Introduction

A group of organic compounds, Hydrazones are formed by the synthesis of ketones or aldehydes with hydrazine, which has the functional group =N˗NH₂in 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, Thorat, Shelke, & Yamgar, 2015). The build-out of the field 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, Viswanathamurthi, & Natarajan, 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 & Senter, 2005). Since the metal complexes of hydrazones possess significant potencies, i.e. antimicrobial, antidepressant, anti-inflammatory, 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, scientific 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).

Biological Potential of Hydrazone Derivatives

Antimicrobial activities

Chemicals are used to resist transmittable diseases against different bacteria. As an antibacterial agent, hydrazones containing imidazoles fight against different bacterial strains. In one research paper, Researchers have evaluated the antibacterial activity of cobalt(II), nickel(II), zinc(II), copper(II) and cadmium(II) complexes of acetophenone-4-amino benzoyl hydrazone and 4-hydroxy acetophenone-4-amino benzoyl hydrazone against Escherichia coli and Aspergillus niger. They also reported that copper(II) is more active than zinc(II) of these hydrazone complexes at every concentration. The authors of the previous research have reported the antibacterial activity of 2, 3, 4-pent aneotrione-3[4-[(5-nitro-2-furyl)methylene hydrazide]carbonyl]phenyl] hydrazone against Staphylococcus aureus and Mycobacterium tuberculosis (Savini et al., 2004).

Some novel transition metal complexes of benzylidene-hydrazo derivatives containing quinoline ring were evaluated against some Gram (+)ve, Gram (-) ve and fungi. Thiosemicarbazone, along with hydrazone derivatives, has promising effectiveness against Mycobacterium tuberculosis, and ethyl-2-arylhydrazone-3-oxobytyrates has antibacterial activity against Staphylococcus aureus (Pavan et al., 2010).

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 modified the hydrazine-thiazole ring in two ways-firstly, the modification of indane part and secondly, replacement of phenol moiety (Maillard et al., 2013).

(Al-Shaalan, 2011) investigated different metal complexes with the modified Schiff base of hydrazone nucleus with quinolone moiety. The metal complexes like copper (II), cobalt (II), manganese (II), nickel (II), iron (II) and uranium dioxide (VI) were used in the study. Moreover, the researchers proved that all the complexes were highly effective against Gram (+)ve and gram (-)bacteria and fungi. Novel pyrazole-amide derivatives attached with hydrazone moiety were subsequently analyzed for potent antifungal activities against Gibberellazeae.

Kandile and co-workers synthesized hydrazone metal complexes from 1-[4-(2-methoxybenzyl)-6-aryl pyridazine-3(2H)-ylidene]hydrazines and diacetyl. These synthesized products have the antimicrobial activity against S.aureus, S.faecalis, E. coli and P.aeruginosa. The hydrazone derivative (1-[4-(2-methoxybenzyl)-6-methyl phenyl pyridazine-3(2H)-ylidene] hydrazine shows the highest biological activity than the former product (Kandile, Mohamed, Zaky, & Mohamed, 2009). Hydrazone derivatives containing transition metal complexes are synthesized and evaluated for antimicrobial activity of N2-substituted alkylidene/arylidene-6-phenylimidazothiazole-3-aceticacidhydrazides, which show antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis. (Deep et al., 2010) designed biphenyl-4-carboxylic acid hydrazide which has the potency against a harmful strain of Escherichia coli, Pseudomonas aeruginosa and positive strain of Bacillus subtilis, Staphylococcus aureus. New sulfonylhydrazone derivatives and their nickel complexes show their antibacterial activity against gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, Bacillusmagaterium) and gram-negative bacteria (Salmonella enteritidis, Escherichia coli) by using Minimum Inhibitory Concentration (MICs) method. Some of the important structures bearing antimicrobial activity have been mentioned in Figure 3 .

Anti-malarial activity

Malaria is a global burden as it causes morbidity in developing countries. (Melnyk, Leroux, Sergheraert, & Grellier, 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-Butyl-phenyl derivatives showed maximum potency without 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-oxygen-species) 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 –NO₂ and –OCH₃ group enhanced the anti-oxidant activity of the synthesized compounds (Kamboj, Randhawa, & Saluja, 2014). Significant anti-oxidant activity of hydrazones attached with imidazoline ring was reported in the previous research.

