Synthesis and Pharmacological Profile of Hydrazide Compounds

 

Ghufran Th. Sadeek¹, Zainab Faiyq Saeed², Mohanad Yakdhan Saleh¹*

¹Department of Chemistry, College of Education for Pure Science, University of Mosul. Mosul – Iraq.

²Department of Physiology, Biochemistry, and Pharmacology, College of Veterinary Medicine, University of Mosul.

 

ABSTRACT:

This class of compounds, which is known as Hydrazide has great significance in organic chemistry. This is the reason why methods of preparation of different types of compounds that are useful in many fields are studied here. It is characterized by containing an active group, which is (-CONHNH₂), which consists of two nitrogen atoms attached to four substitutes, and at least one of these substitutes must be an (acyl) or (aryl) group. It is known that these compounds have very important medical, pharmaceutical and industrial functions and applications. Some of them have been employed in the treatment of many common and dangerous diseases, such as respiratory diseases and malaria. In addition, they are highly useful in preparing some important drugs used in the treatment of some chronic diseases related to blood vessels and muscle spasms, showing a wide variety of biological activities, including antibacterial, mitigating, anticonvulsant, antiviral, and antiprotozoal activity. Moreover, they may be used as raw materials in preparing many classes of heterocyclic compounds, including oxadiazole and diazole compounds. Finally, they show significance in industrial applications, particularly in the manufacture of dyes, agricultural pesticides, and growth stimulants for plants and Agricultural crops.

 

 

 

1. INTRODUCTION: 

Hydrazide derivatives, which play an important role in organic and medicine Chemistry, have attracted a large number of researchers over the years because of their promising Biological activities, including  antimicrobial^1-4 anticancer^5-7_, anti-tuberculosis^2,8-10 Antiviral¹¹ and anticonvulsant² activities. According to their respective importance of these compounds, we are interested in collecting some of the literature numbers of methods for the preparation of hydrazide derivatives.

 

2. REACTIONS BETWEEN CARBOXYLIC ACIDS AND HYDRAZINE THERMAL DEHYDRATION OF HYDRAZINIUM SALTS:

The method of thermal drying of hydrazinium salts for the preparation of hydrazides is not commonly used, because of the precise conditions required by this method.

The percentage of the yield obtained, however, is good, as the researcher (co-worker and Kratzal) in 1958 prepared 1-acyl-1-methyl 2-phenylhydrazine compound (1) by reflux of acetic acid with 1-methyl-2-phenylhydrazine^12,13

 

3. CARBODIIMIDE METHOD:

According to this method, the compound N'-N-dicyclohexyl carbodiimide (DCC) is employed as a drying agent when reacting carboxylic acids with hydrazine, and such reactions usually take place at room temperature using dichloromethane as a solvent, and the percentage of the obtained product is good compared with the method of reaction of esters with hydrazine¹⁴. In 1968, researcher (Smith & co-worker) was able to prepare several hydrazide substitutes, which are those of compound (2), through the reaction of a series of aromatic carboxylic acids with hydrazine in the presence of (DCC) as a drying agent¹⁵.

 

 

3.1 N-AMINATION OF AMIDE:

3.1.1 Schestakov’s reaction:

Through this reaction, hydrazide can be obtained in a similar way to (Hofmann's amide degradation) reaction, as this reaction involves the conversion of monoacyl urea compounds with sodium hypo chlorate as a catalyst into hydrazide. The obtained benzoic hydrazide is shown in the following equations:¹⁴

 

3.1.2. N-amination with sodamide:

In this method, N-chloroamide compounds obtained from secondary amides are used and then reacted with sodium amide to obtain hydrazide, for it is quite possible to obtain mono-compensated hydrazide when using sodium amide. When using sodium salts of the substituted amide such as Sodium acetanilide, however, it is obtained on diacyl hydrazine as shown below¹⁵:

 

 

3.1.3 N-amination with 0-(2, 4-dinitrophenyl)hydroxylamine

Ortho (2, 4-dinitrophenyl) hydroxylamine is a very effective amine introduction agent for nucleophile nitrogen compounds. In 1968, the scientist (Sheradsky) obtained the compound N-aminophthalmide (6) with a percentage of 88% through the reaction of phthalimide anion, and with the above reagent, as noted in the following reaction¹⁶

 

 

