Therapeutic Potential of Hydrazones as Anti-Inflammatory Agents

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 like antioxidant, anti-inflammatory, anticonvulsant, analgesic, antimicrobial, anticancer, antiprotozoal, antioxidant, antiparasitic, antiplatelet, cardioprotective, anthelmintic, antidiabetic, antitubercular, trypanocidal, anti-HIV, and so forth. The present review summarizes the efficiency of hydrazones as potent anti-inflammatory agents.


Introduction
Inflammation is a physiological reactionwhich involves cellular and biochemical responses, which is not only symptom for common diseases but also known to be an early phase for some serious diseases such as alzheimer's disease, cancer, heart vascular diseases [1] etc. Nonsteroidal antiinflammatory drugs (NSAIDs) like ketoprofen, ibuprofen, aceclofenac, and so forth under current clinical usage for the treatment of inflammation, algesia and pyresis [2] are associated with major drawbacks of gastrointestinal disorders like dyspepsia, gastric ulcers, and so forth, due to the direct contact of free carboxylic group with the gastric mucosa [3,4] and due to decrease in production of prostaglandins in tissue [5]. In order to overcome these drawbacks, there is an urgent need for design and synthesis of new chemical entities with excellent anti-inflammatory response and minimum side effects. Hydrazones are a class of organic compounds in the Schiff base family [6]. Hydrazones constitute a versatile compound of organic class having the basic structure R 1 R 2 C=NNR 3 R 4 [7,8]. Two nitrogen atoms of hydrazone are nucleophilic but the amino type nitrogen is more reactive, whereas the carbon atom possesses both characters, that is, nucleophilic and electrophilic. The active centers of hydrazine, 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 [9,10]. The general method for the synthesis of the hydrazones is the reaction of hydrazine with carbonyl compounds such as aldehydes or ketones in solvents like ethanol, methanol, butanol [11][12][13], and so forth. Hydrazones and their derivatives are known to exhibit interesting diverse biological activities like antioxidant [14], anti-inflammatory [15,16], anticonvulsant [17,18], analgesic [19,20], antimicrobial [21][22][23], anticancer [24,25], antiprotozoal [26], antiparasitic [27], cardioprotective [28], antidepressant [29], antitubercular [30,31], anti-HIV [32], and trypanocidaletc. Hydrazones are also emerging as moiety of interest in medical biotechnology. Hydrazones are also used to couple with certain drugs and the bonds based on hydrazones are stable at the neutral pH [33]. The hydrazone Schiff bases of aroyl, acyl, and heteroaroyl compounds are known to have an additional donor site, that is, C=O, which make them more versatile and flexible. This versatility has leaded the hydrazones to emerge           as good chelating agents that can form a variety of complexes with different transition metals [6]. Some hydrazones have been introduced by the researchers as potent drugs, such as nifuroxazide, an intestinal antiseptic [34,35], dihydralazine as hypertensive, and gyromitrin, a toxin.
Synthesis of a novel series of some amidine and hydrazone derivatives 4 was reported ( Figure 4). The synthesized compounds were further subjected to evaluation of antiinflammatory and analgesic activities. Anti-inflammatory activity evaluation was carried out using carrageenaninduced rat paw oedema assay and compound 4a was found to have good anti-inflammatory activity [39].
A series of nineteen pyrazine N-acylhydrazone (NAH) derivatives 5(a-s) was ( Figure 5) designed by molecular simplification of the prototype (LASSBio-1018), a nonselective cyclooxygenase inhibitor. Synthesis of the designed compounds was carried out and they were evaluated for their anti-inflammatory and analgesic activities in several animal models of pain and inflammation like writhing test, formalin test, hot plate test, zymosan-induced peritonitis, capsaicin-induced ear edema, and Freund's adjuvantinduced arthritis model. Thalidomide (TNF-inhibitor), celecoxib (COX-2) inhibitor, and indomethacin (selective COX-1 inhibitor) were employed as standard drugs. Results enlightened that compound 5o (2--[(E)-(3,4,5-trimethoxyphenyl)methylidene]-2-pyrazinecarbohydrazide, LA-SSBio-1181, had better pharmacological activities and can be used as a lead compound for development of new analgesic and anti-inflammatory agents [40].
Carrageenan-induced rat paw oedema model was used for evaluation of anti-inflammatory activity and indomethacin was employed as standard drug. It was found that the compounds 6f, 6h, and 6j substituted at fifith position with methyl, chloro, and nitro groups, respectively, exhibited significant anti-inflammatory activity [41].
Synthesis of a novel series of substituted--[(1E)-substituted phenylmethylidene]benzohydrazide analogs, 9(a-n) (Figure 9) was reported and evaluated for their in vitro anti-inflammatory, antimicrobial and antioxidant activities. Albumin denaturation studies were carried out in order to evaluate the anti-inflammatory activity by employing diclofenac sodium as standard. Compounds 9c, 9d, and 9e were reported to have good anti-inflammatory activity due to presence of 4-nitro, 4-methyl, and 2-hydroxy groups, respectively, whereas 9e was found to be the most active antiinflammatory agent [43].
Synthesis and biological evaluation of some new benz[b]thiophene derivatives like thiadiazole, pyrazoline, oxadiazole and diaryl pyrazoles was carried out.        -1064), was carried out. The complexes were further subjected to evaluation for peripheral and central nociception and acute inflammation in animal models. Both of the complexes exhibited antiinflammatory activity. Complex 11 has shown activity in both phases of formalin test like indomethacin and indicated its ability to inhibit nociception associated with the inflammatory response, whereas H 2 LASSBio-466 was active only in first phase of formalin test. H 2 LASSBio-1064 inhibited both phases but no improvement was indicated by the complex [45].
