Pharmacological aspects of hydrazides and hydrazide derivatives Farmakologiczne aspekty hydrazydów i pochodnych związków hydrazydowych

Intensywne poszukiwania nowych leków przeciwbakteryjnych, łącznie ze środkami przeciwguźliczymi, dyktowane są występowaniem zjawiska wielolekowej oporności bakteryjnej. Hydrazydy uważane są za kluczowe intermediaty i wartościowy początkowy materiał dla nowych biologicznie aktywnych związków chemicznych. Ocenę biologicznych właściwości przeciwbakteryjnych lub/i przeciwgrzybiczych wykonuje się dla ponad 70% ostatnio zaprezentowanych syntetycznych pochodnych hydrazydowych. Najpowszechniej stosowanym hydrazydem jest przeciwgruźliczy lek izoniazyd/hydrazyd kwasu izonikotynowego (NIH). Hydrazydowe związki chemiczne posiadają charakterystyczną wspólną grupę funkcjonalną, w której występuje wiązanie kowalencyjne azot-azot, z czterema podstawnikami, z których przynajmniej jeden stanowi acyl, z kolei pochodne związki hydrazynowe nie posiadają grupy acylowej. Hydrazydy mogą być dalej sklasyfikowane na podstawie rodzaju pierwiastków przyłączonych do tlenu: karbohydrazydy, sulfonohydrazydy, fosfodihydrazydy, hydrazydy hydrazonowe oraz hydrazydy ftalowe. Poza właściwościami przeciwbakteryjnymi i przeciwgrzybicznymi, pochodne związki hydrazydowe stały się ostatnio Musa T. Abidov*


Streszczenie
Hydrazides are important starting materials for a wide range of derivatives, uti-lizable as potential pharmaceutical products for human use.Over 70% of recently reported synthetics of hydrazide deriva-tives were evaluated for antimicrobial and/or antifungal activity in preclinical studies (Table 1).

Synthesis of hydrazide derivatives
Reference Intended use as a pharmaceutical product

Hydrazones and hydrazone-hydrazides
Hydrazones possess an azometine -NHN=CH-proton that has found broad utility in organic synthesis.The biological activities and applications of hydrazone derivatives were reviewed by several authors [33][34][35][36].The synthesis of novel hydrazone derivatives is promising because of their potential use as antimicrobial or therapeutic drugs.For example, new aryl hydrazone derivatives, containing thiazole moiety, displayed a fair degree of antimicrobial activity [23].Analgetic activity of new hybrid molecules, containing both hydrazone and 2-phenoxyphenyl structures, was confirmed in vivo [37].Some changes were made in normal bilirubin level [10,11].

Isoniazid
The most frequently applied and studied anti-tuberculosis agent is isoniazid, isonicotinic acid hydrazide (INH).Some 60 years after its discovery, isoniazid is still a centerpiece of anti-tuberculosis therapy.According to some authors, the drug itself is not toxic for Mycobacterium tuberculosis, however, after passive diffusion into the mycobacterial cells, acts as (Table 1), diarylquinoline derivatives and nitroimidazo-compounds.

Hydrazide safety issues
Generally, substituted amides and hydrazides of 1,4-dicarboxylic acid, as well as their linear derivatives (esters, amides and hydrazides) were characterized by low toxicity [44].Isoniazid is cleared mostly by the liver, primarily by acetylation to acetyl-izoniazid and further to mono-acetyl hydrazine (MAH) and to nontoxic diacetyl hydrazine [42].The incidence and severity of DILI in tuberculosis patients taking isoniazid is variable in different geographic groups and those co-infected with HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV).Patients with polymorphism of fast acetylation excrete more than 90% of the drug as acetyl-isoniazid, whereas at slow acetylation polymorphism, 67% of the drug is excreted as acetyl-izoniazid, and to a substantial degree as unchanged drug.
The cause-effect relationship between acetylation rate and isoniazid-related DILI is controversial [45].Satisfactory safety data and promising pharmacotherapy effects were reported for different treatment protocols for phthalhydrazide tamerit/galavit [10,11], although teratogenicity, mutagenicity and carcinogenic potential of phthalhydrazides require further elaboration.Phthalhydrazide luminol did not exhibit mutagenic activity in Salmonella typhimurium test with or without S9 metabolic activation [46].