4. HYDROLYTIC METHODS:

4.1 Hydrolysis of nitrile:

The method of hydrolysis of nitriles proves of no practical importance in the preparation of hydrazides due to the side reactions that accompany this method, as hydrazide is obtained through partial hydrolysis of nitriles to convert them to amides and then react the latter with hydrazine. Gasson & co-worker, as well as researcher Dutta & co-worker, managed to obtain isonicotinic hydrazide (7) in one step by heating 4-cyanopyridine with aqueous hydrazine in the base medium^17,18, yet the percentage of the product shows that the obtained results are not good due to the formation of the compound 5,3-di(4-pyridyl)-4,2,1-triazole as a by-product due to the instantaneous cycle between the formed hydrazide and the unreacted nitrile. Nevertheless, the proportion of the formed hydrazide can be increased to 65% by converting nitrile to amide using a dilute solution of sodium hydroxide first and then heating the reaction mixture with aqueous hydrazine ¹⁹

 

 

In addition, the reaction of cyclohexane-1,3-dione with either malononitrile or ethyl cyanoacetate resulted in the 4-amino-6,7-dihydro-5H-chromene-5-one derivatives, respectively. The reaction of the latter compounds with cyano acetyl hydrazine gave the hydrazide–hydrazone derivatives²⁰

 

4.2 Hydrolysis of hydrazidic halide:

The hydrazides (8) could be obtained through the hydrolysis of hydrazide bromides, which are easily gained by brominating aldehydes hydrazone using a mixture of acetic acid and acetic anhydride as solvent^21. In a good percentage, the hydrolysis of alkyl hydrazide bromides is usually carried out using aqueous acetone at a temperature of 70°C²², the hydrolysis rate of the decompensated compounds is faster than that of the mono-compensated compounds²³, while the aryl hydrazide bromides are hydrolyzed using 50% dioxane at a temperature of 100°C or using dimethylformamide at a temperature of 150 and in the presence of potassium bicarbonate²⁴ as shown in the equations below:

 

 

5. ACYLATION OF HYDRAZINE:

The reactions of hydrazine and aryl or alkyl hydrazine compounds with different acyl reagents are among the most widely used methods for preparing hydrazides.²⁵_.

 

5.1 Hydrazinolysis of amide:

Through this method, amides can be converted into hydrazides by heating the amide with aqueous hydrazine. This process takes a long period. In 2009, the researcher (Siddiqui & co-worker) prepared the compound (9) benzoic hydrazide by heating it with 1H-imidazole-1-y1) (phenyl) methanone from aqueous amide hydrazine for (16) hours according to the following equation :²⁶

 

5.2 Acylation with ester:

The method of preparing hydrazides through the reaction of esters with aqueous hydrazine is one of the best and most practical methods. This reaction can be carried out without using a solvent (milling method) or in the presence of a solvent such as ethanol or other organic solvents. Furthermore, this reaction can be carried out in different conditions. For example at room temperature or during heat escalation, it is most used²⁷_.

 

In 2009, a researcher (Ghoneim) was able to prepare 3-(3-cyano -4-phenyl 5,6,7,8- tetrahydroquinoline -2-yl ) propanhydrazide(10) by sublimating the corresponding ester with aqueous hydrazine, using ethanol as a solvent. The interaction is as shown below:²⁸

 

 

 

In 2012, researchers Samshuddin & co-worker were able to prepare the compound (11) difluoro-5-hydroxy-[1,1':3',1"-terphenyl]-4 carbohydrazide-4,4" through sublimation of the corresponding ester with aqueous hydrazine, using ethanol as a solvent for the reaction and as shown in below:²⁹

 

 

 

In 2012, researchers Kumar & co-worker prepared a series of substituted benzoic hydrazide (12) by grinding a mixture of substituted esters of benzoic acid with aqueous hydrazine for fifteen minutes at room temperature, and the result was (92-82%), as is shown below:³⁰

 

 

 

Researchers Joshi & co-workers 2013 were able to prepare 4-pyryl benzohydrazide (13) from the sublimation of the corresponding ester with aqueous hydrazine using ethanol as a solvent for the reaction. This is shown in the following equation : ³¹

 

 

At the same time, researchers Srivastava & co-worker 2013 prepared the compound (14) hydroxy-6-phenoxybenzohydrazide-2 from the reaction of the corresponding ester with aqueous hydrazine at room temperature, using ethanol as a solvent for the reaction as shown in the following equation³²:

 

5.3 Acylation with acyl chloride and anhydride:

The reaction of carboxylic acid chlorides and anhydrides with aqueous hydrazine is a very violent and rapid reaction that is needed to prepare hydrazides. in presence of one of the suitable solvents such as diethyl ether³³, benzene^34, or hexane^35, and then Add aqueous hydrazine drop by drop at a low temperature.³⁶

 

 

 

This method is used to prepare hydrazides if the ester of the carboxylic acid to be converted into the corresponding hydrazide is of little reactivity or if hydrazine derivatives with weak basic character are utilized³⁷.

