Indonesian J. Pharm. Vol. 23 No. 4 : 193 – 202 ISSN-p : 0126-1037 Review Article

REVIEW OF BIOLOGICAL ACTIVITIES OF

Md. Rahmat Ali1, Akranth Marella1, Md. Tauquir Alam1, Ruksar Naz1, Mymoona Akhter1, Md. Shaquiquzzaman1, Rikta Saha1, Omprakash Tanwar1, Md. Mumtaz Alam1*, Jyoti Hooda2

1Department of ABSTRACT Pharmaceutical Chemistry, Hydrazones possess an azomethine –NHN=CH group and Faculty of Pharmacy, are considered as derivatives of and in which Jamia Hamdard, New Delhi the oxygen atom has been replaced by the NNH2 functional 110062, India. group. These are widely studied molecules owing to their ease of 2CHRD- Competitive and preparation and diverse pharmacological potential. This has led Scientific Intelligence researchers to synthesize different heterocyclic compounds (CSI), WNS Global bearing hydrazones. Medicinal chemists across the world have Services (P) Ltd, Gurgaon done immense work on hydrazones and developed agents with 122002, India. better activity and low toxicity profiles. Following different

Submitted: 10-08-2012 synthetic protocols and through proper SAR studies differently Revised: 14-09-2012 substituted hydrazones have been developed and found to be Accepted: 13-10-2012 active against different pharmcological targets. They are known to possess different biological activities viz. antimicrobial, anti- *Corresponding author inflammatory, anticancer, antimalarial etc. These observations Md. Mumtaz Alam have been guiding for the development of new hydrazones that possess varied biological activities. The review aims at Email : highlighting the diverse biological activities of hydrazones. [email protected] Key words: Azomethine, Hydrazones, Pharmacological Potential

INTRODUCTION The C=N bond of and Hydrazones are a class of organic terminal atom containing a lone pair compounds which possess the structure of electron is responsible for the physical and R1R2C=NNH2. They are related to and chemical properties. The C-atom in hydrazone in which oxygen has been replaced has both electrophilic and nucleophilic with NNH2 group. These azometine - character and both the N-atoms are NHN=CH- proton constitute an important nucleophilic although the amino type nitrogen class of compounds for new drug development. is more reactive. Due to these properties Hydrazones are formed by the reaction of hydrazones are widely used in organic hydrazine or hydrazide with aldehydes and synthesis. The chemical structure of hydrazone ketones. They act as reactants in various derivatives were showed in figure 1-4. important reactions such as hydrazone iodination, Shapiro reaction and Bamford- BIOLOGICAL ACTIVITY Stevans reaction to form vinyl compounds. Antimicrobial activity They act as intermediate in Wolff-Kishner The overuse of chemicals against various reaction. Hydrazones can also be synthesized infectious diseases has led to rapid emergence by the Japp-Klingemann reaction (from β- of resistivity against different bacteria. ketoacids or β-ketoester’s and aryldiazonium Therefore, the search for antimicrobials is a salts). The N,N’-dialkyl type of hydrazones can never ending task. Consequently, there has be hydrolysed, reduced and oxidized this leads been an immense research on hydrazones as to the formation of amines by reduction of N- antibacterial agents. Sharma et al. (2011) N bond. The C=N double bond in hydrazones reported the antibacterial activity of hydrazine are important compounds in drug design as derivatives (1) against various bacterial strains. they act as ligands for metal complexes, Hydrazine derivatives (2, 3) synthesized by organocatalysis and synthesis of organic Jubie et al. (2010) are promising antibacterial compounds. agents. Ozkay et al. (2010) synthesized novel benzimidazole derivatives bearing hydrazone

