Hydrazones and their metal complexes: A short review on their biological potential

KushalNath Mishra1, Shambaditya Goswami*2, Kumudhavalli M.V.3, Kamal Saini2, Nikita Pal2, Nilesh Sharma2, Pragya Pandey2 1Department of Chemistry, Institute of Technology and Management, GIDA, Gorakhpur-273209, Uttar Pradesh, India 2Department of Pharmacy, NIMS Institute of Pharmacy, NIMS University, Jaipur-303121, Rajasthan, India 3Department of Pharmaceutical Chemistry, Vinayaka Mission College of Pharmacy, Vinayaka Mission Research Foundation (Deemed University), Salem-636008, Tamil Nadu, India


INTRODUCTION
A group of organic compounds, Hydrazones are formed by the synthesis of ketones or aldehydes with hydrazine, which has the functional group =N−NH 2 in the replacement of oxygen (Figure 1).
Hydrazone complexes act as an intermediate in many chemical reactions; one of them is Fischer indole synthesis that makes indole group which can be found in many drugs. It's proven to be useful intermediate in the conversion of ketones into highly sterically hindered thioketones. A new series of quinoline ligands of hydrazones are tested against H37 RV strain of Mycobacterium tuberculosis by MIC (Minimum Inhibitory Concentration) method (Mandewale et al., 2015). The build-out of the ield of bioinorganic chemistry with hydrazone complexes has increased interest as biological important chemical compounds from aryl hydrazones are acting as enzyme inhibitors and also useful for pharmacological applications (Dharamaraj et al., 2001). Hydrazone bonded drugs are moored in blood's neutral pH, i.e. 7.4 that rapidly destroy the lysosome's acidic environment. Hydrazonesare used in medical biotechnology for making drugs through the coupling methods that target antibodies against certain types of cancer cells (Wu and Senter, 2005). Since the metal complexes of hydrazones possess significant potencies, i.e. antimicrobial, antidepressant, anti-in lammatory, anti-malarial, anti-cancer, antifungal, anti-tubercular, anti-viral, cardioprotective etc. and they have a high impact on diagnosis and therapy in medical practice, this writes up aims to highlight the diverse biological activities of hydrazone and its metal complexes from 2000 to 2020 ( Figure 2 ).

METHODOLOGY
The various works of literature, scienti ic papers, original articles are surveyed and reviewed from different search engines viz. Research Gate, Google Scholar, PubChem, ChemSpider, Scopus etc. for this write up. The authors have gone through and reviewed many full-text articles with abbreviations as hydrazone and its metal complexes; imidazole based heterocyclic compounds, biological potencies of hydrazones and its derivatives, QSAR study of these metal complexes etc. for the successful review. The authors drew all the structures in ACD/ChemSketch 2017.2.1(Freeware).
Fungal infections are generally observed as topical or systemic infections in humans, animals as well as plants. The antifungal potency of the metal complexes is less than the activation of their parent ligands. The previous research also reported regarding the evaluation of hydrazone derivatives (iodophenyl thiazole derivative) to show its inhibitory effect against Candida Species. The indole derivatives of hydrazone were also reported as an effective agent against Candida albicans. The new eighteen derivatives were evaluated by the researchers in which indol-3-yl derivatives were proved to be more potent. The researchers modi ied the hydrazinethiazole ring in two ways-irstly, the modi ication of indane part and secondly, replacement of phenol moiety (Maillard et al., 2013).

Anti-malarial activity
Malaria is a global burden as it causes morbidity in developing countries. Melnyk et al. (2006) synthesized and established a library of acyl-hydrazones (Figure 4) to evaluate the potency of these compounds against Plasmodium falciparum. Among them, eleven were more potent candidature. 4-Chloro-phenyl, 4-Methoxy-phenyl, and 4-tert-Butylphenyl derivatives showed maximum potency with-out any toxicity.

Anti-oxidant activity
Oxidative stress is the leading cause of many degenerative and severe diseases viz.diabetes Mellitus, IHD (ischemic heart disease), atherosclerosis, cancer etc. In recent years anti-oxidant has an essential role as it can neutralize the ROS (reactive-oxygenspecies) and free radicals.
New hydrazone derivatives are synthesized from thiophenechalcone ( Figure 5A) and evaluated for their anti-oxidant activity. It has been found that the presence of -NO 2 and -OCH 3 group enhanced the anti-oxidant activity of the synthesized compounds (Kamboj et al., 2014). Signi icant antioxidant activity of hydrazones attached with imidazoline ring was reported in the previous research.
Coumarin, a benzo-pyrone derivative, is a signi icant plant source derivative that is synthesized by the metabolism of phenylalanine. Hydroxy-coumarin heterocyclic derivatives were analyzed for different activities along with anti-oxidant properties. Acetyl hydroxyl coumarin acyl hydrazones derivatives were prepared with hydroxyl-coumarin derivatives and selective hydrazides ( Figure 5B). Antioxidant activity was performed by the inhibition of DPPH (2,2-diphenyl-1-pirylhydrazil) and lipid peroxidation. Some oxadiazole, pyrazoleandisoxazole derivatives were synthesized by using di-aryl hydrazones with the help of chloramine-T followed by reaction with hydrazine hydrate. These compounds were analyzed for DPPH scavenging potential (at 10µg/ml concentration) and after that were proved as potent anti-oxidant candidates (Kotali et al., 2016).