Hydrazide anti-inflammatory activity
Common target in many therapeutic ef- For example, comparable to the standard drug diclofenac, several nicotinic acid hydrazides having NO2 substitution at ortho and meta position, exhibited comparable anti-inflammatory activity [48].
Involvement of macrophages in human inflammatory diseases can be both detrimental but also protective.According We hope to evidence the macrophage-targeting effects of phthalhydrazide galavit/ tamerit (monosodium 5-amino-2,3-dihydro-1,4-phthalazine dione), as the macrophage silencing was observed both in preclinical and clinical studies [10,11].
In summary, macrophage deletion might not be the ideal clinical approach since macrophages can fulfill both detrimental and protective functions.However, macrophage-specific therapeutic strategies are expected in combating inflammation [54]. Piśmiennictwo/References: Abbreviations: DILI: drug-induced liver injury, ESBLs: extended-spectrum β-lactamase bacteria, HBV: hepatitis B virus, HCV: hepatitis C virus, HIV: human immunodeficiency virus, INH: isonicotinic acid hydrazide (isoniazid), IL 1: interleukin 1, MAH: mono-acetyl hydrazine, MRSA: methycillin-resistant Staphylococcus aureus, NSAIDs: non-steroidal anti-inflammatory drugs, ROS: reactive oxygen species, TNF-α: tumor necrosis factor-α, VRE: vancomycin-resistant enterococci, WHO: World Health Organization.General characterization of hydrazones and hydrazides Over the past few decades, intense search for new antibiotics is dictated by the phenomenon of bacterial multidrug resistance.Common multidrug-resistant bacteria are vancomycin-resistant enterococci (VRE), methycillin-resistant Staphylococcus aureus (MRSA), extended-spectrum β-lactamase (Gram-negative) bacteria (ESBLs), Enterobacter the aryl group attached to acyl and imine subunits at N-acetyl hydrazide (NAH) moiety.These NAH derivatives were ex-amined in vivo in acute inflammation model showing anti-tumor necrosis factor-alpha (TNF-α) and anti-inflammatory properties.All these new compounds reduced leukocyte migration, TNF-α level, NO production, inhibition of NF-κB enzyme expression and inhibition of ROS production, however with poor aqueous solubility [38].A series of hydrazones of 1,2-benzisothiazole hydrazides as well as their cyclic and acyclic 1,2-benzisothiazole parent hydrazides, were synthesized and successfully evaluated as antibacterial and antifungal agents [1].Generally hydrazone-hydrazides are known as antimicrobial compounds with activity against both Gram-positive and Gram-negative microorganisms.Derivatives of hydrazide-hydrazone play an important role in development of various pharmacolog-as anticonvulsant, antimalarial, analgesic, anti-inflammatory, antiplatelet, antimicrobial, antihypertensive, antiviral, anti-tubercular, antiproliferative and antitumor activities.Phthalhydrazides Phthalhydrazides, bicyclic nitrogen-containing phtalimide derivatives, are wellknown heterocyclic chemicals possessing biological, industrial, and other properties including chemiluminescence phenomenon of cyclic diacylhydrazide/ luminol (5-amino-2,3-dihydrophtalazine-1,4-dione).A number of methods have been reported for the synthesis of phthalazine derivatives including reaction of phtahlhydrazide and acetylendedicarboxylates in the presence of N-heterocycles[39].Pyrazolones are heterocyclic compounds containing one ketonic group and two nitrogen atoms adjacent to each other[40].A new series of pyrazolo[1,2-b] phthalazine derivatives bearing 5-aryloxypyrazole nucleus was evaluated for their antimicrobial, anti-tuberculosis and antioxidant activities[41].Phthalhyd razide galavit /tamerit (monosodium 5-amino-2,3-dihydro-1,4-phthalazine dione), available for over two decades in Russian Federation[10,11], was applied in addition to standard therapies in patients of different age (10-75 years) with several pathologies, sometimes with concomitant diseases.Clinical effects of this phthalhydrazide derivative were described in viral hepatitis B, viral hepatitis C, otitis media, chronic bronchitis, children typhoid fever, benign prostatic hyperplasia (BPH), female endometriosis, and in wounds healing [10].Generally the positive clinical effects of the tamerit/galavit therapy