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moiety (4) and evaluated their antibacterial virulent H37Rv strain. Few hydrazone activity against different bacterial strains. Novel derivatives (27) synthesized by Raja et al. (2010) chloropyrrole derivatives of aroylhydrazone (5) have been screened and reported to have MIC developed by Rane et al. (2010) have been of 6.3µg/mL. 4-hydroxy-8-trifluromethyl- evaluated for antibacterial activity against quinoline derivatives (31) with a MIC of different bacterial strains. Edress et al. (2010) 0.625µg/mL have been reported by Thomas et synthesized some hydrazonoyl substituted al. (2011). Vavrikova et al. (2011) synthesized pyrimidinones (6, 7) and evaluated their fluorine-containing hydrazones (32) with a MIC antibacterial activity. Govindasami et al. (2011) of 0.5µg/mL and a selectivity index of 1268.6 synthesized vanillin based hydrazine derivatives Pavan et al. (2010) synthesized some hydrazines (8, 9) and reported their antibacterial ( 35 ) with promising results. Ferrocenyl activity specifically against Staphylococcus aureus hydrazones (38, 39) with a MIC of 0.75 and and Pseudomonas aeruginosa. Ajani et al. (2010) 0.7µmol/L have been reported by Maguene et have reported the antibacterial activity of al . (2011) Mahajan et al. (2011) synthesized 2-quinoxalinone-3-hydazine derivative (12) ferrocene-based hydrazone derivatives (43) against different bacterial strains. Lee et al. with significant potential. Eswaran et al. (2010) (2012) synthesized various hydrazones (13, 14) synthesized hydrazones (44) with a MIC of as selective inhibitors of Staphylococcus aureus β- 6.25µg/mL. Jordao et al. (2011) synthesized ketoacyl carrier proteinsynthase III. The hydrazone derivatives (45) with antitubercular compound was found to have an MIC of 1- activity. The compound is reported to have 2µg/mL. Aryloxyacetic acid hydrazide (15) MIC of 2.5µg/mL. Fungal species are known having promising antibacterial activity with to cause many superficial and systemic MIC of 4.1-16.5µg/mL against an array of infections in humans, plants as-well-as bacterial strains has been reported by Wahab et livestock. Hydrazone derivatives (49) al. (2012). Rasras et al. (2010) synthesized synthesized by Ozdemir et al. (2010) after being various cholic acid based hydrazones (22) and screened against different Candida spp have been screened them as antibacterials. The best reported to have promising antifungal potential. compound among the series is reported to have Viruses are obligate parasites which MIC of 2µg/mL and 3.9µg/mL against require cellular machinery of the host to Escherichia faecalis and Escherichia coli. Anthra- prosper. They are capable of causing immense quinone based hydrazones (23) synthesized by harm to host. Hydrazone derivatives (53, 54) Gouda et al. (2010) are reported to have promi- synthesized by Jin et al. (2010) have been sing bacteriostatic activity against P. auriginosa. reported to have EC50 value of 0.6 and 0.4µM Kumar et al. (2010) synthesized various respectively against HIV1-CA. benzyledine-hydrazides (24) and reported their bactericidal activity against S. aureus. The Analgesic and Anti-inflammatory activity agent is reported to have a MIC of 1.5µM/mL. Much work has been done describing the Abdel-Wahab et al. (2011) synthesized different analgesic and anti-inflammatory potential of hydrazone bearing imidazoles (25). The hydrazides. Harnandez et al. (2012) reported synthesized compounds were screened for their analgesic and anti-inflammatory activity of antibacterial activity against numerous bacterial furoxanyl-N-acylhydrazones (55, 56). Rajitha et strains. Vijesh et al. (2010) synthesized 2,4- di- al. (2011) evaluated the anti-inflammatory substituted thiazoles (26). The compound has a activity of some aryl hydrazones (58) and got MIC value ranging between 1.6µg/mL and good results. Moldovan et al. (2011) synthesized 3.1µg/mL when tested against different strains. various hydrazone derivatives (60) and reported Tuberculosis is a chronic infection them to have promising in-vivo anti-inflamma- caused by different strains of Mycobacterium tory activity. El-Sayed et al. (2011) synthesized tuberculosis. The bacterium affects almost any hydrazone derivatives (62) with selective organ but the favorite site is lung. The activity COX-2 inhibition. The compound is reported of the newer agents is mostly tested against to have an ED50 value of 0.2 mmol/Kg.

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Figure 1. Chemical structure of hydrazone derivatives no.1-42