Anti-cancer activity
Cancer is a lethal disease involving uncontrolled cell division with a high level of penetrating potency affecting almost every organ of the body. Some of the dihydropyridines, thiophenes and thiazole derivatives were synthesized by the derivatives of acetohydrazides and evaluated for anti-cancer activ-ity against the breast cancer cell line (MCF7) of humans (Al-Said et al., 2011). Hydrazone derivatives containing pyrazole ring ( Figure 6A) were synthesized and were checked for anti-cancer activity against adenocarcinoma of the human breast.
Pyrazole-pyrimidine derivatives with benzenesulfonohydrazide as PI3K (Phosphoinositide-3kinases) p110α inhibitors were evaluated against the human tumour xenograft model (Kendall et al., 2012). Some imidazo-[1,3,4]-thiadiazole-5carbohydrazides ( Figure 6B) were reported to be useful for their inhibitory effects on the growth of a wide range of cancer cell lines (Cocco et al., 2006). Some novel substituted phenyl methyleneimidazole-thiadiazole-carbohydrazidehydrazones were synthesized and evaluated for the anti-cancer activity in human cell lines.
Acyl hydrazones derivatives with furan (Figure 6C) were also reported as an active cytotoxic agent against lung carcinomic cell lines, whereas, palladium-based hydrazones were effective against human head and neck squamous carcinomic cell lines. Derivatives of acetyl-pyridine and benzoylpyridine of hydrazones were evaluated against human brain tumour cell lines (Abu-Surrah et al., 2010).

Anti-viral activity:
Viruses are microscopic parasites that replicate only inside the living cell of an organism. It infects all types of organisms-humans, animals as well as plants. Some novel acridines and hydrazone derivatives obtained from β-diketone (dimedone) were reported as potent anti-viral drugs, and the evaluation was carried out against Hepatitis A Virus (El-Sabbagh and Rady, 2009). Acyl-hydrazones were synthesized with natural amino acids and triethylamine. These acyl-hydrazones derivatives were targeted against HIV (human immune de iciency virus) type-1, and promising results were obtained in which EC 50 were reported as 0.21 and 0.17 µM (Tian et al., 2009).

Anti-in lammatory activity:
In lammation is a localized physical, chemical or biological response of the immune system, under-standing by injury any process able to cause tissue or cellular damages. Non-steroidal antiin lammatory drugs (NSAIDs) of different classes were used as analgesics and hence used in the treatment of pain and in lammation. In the past years, aryl hydrazones were synthesized as the derivatives of mefenamic acid ( Figure 7A) and were evaluated for the anti-in lammatory effects (Almasirad et al., 2005).
The synthesis of zinc(II) complexes with salicylaldehyde-2-chlorobenzoyl hydrazone (Figure 7B) and its region isomersalicylaldehyde-4chlorobenzoyl hydrazone are combined and make a pharmacological evaluation of all acyl hydrazones and zinc(II) complexes in animal models of peripheral and central nociception and acute in lammation. The authors proved that all the compounds could inhibit peritonitis while compared to indomethacin (Júnior et al., 2011). Some furoxanyl-acyl hydrazones derivatives were also reported as analgesics and anti-in lammatory drugs (Hernández et al., 2012).
Some novel aryl-hydrazones were successfully evaluated for anti-in lammatory activity. Pyridyl-arylhydrazone derivatives were also proved to be potent for the analgesic and anti-in lammatory along with antiplatelet activities. The most trusted mechanism as suggested for the activity was the interference with the arachidonic acid metabolism, and formyl furanepyridyl hydrazone derivative was proved as most potent (79% inhibition of pleurisy) (Rajitha et al., 2011). Salicaldehydechlorobenzyl (2 and 4 substituted) hydrazones and their complexes with zinc were evaluated for the anti-in lammatory and anti-nociceptive activity in animal models, and all the compounds were reported for their signi icant inhibition of acetic acid writhing responses. Inhibition of zymosan-induced peritonitis was recorded while comparing with indomethacin as standard (Júnior et al., 2011).

Antimycobacterial activity
Tuberculosis is a contagious bacterial disease, which is responsible for the mortality of nearly three million people every year worldwide. The drugs which are used to treat infections caused by Mycobacterium that include leprosy and tuberculosis (TB) are called as antimycobacterial or anti-tubercular agents. Some of the agents are rifampicin, isoniazid, ethambutol etc. Some novel approach has been attempted by the researchers (Dasgupta, 2012). The researcher put their efforts to synthesize several novel hydrazone derivatives that were assessed for the antimycobacterial activity. Among them, diclofenac acid hydrazones ( Figure 8A) were synthe-sized from diclofenac, methanol, sulphuric acid with dichloro substituted phenyl amino phenyl Acetohydrazides for the in-vivo antimycobacterial activities against Mycobacterium tuberculosis.

CONCLUSION
The synthesis and application of medicines from bioinorganic complexes is a rapidly developing ield due to the formation of stable compounds in coordination chemistry. The metal complexes and their parent ligands have a signi icant impact on clinical practice as diagnostic and therapeutic agents. Advances and innovations in bioinorganic chemistry are essential for improving the design of compounds to maximize its therapeutic effects along with minimizing the toxic side-effects. As hydrazones and its metal complexes possess antibacterial, anti-oxidant, analgesic, anti-in lammatory, anti-cancer properties, so this review article focuses the development of newer compounds from hydrazones with proper designing, synthesis and structure-activity relationship (SAR).