydrazones are a class of organic compounds which possess the structure R 1 R 2 C=NNH 2 .They are related to ketone and aldehyde in which oxygen has been replaced with NNH 2 group.These azometine -NHN=CHprotons constitute an important class of compounds for drug development.Hydrazones are formed by the reaction of hydrazine or hydrazide with aldehydes and ketones.Hydrazones are widely used in organic synthesis.Many effective compounds, such as iproniazide and isocarboxazid, are synthesized by the reduction of hydrazide-hydrazones. Another effective hydrazide-hydrazone is nifuroxazide, which is used as an intestinal antiseptic [26][27][28][29][30].This review highlights analgesic, anti-inflammatory, antipyretic, and antiplatelets activities shown by hydrazones.

Analgesic and Anti-Inflammatory Activites
Nonsteroidal anti-inflammatory drugs (NSAIDs) are largely used in the treatment of pain and inflammation.Hydrazones that are dual inhibitors of both cyclooxygenase (COX) and 5-lipoxygenase (5-LO) are being studied as potential analgesic and anti-inflammatory agents in comparison to NSAIDs [31].Nonsteroidal anti-inflammatory drugs (NSAIDs) have a wide clinical use for the treatment of inflammation, pain, rheumatoid arthritis, soft tissue and oral cavity lesions, respiratory tract infections, and fever.The two isoforms of COX are poorly distinguishable by most of the classical NSAIDs, and these agents actually inhibit COX-1 extensively, besides COX-2, leading to gastrointestinal (GI) injury, suppression of TXA2 formation, and platelet aggregation.The combination of these interactions is probably the reason for GI bleeding which is the most serious complication of these drugs.Some evidence suggests that the hydrazone moiety present in some compounds possesses a pharmacophoric character for the inhibition of COX.In fact, some evidence suggests that the hydrazone moiety present in derivative possesses a pharmacophoric character for the inhibition of COX [32].The results showed that pyridine ring at the aryl moiety of the arylhydrazone is having good analgesic activity in comparison to mefenamic acid.Compounds possessing the 4-tolyl or 4-fluorophenyl moiety are more active than 4-bromophenyl and 4-N,N-dimethylaminophenyl. The anti-inflammatory evaluation showed that the replacement of carboxylic acid group of mefenamic acid with N-arylhydrazone moiety cannot produce any advantage in the anti-inflammatory property [33].Analgesic activity of some (4Z)-3-methyl-1-[(2-oxo-2Hchromene-4-yl)carbonyl]-1H-pyrazole-4,5-dione4-(4-substitutedphenyl)hydrazone, some of them showed significant analgesic activity.Pharmacological evaluation was done by using acetic acid-induced writhing model in mice which showed that the presence of 4-chloro, 4-bromo, 3,4-dichloro, 3,4-dibromo, and 4methyl group in the aromatic ring of 4-position of the pyrazole-hydrazono nucleus gave rise to increased analgesic activities [34].Hydrazone derivatives of quinoxalinone and evaluated for anti-inflammatory activity showed that compounds having methoxy group at the para-position showed comparatively good percentage of inhibition of edema than the other compounds [35].Treatment of 3-cyano acetylindole with diazonium salts of 3-phenyl-5-amino pyrazole and 2-amino pyrazole gave the corresponding hydrazones.Compound 3-(1H-Indol-3-yl)-3-oxo-2-[(5-phenyl-2H-pyrazol-3-yl)-hydrazono]-propionitrile was found to possess appreciable analgesic and anti-inflammatory activity [36].The anti-inflammatory derivative 2-(2-formylfuryl) pyridylhydrazone (1) presented a 79% inhibition of pleurisy at a dose of 80.1 mol/kg.The results concerning the mechanism of the action of these series of N-heterocyclic derivatives in platelet aggregation suggest a Ca 2+ scavenger mechanism.Compound 2 was able to complex Ca 2+ in in vitro experiments at 100 M concentration, indicating that these series of compounds can act as Ca 2+ scavenger depending on the nature of the aryl moiety present at the imine subunit [37].A series of analgesic compounds that belong to the N-acylarylhydrazone class were synthesized from natural safrole.[(4  -N,N-Dimethylaminobenzylidene-3-(3  ,4  methylenedioxyphenyl)propionyl hydrazine] (2) was more potent than dipyrone and indomethacin [38].Analgesic and anti-inflammatory activity of furoxanyl-Nacylhydrazones (3, 4) [39].The anti-inflammatory activity of some aryl hydrazones (5) got good results [40].Various hydrazone derivatives (6) reported them to have promising in vivo anti-inflammatory activity [41].Hydrazone derivatives (7) with selective COX-2 inhibition.The compound is reported to have an ED 50 value of 0.2 mmol/Kg [42].Benzothiophene derivatives (8) with inhibition of 50.2% have been developed [43]; see Figure 1.

