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.
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  etc. Nonsteroidal anti-inflammatory drugs (NSAIDs) like ketoprofen, ibuprofen, aceclofenac, and so forth under current clinical usage for the treatment of inflammation, algesia and pyresis  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 . 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 . Hydrazones constitute a versatile compound of organic class having the basic structure R1R2C=NNR3R4 [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 [11–13], and so forth. Hydrazones and their derivatives are known to exhibit interesting diverse biological activities like antioxidant , anti-inflammatory [15, 16], anticonvulsant [17, 18], analgesic [19, 20], antimicrobial [21–23], anticancer [24, 25], antiprotozoal , antiparasitic , cardioprotective , antidepressant , antitubercular [30, 31], anti-HIV , 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 . 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 . 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.
2. Anti-Inflammatory Activity
A series of benzothiazine N-acylhydrazones 1(a–h) was designed by structural modification of piroxicam and synthesized and evaluated for the anti-inflammatory and antinociceptive activities (Figure 1). The pharmacological screening revealed that compounds 1(a–h) have exhibited better activity than standard drug piroxicam. Compounds 1f and 1g were identified as new anti-inflammatory and antinociceptive agents which were capable of inhibiting cell recruitment by 70% and 80%, respectively, at dose of 100 μmol/kg, p.o in zymosan- and carrageenan-induced peritonitis .
A novel series of 6-substituted-3(2H)-pyridazinone-2-acetyl-2(p-substituted/nonsubstituted benzal)hydrazine 2(a–i) was synthesized and evaluated for their analgesic and anti-inflammatory activity (Figure 2). The activity was evaluated by using carrageenan-induced paw oedema assay and indomethacin was employed as standard for comparison of results. The results revealed that 6-substituted-3(2H)-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-chlorophenyl)piperazine]-3(2H)-pyridazinone-2-acetyl-2(p-substituted/nonsubstituted benzal)hydrazine, was found to be slightly better than standard drug indomethacin .
A novel series of N-(substituted benzylidene)-2-(N-(4H-1,2,4-triazole-4-yl) benzamido)acetohydrazide derivatives 3(a–j) was synthesized and evaluated for the anti-inflammatory and antimicrobial activity (Figure 3). Indomethacin was used as standard drug and carrageenan-induced paw oedema method was employed for the anti-inflammatory screening of the test compounds. It was found that compounds 3f, 3g, and 3j substituted with 4-chloro, 4-dimethylamino, and 4-nitro exhibited 66.7, 61.7, and 63.2% inhibition, respectively, at 50 mg/kg, oral dose, whereas standard drug indomethacin had shown 64.2% inhibition at 10 mg/kg, oral dose .
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 anti-inflammatory and analgesic activities. Anti-inflammatory activity evaluation was carried out using carrageenan-induced rat paw oedema assay and compound 4a was found to have good anti-inflammatory activity .
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 adjuvant-induced arthritis model. Thalidomide (TNF-α 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, LASSBio-1181, had better pharmacological activities and can be used as a lead compound for development of new analgesic and anti-inflammatory agents .
A novel series of isatin derivatives, that is, isatin-3-[N2-(2-benzalaminothiazol-4-yl)]hydrazones 6(a–j), was synthesized and evaluated for anti-inflammatory, analgesic, and antipyretic activities (Figure 6) .
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 .
Synthesis of a novel series of orally active N-phenylpyrazolyl-N-glycinyl-hydrazone derivatives, 7a–g (Figure 7) and 8 (Figure 8), was carried out. Synthesized compounds were evaluated for their in vivo analgesic and anti-inflammatory activities and in vitro inhibition of TNF-α (tumor necrosis factor). Compounds 7a, (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)--((4-(2-morpholinoethoxy)naphthalen-1-yl) methylene)acetohydrazide, and 7f, (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)--(4-chlorobenzylidene)acetohydrazide, were known to possess anti-inflammatory activities when compared to the standard drug used, that is, SB-203580 .
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 anti-inflammatory agent .
Synthesis and biological evaluation of some new benz[b]thiophene derivatives like thiadiazole, pyrazoline, oxadiazole and diaryl pyrazoles was carried out. N1-(3- chlorobenzo[b]thiophene-2-carbonyl)-3-methyl-4-9 substituted phenylhydrazono pyrazolin-5-one 10(a-e) were subjected to anti-inflammatory and antimicrobial evaluation (Figure 10). Compound 10b substituted with 2-nitro-4-methyl was found to have 50.25 % inhibition which is near about the standard drug diclofenac sodium i.e. 51.88% .