 

 

 

In 2010, scientists Aanandhi and co-workers prepared nicotinic hydrazide (16) by converting carboxylic acid to acid chloride, using phosphorous pentachloride, and then converting the latter to the corresponding hydrazide through the use of aqueous hydrazine at a temperature of zero degrees Celsius. This is illustrated in the following interaction³⁸:

 

 

Also, researcher (Mohamed) prepared, in 1912, a new compound hydrazide (17) by sublimating the corresponding acid chloride with aqueous hydrazine, employing ethanol as a reaction solvent for 10 hours, as shown below³⁶

 

 

5.4 Acylation with carboxylic acid:

In 2014, (Lukas Popiolek) synthesized 1,3-thiazolidine -4-one derivatives(18),(19) obtained from carboxylic acid hydrazides. These hydrazides were resultant from the solution of benzoic or nicotinic acid hydrazide with appropriate aromatic aldehydes, where corresponding N-substituted hydrazide derivatives in of 1,4- dioxane and mercaptoacetic acid gave 2,3-disubstituted -1,3- thiazolidine-4-one derivatives³⁹_.

 

 

In 2019, some researchers prepared admontane -1-carbohydrazide by esterification of 1-admontane carboxylic acid and methanol under the catalysis of 98% H₂SO₄^40, and in (2021) (amgad) can synthesize galloyl hydrazide through (esterification and hydrazinolysis reactions using both conventional heating and one-pot solventless greener microwave heating techniques⁴¹.

 

6. HYDRAZIDE COMPOUNDS DERIVED FROM OTHER METHODS:

In 2021, other scientists Surjit & Rajat synthesized organozinc hydrazide by reacting dialkyl zinc and hydralazine in the presence of secondary ligands. ⁴² Also, some researchers synthesized hydrazides directly from carboxylic acids which were ground with hydrazine hydrate under solvent-free conditions using the grinding technique²⁷.

 

 

 

 

6.1 Pharmacological profile of hydrazides derivatives:

The compounds of hydrazide have very wide medical, pharmaceutical⁴³ and industrial uses as the compound isonicotinic hydrazide (20), which was more intense in 1912 by Meyer⁴⁴ (Malley), showed biological efficacy as it was used as a drug compound in the treatment of tuberculosis, which was implemented in 1958⁴⁵.

 

 

 

As researchers, Rando & co-workers tested the effectiveness of a series of derivatives of the compound (21) Benzoic acid [(5-nitro-thiophene-2-yl) methylene] hydrazide against pulmonary tuberculosis and found that the compound shows a good antifungal activity.⁴⁶

 

 

 

It was also found that hydrazone compounds are involved in the treatment of many diseases, including breast cancer, malaria, pulmonary tuberculosis, muscular convulsions as well as the expansion of contracted blood vessels. Moreover, it was shown, for example, that the compound -4,5-E)-2-(4-amino-5-oxo-3-substituted)dihydro-1H-1,2,4-triazole-1-yl)-N-benzylideneacetohydrazide (22) is used in the treatment of breast carcinomas⁴⁷.

 

 

 

It was found that the derivatives of the (E)-N'-(4-substituted benzylidene)-1-(4-substituted phenyl)-4,5-dihydro-1H-pyrazole-4-carbohydrazide(23) display good activity against malaria⁴⁸.

 

 

 

The substitution of pyrazinoyl-thiosemicarbazide (24) indicated the highest activity against M. tuberculosis H37Rv ⁽⁴⁹⁾

 

 

 

Two series of 4-thiazolidinones and thiosemicarbazides derived from diflunisal hydrazide were synthesized and screened by Kucukguzel et al. to support their anti-mycobacterial activity against M. tuberculosis H₃₇Rv in BACTEC 12B medium with the help of a broth microdilution assay, the Microplate Alamar Blue Assay (MABA). 1-(2^ـ, 4^ـ-Difluoro-4- hydroxyphenyl-3-carbonyl)-4-ethylthiosemi-carbazide (25) was discovered to offer 25% prevention of mycobacterial growth of M. tuberculosis at 6.25 µg/ml concentration⁵⁰.