Coumarin, a benzo-pyrone derivative, is a significant 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). Anti-oxidant 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 activity against the breast cancer cell line (MCF7) of humans (Al-Said, Bashandy, Al-qasoumi, & Ghorab, 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-3-kinases) p110α inhibitors were evaluated against the human tumour xenograft model (Kendall et al., 2012). Some imidazo-[1,3,4]-thiadiazole-5-carbohydrazides (Figure 6B) were reported to be useful for their inhibitory effects on the growth of a wide range of cancer cell lines (Cocco, Congiu, Lilliu, & Onnis, 2006).

Some novel substituted phenyl methylene-imidazole-thiadiazole-carbohydrazidehydrazones were synthesized and evaluated for the anti-cancer activity in human cell lines.

The cytotoxic action of acyl hydrazones was evaluated against leukaemia (HL-60) and melanoma. Benzimidazole-hydrazone derivatives were reported as active anti-cancer compounds as they showed potent effect against different cell lines like epithelial cells of alveoli (A549), lung tissue-adenocarcinomas (PC-9), colorectal cell line (HCT116), liver (HepG2) and melanoma cell line (A-375) (Liu et al., 2012).

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 benzoyl-pyridine 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 & Rady, 2009). Acyl-hydrazones were synthesized with natural amino acids and triethylamine. These acyl-hydrazones derivatives were targeted against HIV (human immune deficiency virus) type-1, and promising results were obtained in which EC₅₀ were reported as 0.21 and 0.17 µM (Tian et al., 2009).

Anti-inflammatory activity:

Inflammation is a localized physical, chemical or biological response of the immune system, understanding by injury any process able to cause tissue or cellular damages. Non-steroidal anti-inflammatory drugs (NSAIDs) of different classes were used as analgesics and hence used in the treatment of pain and inflammation. In the past years, aryl hydrazones were synthesized as the derivatives of mefenamic acid (Figure 7A) and were evaluated for the anti-inflammatory effects (Almasirad et al., 2005).

The synthesis of zinc(II) complexes with salicylaldehyde-2-chlorobenzoyl hydrazone (Figure 7B) and its region isomersalicylaldehyde-4- chlorobenzoyl 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 inflammation. 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-inflammatory drugs (Hernández et al., 2012).

Some novel aryl-hydrazones were successfully evaluated for anti-inflammatory activity. Pyridyl-aryl-hydrazone derivatives were also proved to be potent for the analgesic and anti-inflammatory 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, Saideepa, & Praneetha, 2011). Salicaldehydechlorobenzyl (2 and 4 substituted) hydrazones and their complexes with zinc were evaluated for the anti-inflammatory and anti-nociceptive activity in animal models, and all the compounds were reported for their significant 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 synthesized from diclofenac, methanol, sulphuric acid with dichloro substituted phenyl amino phenyl Aceto-hydrazides for the in-vivo antimycobacterial activities against Mycobacterium tuberculosis.

The findings showed that 1-cyclopropyl-6-fluoro-8-methoxy-7-[N4-(2-(2-(2,6-dichloro phenylamino)phenyl) acetyl)-3-methyl]-N1-piperazinyl]-4-oxo-1,4-dihydro-3- quinoline carboxylic acid was proved to be the most active candidate while compared with standard drug Isoniazid (Sriram, Yogeeswari, & Devakaram, 2006).

Researchers used coumarin-4-acetic acid hydrazides to synthesize benzylidene derivatives that were evaluated against M. tuberculosis. The benzylidene hydrazide derivatives (Figure 8B) of 4-adamantan-1-yl-quinoline-2-carboxylic acid showed the maximum inhibition (99% at 1µg/ml) while comparing with isoniazid, the standard treatment. 4-(adamantan-1-yl)-2-substituted quinolines were also tested for the same. Some heterocyclic arylidene-hydrazide derivatives were also synthesized and evaluated their derivatives for the in-vitro antimycobacterial activity against the tested strain of Mycobacterium tuberculosis and Mycobacterium avium (Mamolo et al., 2003).

Conclusion

The synthesis and application of medicines from bioinorganic complexes is a rapidly developing field due to the formation of stable compounds in coordination chemistry. The metal complexes and their parent ligands have a significant 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‑inflammatory, anti-cancer properties, so this review article focuses the development of newer compounds from hydrazones with proper designing, synthesis and structure-activity relationship (SAR).