Synthetic Approach for the Novel Hydrzonone and Its Biological Activity
A number of organic compounds obtained by chemical synthesis as model compounds have useful analgesic, antiinflammatory, antipyretic, and antiplatelets activities.Many of hydrazonones its derivatives possess interesting biological activities, such as analgesic, anti-inflammatory, antimicrobial, and antitumor activites.The biological activity of synthesized hydrazonone derivatives was characterized and detailed study is in progress to modify the synthetic route, structural activity, and toxicological barriers for the enhanced pharmacological efficiency of synthetic hydrazones [37,[45][46][47][48][49].

Development of New NSAIDs
The NSAIDs preparations are among the most commonly prescribed drugs.NSAIDs are sometimes known as the aspirin-like drugs because they have an activity profile that is broadly similar to that of aspirin; that is, they all possess analgesic, anti-inflammatory, and antipyretic properties to some degree and produce characteristic side effects, including gastric intolerance and depression of blood clotting through inhibitory action on platelet function.Two closely related forms of the cyclooxygenase have been identified which are now known as COX-1 and COX-2.Both isoenzymes transform arachidonic acid (AA) to prostaglandins (PGs) but differ in their distribution and their physiological roles.Meanwhile, the responsible genes and their regulation have been clarified.COX-1, the predominantly constitutive form of the enzyme, is expressed throughout the body and performs a number of homeostatic functions such as maintaining normal gastric mucosa and influencing renal blood flow.Simmons also recently codiscovered COX-3 in 2002 and analyzed this new isozyme's relation which acetaminophen (paracetamol), arguably the most widely used analgesic drug in the world.The clinical ramifications and knowledge of COX isozymes are therefore rapidly expanding and could perhaps offer significant hope for future treatments of pain, inflammation, and fever [37,[45][46][47][48][49].

Discussion
Hydrazones, possessing an azomethine -NHN=CH-group, constitute an important class of compounds as target structures for their biological activities.These observations guide us for the development of new hydrazones that possess varied biological activities.The literature studies on hydrazones have shown that these derivatives possess a wide variety of biological activities such as antitumor, antibacterial, antiviral, antihypertensive, anticonvulsant, anti-inflammatory, analgesic, antipyretic, antiplatelets, vasorelaxant, anticoagulant, and antiprotozoal activities.There has been considerable interest in the development of novel compounds with wide varieties of biological activities.These molecules are easily prepared and have diverse pharmacological potential.This encourages to the researchers to synthesize different new compounds bearing hydrazones with low toxicity.Differently substituted hydrazones have been developed and found to be active against different pharmacological targets.These observations have been guiding the development of new hydrazones that possess varied biological activities.Hydrazone derivatives of carbonyl compounds constitute an important class of biologically active compounds [50][51][52][53][54][55][56][57].

Conclusion
Hydrazonone nucleus exhibited immense pharmacological activities.The simple hydrazonone nucleus is present in compounds are evaluating for new products that possess some remarkable pharmacological activities, such as analgesic, anti-inflammatory, antipyretic, antiplatelet aggregation, cardiotonic, antihypertensive, analgesic, vasodilatory, antidiabetic, and anticonvulsant activites.The present review focuses on hydrazonone which possesses potential analgesic, anti-inflammatory, antipyretic, and anti-platelet aggregation activities that are new in development.