Benzo-thiophene derivatives (66) with with potent activity against HL-60 leukaemia inhibition of 50.2% have been developed by and 518A2 melanoma. Acylhydrazones (79) by Isloor et al. (2010). Cui et al. (2010) have been reported to have potent activity against the human Anticancer activity promyelocytic leukemic cells (Hl-60). Copper Cancer is a lethal group of diseases with based hydrazone derivatives (82) are reported a high level of penetrating potency affecting to act against integrin β4 in H322 lung almost every organ of the body. Al-Said et al. carcinoma cell lines by Fan et al. (2010). (2011) synthesized compounds (67) active Palladium based hydrazones (86) by Abu- against human breast cancer cell lines MCF7. Surrah et al. (2010) have been reported to be Hassan et al. (2011) synthesized pyrazole based active against human head and neck squamous hydrazone derivatives (69) with potential to carcinoma cell lines SQ20B and SCC-25. 2- treat breast carcinoma. Kendall et al. (2012) phenylindole based hydrazone (87) synthesized evaluated some derivatives (70) as PI3K p110α by El-Nakkady et al. (2012) have been inhibitors. P13K are signaling proteins in developed against breast carcinoma cell lines different cell types responsible for and reported to have an IC50 of 1.60nM. phosphorylation of lipids in cell membranes. Kumar et al. (2012) synthesized various Central Nervous System Activity bis(indolyl) based hydrazones (72, 73) active Hydrazones are reported to have activity against multiple cancer cell lines. Effenberger et against various illnesses’ of central nervous al. (2010) reported a hydrazone derivative (75) system. Hydrazones (88) synthesized by

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Figure 2. Chemical structure of hydrazone derivatives no.44-75

Gage et al. (2011) have been evaluated for Antiprotozoal activity inhibition of PDE10A- a phosphodiesterase Protozoal diseases are highly prevalent in responsible for neurological and psychological tropical countries affecting human and animal disorder such as Parkinson’s, Schizophrenia populations’ and causing suffering and death. and Huntington’s disease. Kaushik et al. (2010) Caputto et al. (2011) reported the inhibitory reported the anticonvulsant potential of some activity of hydrazones (98, 99) against cruzipen- hydrazone derivatives (91, 92) having long a major cysteine protease of T.cruzi. Hayat et al. duration of action and a rapid onset of action. (2010) reported the in-vitro antiamoebic activity Antidepressant activity of hydrazones of hydrazones (102, 103) against the HM1:IMSS (93) has been reported by de Oliveira et al. strain of Entamoeba histolytica. The compounds (2011). Catto et al. (2010) reported the in-vitro are reported to have IC50 value of 0.03 and β-amyloid aggregation inhibition of hydrazone 0.04µM respectively. Vaio et al. (2009) derivatives (96) with an IC50 of 23µM. synthesized hydrazone derivatives (106, 107) and described

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Figure 3. Chemical structure of hydrazone derivatives no.81-111 them to be of high utility in Chagas disease. Miscellaneous activity Siddiqui et al. (2012) described the antiamoebic In addition to the mentioned activities activity of hydrazone derivatives (108, 109). hydrazines are also reported to have other Romeiro et al. (2009) developed hydrazone activities, as mentioned below: derivatives (110, 111) as cruzin inhibitors. Aponte et al. (2010) evaluated the anti- Antioxidant activity trypanosomal activity of hydrazone derivatives Oxidation reactions are crucial for (112). sustenance of life but they can also be damaging.

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Figure 4. Chemical structure of hydrazone derivatives no.112-132

Oxidative stress is the cause of different Antiplatelet activity pathological states. Hydrazone derivatives (116, Antiplatelets decrease platelet aggre- 117) synthesized by Musad et al. (2011) are gation, hold back the formation of thrombus. reported to have radical scavenging activity Jordao et al. (2009) synthesized hydrazone (RSA) at the concentration of 10µg/mL. derivatives (126, 127, 128) and evaluated them Abdel-Wahab et al. (2011) evaluated imidazoline for in-vitro antiplatelet activity. based hydrazones (118, 119) by 2,2'-azino-bis(3- ethylbenzothiazoline-6-sulphonic acid (ABTS) Antiparasitic activity assay method and reported them to have Ali et al. (2010) evaluated the in-vitro anti promising antioxidant activity. parasitic activity of hydrazone derivatives (129, 130) against Ctenocephalides felis and Rhipicephalus Cardioprotective activity sanguineusas. LD50 of 0.39 and 0.28µg/tick has Despite the intensive drug research been reported. cardiovascular diseases still remain the leading Aslam et al. (2011) synthesized cause of mortalities worldwide. El-Sabbagh et hydrazone derivatives (132) as urease inhibitors. al. (2010) synthesized octahydroquinazoline- Urease catalyzes the hydrolysis of urea to hydrazones (121, 122, 123) and reported them ammonia and carbamate. This is beneficial for to be potential hypotensive agents. The activity the pathogenesis of urolithiasis, pyelonephrities, was attributed to α-blockage. The chemical ammonia and hepatic encephalopathy, hepatic structure of hydrazone derivatives no.112-132 coma and urinary catheter encrustation. were showed in figure 4.