Synthesis of zinc complexes 11, [Zn(LASSBio-466)H2O]2 of salicylaldehyde 2-chlorobenzoyl hydrazone (H2LASSBio-466), and 12, [Zn(HLASSBio-1064)Cl]2 salicylaldehyde 4-chlorobenzoyl hydrazone (H2LASSBio-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 anti-inflammatory 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 H2LASSBio-466 was active only in first phase of formalin test. H2LASSBio-1064 inhibited both phases but no improvement was indicated by the complex .
Synthesis of some new hydrazide derivatives of 2-napthoxy acetic acid , nicotinic acid [47, 48] and napthlene-1-acetic acid  has been reported. Out of these hydrazide derivatives most active antimicrobial compounds were selected and subjected to evaluation of the anti-inflammatory activity. Carrageenan induced rat paw oedema model was employed for the evaluation of theses active compounds using diclofenac sodium as standard drug. Results revealed that naphthalen-1-yloxy)-acetic acid [1-(2-bromo-4-cyano-phenyl)-ethylidene]-hydrazide 13 (Figure 11) has shown percent inhibition of 20.90% at a dose of 50 mg/kg .
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 anti-inflammatory 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 .
Synthesis of benzophenone semicarbazone (BSC) 15a and acetophenone semicarbazone (ASC) 15b was carried out (Figure 13). The anti-inflammatory activity was determined on Swiss albino mice by using carrageenan-induced mice paw oedema model. Both of the compounds were screened at two different doses, that is, 25 mg/kg and 50 mg/kg (p.o.). Compound 15a showed 36.6% and 46.6% of inhibition at 25 mg/kg and 50 mg/kg, respectively, whereas compound 15b showed 34.6% and 41.5% inhibition. Diclofenac sodium was used as standard drug which showed 70.29% inhibition at 10 mg/kg (p.o.). From the above observations, it was concluded that both of the test compounds possessed anti-inflammatory activity .
A novel series of 2-[4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio]acetic acid, 16(a–l), was synthesized (Figure 14). All the newly synthesized compounds were evaluated for in vivo anti-inflammatory and analgesic activities. Among the series 16d, 16e, 16j, and 16k showed significant activity with 63.4%, 62.0%, 64.1%, and 62.5% edema inhibition, respectively, as compared to standard drug diclofenac 67.0% after the third hour. Compounds 16g, 16h, 16i, and 16l showed good anti-inflammatory activity, whereas compounds 16a–c and 16f were found to be the least active. The results enlightened the effect of electron withdrawing moiety, that is, chloro group on the anti-inflammatory activity .
A series of bis-hydrazone derivatives, that is, (Z)-,-(1-(4-substituted phenyl)ethene-1,2-diyl)bis(4-substituted benzhydrazide), 17(a–d), was synthesized by reaction of 2-chloro-1-(4-chloro phenyl)ethanone or 2-bromo-1-(4-bromophenyl)ethanone with acid hydrazides (Figure 15). All the synthesized compounds were evaluated for the anti-inflammatory, analgesic, and ulcerogenic activities. Formalin-induced rat paw oedema model was selected and ketoprofen was employed as standard drug. All compounds were found to exhibit good anti-inflammatory activity with percent inhibition of 68.4% and 61.4% of compounds 17b and 17c, respectively, after three hours .
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-κB were selected for determination of anti-inflammatory 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 .
Inhibition of NF- κB mediated transcription was seen in human chondrosarcoma (SW1353) cells and compounds 18a, 18c, and 18h have shown inhibition with IC50 values of 6.9, 7.7, and 6.4 μg/mL, respectively (Figure 17). This observation correlated that methyl and chloro groups have a considerable influence on the inhibition of NF-κB mediated transcription. The other compounds 18d, 18e, 18g, and 18i inhibited the NF-κB activity to a lesser extent with IC50 values in the range of 10–14 μg/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 .
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 in-vivo analgesic and anti-inflammatory activities. The in vitro anti-inflammatory activity was evaluated by decrease in NF-κB activation and interleukin-8 inhibition by using a human pathway-specific reporter cell system (HT-29-NF-κB-hrGFP) whereas carrageenan induced paw oedema was used for in vivo evaluation of anti-inflammatory activity. Furoxanyl-NAH 19 (Figure 17)and benzofuroxanyl-derivative 20 (Figure 18) were reported to have orally anti-inflammatory 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 .
Synthesis of a series of novel acyl-hydrazones bearing 2-aryl-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 .
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) with 2-phenyl-thiazole and [2-(4-methylphenyl)-4-methylen]-thiazole hydrazine moieties was proved to be a more potent inhibitor of the acute phase bone marrow response than meloxicam, the anti-inflammatory standard drug .
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 20), 22b (Figure 20), 22d (Figure 20), 23b (Figure 21), 24b (Figure 22), 25 (Figure 23) and 26b (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 .
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 .
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 and , respectively, after 90 minutes which is comparable with reaction time of diclofenac sodium () after 90 minutes has shown analgesic potency of these derivatives .
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.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
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