The nicotinic acid hydrazide derivatives, 14a and 14b, substituted with nitro group at meta and ortho positions, respectively, were found to be the most active antiinflammatory agents ( Figure 12). The percent inhibition of compounds 14a and 14b was found to be 37.29% and 35.73%, respectively, at the dose of 20 mg/kg and 34.17% and 25.12%, respectively, at the dose of 50 mg/kg, whereas percent inhibition of diclofenac sodium was found to be 38.85%. The conclusion drawn from the results was that the substitution of nitro group and halogens contributed to anti-inflammatory activity [50].
Synthesis of a series of hydrazone derivatives, that is, N-(substituted benzylidene)-3-cyclohexylpropionic acid hydrazide, 18(a-j), was carried out (Figure 16). The synthesized compounds were evaluated for anti-inflammatory activity and cytotoxicity. Inducible nitric oxide synthase (iNOS) and NF-B were selected for determination of antiinflammatory activity. Inhibition of iNOS activity was also observed in LPS-induced RAW 264.7 cells. Compounds 18c, 18e, and 18i were more active than the other synthesized compounds which proved that there is a positive correlation between the inhibitions of iNOS activity and functional groups, that is, methyl, fluoro, and isopropyl, on phenyl ring [54].
Inhibition of NF-B mediated transcription was seen in human chondrosarcoma (SW1353) cells and compounds 18a, 18c, and 18h have shown inhibition with IC 50 values of 6.9, 7.7, and 6.4 g/mL, respectively ( Figure 17). This observation correlated that methyl and chloro groups have a considerable influence on the inhibition of NF-B mediated transcription. The other compounds 18d, 18e, 18g, and 18i inhibited the NF-B activity to a lesser extent with IC 50 values in the range of 10-14 g/mL. Compounds 18b, 18d, and 18j were found to be comparatively less active than other compounds. From the results, it was concluded that substitutions at para position of phenyl ring had significant influence on anti-inflammatory activity [54].
By application of molecular hybridization approach design, and synthesis of thirty two furoxanyl N-acylhydrazones(furoxanyl-NAH) was carried out. Synthesized compounds were evaluated for their in vitro as well as invivo analgesic and anti-inflammatory activities. The in vitro anti-inflammatory activity was evaluated by decrease in NF-B activation and interleukin-8 inhibition by using a human pathway-specific reporter cell system (HT-29-NF-B-hrGFP) whereas carrageenan induced paw oedema was used for in vivo evaluation of anti-inflammatory activity. Furoxanyl-NAH 19 ( Figure 17)and benzofuroxanylderivative 20 ( Figure 18) were reported to have orally antiinflammatory and analgesic activities without interleukin-8 inhibition. Furoxanyl-NAH derivative 21a (Figure 19)was emerged as a structural lead to develop new lipoxygenase (LOX) inhibitors. The active derivatives 19, 21a and 21b were found to be less mutagenic and were proposed as candidates for the further clinical studies [55].
Synthesis of a series of novel acyl-hydrazones bearing 2aryl-thiazole moiety was carried out. The synthesized compounds were screened for invivo anti-inflammatory activity by evaluating three parameters, that is, nitric oxide synthesis, phagocytes activity, and acute phase bone marrow response, in acute experimental inflammation [56].
Compounds 22c, 22e, 22f, 24b, and 26b were found to have a good inhibitory effect on the acute phase marrow response by reducing the absolute leukocytes count due to the lower neutrophils percentage. Compound 22c ( Figure 20  response than meloxicam, the anti-inflammatory standard drug [56]. Phagocytic activity was assessed by calculating phagocytic index (PI) and the phagocytic activity (PA). All the newly synthesized compounds reduced PI significantly and compounds 22a (  Figure 24)were observed as more potent inhibitors than meloxicam. PA was significantly reduced by the compounds 22a, 22d, 23b, 24b, 23c, 25 and 26b from which 22a, 22d, 20 and 26b were found to be more potent inhibitors than meloxicam [56].
Synthesis of NO increases significantly in acute inflammation due to the expression of iNOS. The NO synthesis was significantly reduced by 22a, 22b, 23c, 26a, and 26b and they all, except for 26a, displayed a stronger inhibitory activity than meloxicam [56].
Synthesis of a novel series of phthalic anhydride based substituted benzylidene-hydrazide derivatives, 27a-i, was carried out. All the synthesized derivatives were screened for in vivo anti-inflammatory and analgesic activities by carrageenan-induced rat paw oedema and tail immersion methods, respectively, using diclofenac sodium as standard drug. The results revealed that derivatives 27d, 27e, and 27h ( Figure 25) have shown potent anti-inflammatory activity with percentage inhibition of 58.6%, 61.4%, and 64.0%, respectively, which is comparable with standard drug diclofenac sodium, that is, 68.0%. The reaction time of derivatives 27d and 27h that was found to be 8.91 ± 0.21 and 9.09±0.03, respectively, after 90 minutes which is comparable with reaction time of diclofenac sodium (10.93 ± 0.01) after 90 minutes has shown analgesic potency of these derivatives [57].

Conclusion
Hydrazone derivatives are well known to have various important pharmacological activities and are used for synthesis of a wide variety of medicinally active compounds. This review paper summarizes the anti-inflammatory potential of hydrazone derivatives and the effect of substitutions of different groups on the anti-inflammatory activity. This summarized study is an attempt to bring about the anti-inflammatory activity for awaking the safe use of this important chemical moiety with minimal or no ulcerogenic effects in future.