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CONCLUSION Tarleton RL., Wang Y., Franzblau SG., The review highlights the use of Pauli GF., Sauvain M., and Hammond hydrazones as lead for development of newer GB., 2010, Trypanoside, anti- agents. As mentioned the moiety possesses an tuberculosis, leishmanicidal, and array of activity. With proper synthesis and cytotoxic activities of tetrahy- structure activity relationship, potential drobenzothienopyrimidines, Bioorg. Med. compounds can be designed with different Chem., 18, 2880-2886. biological activity. Aslam MAS., Mahmood S., Shahid M Saeed A., and Iqbal J. 2011, Synthesis, biological REFERENCES assay in vitro and molecular docking Abdel-Wahab FB., Awad AEG., and Badria studies of new Schiff base derivatives as AF., 2011, Synthesis, antimicrobial, potential urease inhibitors, Eur. J. Med. antioxidant, anti-hemolytic and cytotoxic Chem., 46, 5473-5479. evaluation of new imidazole-based Belskaya NP., Dehaen W., and Bakulev VA. heterocycles, Eur. J. Med. Chem., 46, 2010, Synthesis and properties of 1505-1511. hydrazones bearing amide, thioamide Abdel-Wahab FB., Khidre ER. and Awad and amidine functions, ARKIVOC, 1, AEG. 2012, Regioselective synthesis and 275-332. antimicrobial activities of some novel Caputto ME., Fabian LE., Benitez D., aryloxyacetic acid derivatives, Eur. J. Merlinoz A., Rios N., Cerecetto H., Med. Chem., 50, 55-62. Moltrasio GY., Moglioni AG., Gonzalez, Abu-Surrah AS., Safieh KAA., Ahmadb IM., M., and Finkielsztein LM., 2011, Abdalla MY., Ayoub MT., Qaroush AK., Thiosemicarbazones derived from 1- and Abu-Mahtheieh AM. 2010, New indanones as new anti-Trypanosoma palladium (II) complexes bearing cruzi agents, Bioorg. Med. Chem., 19, 6818- pyrazole-based Schiff base ligands: 6826. Synthesis, characterization and Catto M., Aliano R., Carotti A., Cellamare S., cytotoxicity, Eur. J. Med. Chem., 45, 471- Palluotto F., Purgatorio R., Stradis A.D., 475. and Campagna F., 2010, Design, Ajani OO., Obafemi CA., Nwinyi OC., and synthesis and biological evaluation of Akinpelu DA. 2010, Microwave assisted indane-2-arylhydrazinylmethylene-1,3- synthesis and antimicrobial activity of 2- diones and indol aryldiazenylmethylene- quinoxalinone-3-hydrazone derivatives, 3-ones as β-amyloid aggregation Bioorg. Med. Chem., 18, 214-221. inhibitors, Eur. J. Med. Chem., 45, 1359- Ali A., Fisara P., Freemont JA., Kyi S., Meyer 136. AG., Andrew G., Riches A.G., Sargent Corey EJ., and Enders D., 1976, Applications RM., Sawutz DG., Turner KA., of N,N-dimethylhydrazones to synthesis. Winzenberg KN., and Yang Q. 2010, Use in efficient, positionally and Discovery of ectoparasiticidal stereochemically selective CC bond hydrazono-trifluoro- formation, oxidative hydrolysis to methanesulfonanilides, Bioorg. Med. Chem. carbonyl compounds, Tetrahedron Lett., Lett., 20, 649-652. 17, 3-6. Al-Said MS., Bashandy MS., Al-qasoumi SI., Corey EJ., and Enders D., 1976, Synthetic and Ghorab MM., 2011, Anti-breast routes to polyfunctional molecules via cancer activity of some novel 1,2- metallated N,N-dimethylhydrazones, dihydropyridine, thiophene and thiazole Tetrahedron Lett., 17, 11-14. derivatives, Eur. J. Med. Chem., 46, 137- Cui Z., Li Y., Ling Y., Huang J., Cui J., Wang 141. R., and Yang X., 2010, New class of Aponte JC., Vaisberg AJ., Castillo D., potent antitumor acylhydrazone Gonzalez G., Estevez Y., Arevalo J., derivatives containing furan, Eur. J. Med. Quiliano M., Zimic M., Verastegui M., Chem., 45, 5576-5584. Malaga E., Juan RHG., Bustamante B.,

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