were related to a better control of ongoing inflammatory processes in the course of disease.Importantly, in all cases/diseases mentioned, no worsening of the patients' condition was observed after the tamerit/galavit treatment and not a single patient has developed any drug-related adverse effect.It is worth to point out that no adverse effects were noted in the viral hepatitis patients under prolonged tamerit/galavit therapy.Concentrations of serum cytokines interleukin 1 (IL-1) and TNF-α and enzymatic markers of liver damage significantly decreased in tamerit/galavit-receiving patients, as compared to standard therapy, indicating low risk of the incidence of drug-induced liver injury (DILI).Overall clinical signs of the disease were less pronounced at the end of the tamerit/galavit therapy, including diminished fatigue, appetites improvement, disappearing of skin itching, and prodrug and is enzymatically activated by the bacterial multifunctional catalase-peroxidase KatG [42].Isoniazid inhibits the synthesis of mycolic acid, a component of the mycobacterial cell wall.Also some enzymes involved in fatty acids biosynthesis are believed to be targets of activated isoniazid [2].Co-infection with tuberculosis of people living with human immunodeficiency virus (HIV) is the most frequent life-threatening mix of diseases.A preventive therapy 300 mg isoniazid daily for at least 6 months is recommended by World Health Organization (WHO) for adult and adolescent people living with HIV.In children living with HIV the isoniazid preventive therapy reduced early mortality by 50% and incidence of tuberculosis by 70% [43].The anti-tuberculosis effects of isonizid include inhibition of the bacterial cell wall lipid synthesis, depletion of nucleic acid pools and metabolic depression, however, a strong selec-tion for INH-resistant mutants is possible at a site of the katG gene.Mycobacterial resistance to INH trigerred development of new potential antimycobacterial agents, including isoniazide derivatives forts to improve patients-relevant outcomes related to chronic inflammation is combating the oxidative stress.Inflammation, oxidative stress and production of reactive oxygen species (ROS) are frequent symptoms of degenerative diseases, autoimmunity, cancer and infections.High nonphysiological ROS generation can lead to DNA damage, lipid peroxidation, protein modification, and other pathological effects.Pharmacotherapeutic strategies based on scavenging of pro-oxidant molecules, however, can be unsuccessful [47].Also treatment of inflammation by the most prescribed pharmaceuticals, non-steroidal anti-inflammatory drugs (NSAIDs), can be frequently complicated by several adverse effects, particularly gastrointestinal bleeding, ulceration and perforation.Alternative strategies involve silencing of activated macrophages and granulo-cytes, inhibition of enzymatic elements of oxidative burst reaction, activation of endogenous antioxidant defense systems and possible functional repair of ROS-induced damage.For some targets, the respective pharmacology is advanced to clinical development, for others several drugs are already in clinical use [9,10,48].
to this bipolar model, the classically activated pro-inflammatory M1 phenotype can be possibly reprogrammed to anti-inflammatory M2 macrophages.For example, recruited by injury, the inflammatory monocytes mature to M1 macrophages, release ROS and proinflammatory cytokines, and attract neighboring monocytes to clear the wound debris and necrotic tissue.Once this process ter-minates, neutrophils undergo apoptotic elimination and second monocyte population arrive, mostly from tissue-resident macrophages.These monocytes evolve into M2 macrophages and govern the wound remodellng [52].Over the years, this M1/M2 classification has been proven to be too general as several other subpopulations have been described, demonstrating a continuum of different polarization states of macrophages.Pharmacological targeting of macrophages can be possible, reducing the expression and production of pro-inflammatory cytokines, including TNF-α [53].

Table 1 .
Recent applications of hydrazides as starting material for synthesis of pharmaceuticals for preclinical and clinical studies