 

 

 

In 2008, 2-phenyl-quinoline-4-carboxylic acid hydrazide compounds (26) were synthesized by some scientists and they proved to be therapeutically most active and values 0.1 µ g/ml and 800, the respectively maximum non-toxic range that has IC95 and chemotherapeutic index⁵¹

 

Furthermore, Hunoor et al. synthesized Co(II), Ni(II), Cu(II) and Zn(II)complexes with a new heterocyclic Schiff base led to derive condensation of isonicotinic hydrazide and 3-acetylcoumarin. When the compounds that had been synthesized were subjected to anti-TB activity, MIC was determined against M. tuberculosis H37Rv. The anti-mycobacterial activity results demonstrated that all of the compounds that have been tested have no inhibition more than standard. The activity of isoniazid came to be reduced remarkably in coupling with coumarin moiety. The activity of the synthesized compound, however, has improved two folds on a complication with Co(II) and Ni(II) metal ions⁵².

 

To arrive at the previously identified lead to the optimum, a series of pyrazine-2-carboxylic acid hydrazide derivatives needed to be subjected to synthesis and were noticed for their activity against M. tuberculosis in BACTEC 12B medium by means of employing a broth microdilution assay, the microplate Alamar Blue Assay (MABA) in the dose-response assay by Abdel- Aziz et al.⁵³

 

It was also found that hydrazone compounds have medical usage in the treatment of muscle convulsive disease, as it was also found that the compound(27)(E)-N'-(4-(benzyloxy)benzylidene)-N-(2-cyanoethyl) acetohydrazide has likewise therapeutic properties for this disease⁵⁴. 

 

 

Additionally, it was found that the derivatives of the (E) -N'-(thiophene-2-yl methylene) benzo [d][1,3]dioxole-5-carbohydrazide (28) are used for dilating constricted blood vessels⁵⁴ 

 

 

 

The reaction of cyclohexane-1,3-dione that has either malononitrile or ethyl cyanoacetate resulted in the creation of 4-amino-6,7-dihydro-5H-chromen-5-one derivatives^55-57. The coordination chemistry of hydrazide derivatives such as f (Z)-N -(4-Methoxybenzylidene) Benzohydrazide Ligand which is used in some other microbial activities⁵⁸ and 2-(2-hydrazinyl-1, 6-dihydro-6-oxopyrimidin-4-yl) acetic hydrazide are utilized extensively in mild steel corrosion inhibitors and other similar applications.^59.

In (2016)  Yi-Chao Huang, et al. could also synthesize a kind of proteins using hydrazide compound as an intermediate⁶⁰. And in  2018, another researcher whose name is Samir Y. Abbas, and his team synthesized some quinolone N-propionic and O-propionic hydrazide derivatives (29) as an antibacterial agent for different bacterial strains:^61-63

 

 

 

The reaction of the above-mentioned compounds with cyanoacetyl hydrazine yielded the hydrazide derivatives which are used against the activity of three human cell lines of cancer; namely, HCT116 (colon carcinoma cell), MGC803 (gastric carcinoma cell), and Huh7 (hepatoma carcinoma cell).^64-66  some hydrazides, including 5-bromobenzofuran-2-carboxylic acid hydrazine(30) were dealt with carbon disulfide and KOH in ethanol and other treatment with POCl to cyclized to  -(aryl)-3-(5-Bromobenzofurandihydro-[1,2,4]triazole[3,4-b][1,3,4]thiadiazoles. This type of compound triazoles combined with thiadiazoles was the most popular among the systems incorporated widely in a variety of therapeutically significant compounds that have a wide spectrum of biological activities, such as anti-tubercular, analgesic, pesticides, anthelmintic, herbicides, lubricants, colorants, and analytical Reagents^67-69.

 

2-Cyano-N-((2-OXO-1,2- dihydroquinoline -3yl)methylene) ethanohydrazide is dealt with some electrophilic compounds, including pyridine, pyrazole, thiazolidine derivatives to form other substances that have been screened there in vitro antiviral activities to stand and defend against infectious bursal disease virus (IBDV).^70-72                 

 

 

And 2-(1-methyl-1H-benzo[d]imidazol-2-ylthio) acetohydrazide derivatives which have Antifungal and antibacterial activities against some kinds of gram-positive and gram-negative bacteria⁷¹, Moreover E)-3-Amino-N′-benzylidene-7-cyano-1,6-dimethyl-4- (trifluoromethyl)-1H-indole-2-carbohydrazide (33which is made use of as anti-cancer for four human cancer cell lines, such as A549-lung cancer (CCL-185), MCF7-breast cancer (HTB-22), DU145-prostate cancer (HTB-81) and HeLa-cervical cancer(CCL-2).^74-78

 

 

 

7. CONCLUSION:

This review provides an outlook on the introduction and synthesis of hydrazide derivatives. Likewise, the review provides information about the pharmacological activity and structure-activity of these compounds and their significant characteristics as drugs.

 

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Accepted on 17.06.2022        © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(2):975-982.