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Hydrazides and Isoniazid Literature Review

Hydrazides are often produced by reacting acid compounds with hydrazine, such as acyl halides, amides, esters, cyclic anhydrides, and acid chlorides. Heating suitable hydrazides of heterocarboxylic or carboxylic acids with distinct ketones or aldehydes in certain organic solvents like methanol, butanol or ethanol, is the major method to synthesize hydrazide compounds (Bodkea et al, 2017). In this synthesis method, spectral techniques can readily validate the molecular structure of produced hydrazide compounds. Three distinct bands may be seen in the infrared spectrum. Bands at 1550 cm1 indicate the existence of the cyanide group (C=N). The carbonyl group (C=O) has a distinctive band of about 1650 cm1, while the ammonia (NH) group has a band of approximately 3050 cm1 (Bodkea et al, 2017).

Numerous physiologically significant hydrazide–hydrazone combinations with a variety of functional groups have been produced in the past few years from various carbonyl compounds (Popiolek, 2017). Anticonvulsant, anticancer, antiprotozoal, antiviral, and anti-inflammatory effects were discovered (Chavan et al, 2019). Among the biological characteristics of this family of chemicals, antibacterial activity is the most commonly observed in studies. Furthermore, commonly used chemotherapeutic drugs such as nitrofurazone, furazolidone, and nitrofurantoin are known to include the standard hydrazide–hydrazone structure in which the carbonyl group and nitrogen atom are contained in the same molecule (Duangdee et al, 2020).

There are also several ways through which hydrazides can be synthesized. Starting with, it can be done through a process of nucleophilic substitution of the appropriate methyl esters with hydrazine hydrate (Nath et al, 2018). The nucleophilic substitution of easily removing groups that are, CH3S, Cl, and CH3O at position 2 of the pyrimidine ring, (Petkowski et al 2018), occurs when 2-substituted 5-pyrimidinecarboxylic acid methyl esters combine with hydrazine hydrate at zero to five degrees (Liang et al, 2020). The reactivity is followed by the production of hydrazides when heating with an 80 percent organic compound of hydrazine hydrate. Other hydrazides such as lithium hydrazide can be prepared through dissociation of the required hydrazine using an alkyl-lithium base (Volynets et al, 2019).

Isoniazid, also described as an isonicotinic acid hydrazide, has a very basic chemical structure composed of a hydrazine group and a pyridine ring in para position, linked to the pyridine nitrogen (Fernandes et al, 2017). Isoniazid is made by combining hydrazine hydrate and 4-cyanopyridine in an aqueous alkaline solution at 100°C with reflux for an average of seven hours, followed by crystallization of ethanol, resulting in a 62 percent yield of the required chemical (Novotna et al, 2017).

Alternatively, isoniazid may be synthesized from isonicotinic acid in a two-step process. Initially, acid-catalyzed esterification involving ethanol converts isonicotinic acid to an isonicotinic acid-ethyl ester (Gosavi et al, 2019). In the process, the acid protonates the carbonyl group at the start of the reaction, making the carbon increasingly reactive. Now that ethanol has begun a nucleophilic engagement with this carbon, the proton is migrated to the nicotinic acid hydroxide group, and water is produced (Brown a. et al, 2019). Additionally, a proton is released. As a result, the catalyst degenerates, and isonicotinic acid ethyl ester is produced as an intermediate product (Gosavi et al, 2019). Except for the absence of an acid catalyst, the resulting aminolysis is equivalent to esterification (Brown b. et al, 2020). The carbon is therefore oxidized by hydrazine, making ethanol to be separated, leaving isoniazid as the final product.

As suggested by researchers in 1956, isoniazid may also be made from citric acid through a method that involves 2,6-dichloroisonicotinic acid, ethyl isonicotinate, citrazinic acid, and isonicotinic acid (Hu et al, 2017).

Isoniazid’s antibacterial action is specific for mycobacteria, most possibly because it inhibits mycolic acid production, by disrupting cell wall formation, resulting in a bactericidal activity (Badar et al, 2020). It is utilized in combination with other drugs when treating active tuberculosis infections (Mansoori et al, 2017). It can also be taken on its own to prevent active tuberculosis infections in persons who have been exposed to the bacterium (those with positive TB skin test) (Bhilare et al, 2018). The drug also prevents bacteria from growing.

Bonnett et al had earlier discovered a group of hydrazones that were effective against Mycobacterium tuberculosis (Bonnett et al, 2018). He and his team chose 5 sample compounds to investigate extensively. All of the chemicals were effective towards non-replicating Mycobacterium tuberculosis, with two of them having higher effectiveness in hypoxic over aerobic culture (Bonnett et al, 2018). The compounds exhibited bactericidal action towards aerobically reproducing bacteria with an MBC/MIC of four and an inoculum-dependent impact (Bonnett et al, 2018). Microbial death kinetics showed that non-replicating bacilli bacteria formed by nutrition shortage were killed at a quicker rate. The remaining species of bacteria were resistant to the compounds. In terms of anti-tubercular action, they concluded that hydrazones have certain appealing characteristics (Bonnett et al, 2018).

Moreover, Volynets et al created 10 isoniazid derivatives and tested them for antimicrobial efficacy against Mycobacterium tuberculosis SRI 1369 and H37Rv, an isoniazid-resistant bacterium (Volynets et al, 2020). Just one chemical, isonicotinic acid, was shown to be efficacious against isoniazid-resistant strains, with minimal inhibitory activity of 0.14 M. This chemical is non-cytotoxic to human liver cells HepG2: IC50 >100 M and has a high permeability in Caco-2 cells (Hakkimane et al, 2018). The unbonded percentage of isonicotinic acid, which may have a pharmacological effect, is 57.9%, as per the findings of a plasma protein binding experiment (Volynets et al, 2020).

Castelo-Branco et al created two distinct acyl hydrazides and tested their effectiveness over various Mycobacterium tuberculosis strains (Castelo-Branco, 2018). Isoniazid derivatives exhibited significant anti-Mycobacterium tuberculosis activity, with some being more powerful than all first-line anti-tuberculosis medicines (Castelo-Branco, 2018). Furthermore, 3 compounds were shown to be better effective toward resistant Mycobacterium tuberculosis than isoniazid. Two of the compounds performed well in the Ames test in comparison to isoniazid, with one of them exhibiting much-reduced toxicity to HepG2 cells than isoniazid (Castelo-Branco, 2018). This finding suggests that the isoniazid compound can mitigate one of the drug’s most serious side effects on the body.


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