Synthesis of Isatin and Its Derivatives and their Applications in Biological System

Here investigations were made to study the variant developments in the synthesis of isatin and its derivatives. This review comprehended the various synthetic methods especially, sandmeyer synthesis, stolle synthesis and gassman synthesis for the synthesis of isatin. The isatin and its derivatives played a key role in biomedical applications. The isatin and its derivatives are used as bactericide, fungicide, anti-HIV, anti-epileptic, anti-instigative and so on. The isatin derivatives are helpful in inhibiting the activity of the urease and α-glucosidase enzymes and reduce the risks of pyelonephritis, gastric problems and diabetes. This review highlighted the synthetic routes for the synthesis of isatin and the beneficial aspects of isatin and its derivatives in biomedical field. Inhibition; α-Glucosidase Inhibition; Antioxidant Activity; Sandmeyer Synthesi and and


Introduction
Isatin is an indole derivative firstly synthesized in the laboratory by Erdmann and Laurent by oxidation of indigo pigment having chromic acid. It is orange-red in color with freezing point 200 0 C [1,2]. Isatin is heterocyclic compound and acts as important species for the synthesis of various heterocyclic compounds especially, indolic and quinolinic compounds. It is also used in medicines synthesis (Figure 1). Thiosemicarbazide derivatives of isatin were reported as an anti-HIV agent [3]. N-methyl isatinβ-4',4'-diethylthiosemicarbazone prove high inhibition of HIV by their action on contrary transcriptase and viral structural proteins [4].
Zhang et al. first reported the vinylogous, henry reaction between isatin and 3,5-dialkyl-4-nitroisoxazole, leading to isoxazolesubstituted 3-hydroxy-2-oxindole derivatives, medicinally important compounds [20], also provided the basis for removal of industrial dye wastewater [21]. In this study, we discuss with detail "Synthesis of isatin and its derivatives and their applications in biological system" because isatin play a key effects like ascorbic acid, hydroxyl amino acids, omeprazole, thiol compounds and imidazole etc. which is helpful for the pathogenesis of gastric ulcer and peptic ulcer.
Also discuss antioxidants, which are responsible for converting free radicals into stable substances, especially serious diseases caused by diabetes. We can say, that isatin provides a critical and dynamic role in the pharmaceutical industry.

Sandmeyer Synthesis
One of the most famous techniques for the synthesis of isatin is Sandmeyer method. Aniline reacts with chloral hydrate and hydroxylamine hydrochloride conducting aqueous solution of sodium sulfate to produce an isonitrosoacetenilide. In this way, isonitosoacetenilide in the presence of sulphuric acid easily converted into isatin analogs [22] (Figure 2).

Gassman Synthesis
Gassman introduced a new approach, to synthesize isatin.

Urease Inhibition
Urea, which is well-known fertilizer used for the enhancement of fertility of the soil, urea contains (46%) nitrogen. This urea release nitrogen in the form of ammonia gas due to which its action of fertility is also affected [60]. Urease is a well-known enzyme has nickel in their body structure which convert urea to carbon dioxide and ammonia by hydrolytic catalysis [61]. This typical enzyme is isolated by the same catalysis process from different plants, algae, fungi and bacteria [62,63]. As this enzyme has the same amino acid sequence and having Ni +2 in their core structure that is why its origin is very common [62,64,65]  Helicobacter pyroli is the well-known bacterium which causes gastric and peptic ulcer [69]. This bacterium discharge urease which converts urea to ammonia which is basic in nature which increases the pH of the stomach and provides a good environment for their growth. This enzyme is very useful to eradicate the toxic organism from our body [70]. Recently, numerous urease enzymes have been added to literature especially triazoles and coumarin derivatives [71], Schiff bases derivatives [72], omeprazole [73], plan tool and its thiourea derivatives [74], hydroxamic acid [75], lansoprazole [76], thiol-compound [77], phosphorodiamidates [78,79], imidazoles, for example, rabeprazole [80], hydroxyurea [81], quinine [82] and hydroxamic acid derivatives [83]. α-glucosidase is also regarded as exoglycosidase enzyme.

α-Glucosidase Inhibition
This enzyme is present in the intestinal tract which hydrolyzed the carbohydrate and converted into glucose. This glucose is then entering the bloodstream and its excess causes postprandial hypoglycemia [84]. The main aim of the α-glucosidase inhibitors is to delay the hydrolysis of carbohydrate to reduce the risks of diabetes [85], that's why this enzyme is preferably used in anti-diabetic medicines [86]. α-Glucosidase inhibitors retard the function of α-glusidase, which is responsible, to convert carbohydrate into glucose. So, in this, way it, reduces the glucose level in the blood stream and hemoglobin [87].

Antioxidant Activity
Free radicals are atom or molecule with an odd electron in their outmost shell [89], are highly unstable and always in search to gain an electron from any species to complete its outermost shell in order to make itself stable. In our body, during the metabolism process of oxygen, any free radicals are generated in mitochondria.
So, it is very important to eradicate these free radicals, if it is not so, they will cause different diseases especially malignant neoplastic disease, disease relating to the brain and the blood vessels, dotage, heart disease, ulceration, diabetes, heart disease, mucoviscidosis, agedness, gastrointestinal ulcer and acquired immune deficiency syndrome [90,91]. So, to overcome this problem antioxidants are used, because their main function is to convert these highly unstable free radicals to stable substances. Antioxidants are used in a large number of medicines which are used to cure the diseases caused by the free radicles [92][93][94]. Here also experimental and theoretical results, compatible with (H25MI3ClPT) and (H25MI3PT) concentration of free radical scavenging in DPPH. The proportionality increased in the antioxidant activity. In particular, it is theoretically confirmed that the antioxidant activity of DPPH products with high energy volume (H25MI3ClPT) -IC50 is lower than (H25MI3PT)-DPPH products [95].

Conclusion
In this paper, isatin and its derivatives were studied and evaluate their biological activates, such as urea enzyme inhibition, alphaglucosamine inhibition and antioxidant activity. Various synthetic methods especially, sandmeyer synthesis, stolle synthesis and gassman synthesis were discussed for the synthesis of isatin. The isatin and its derivatives played a phenomenal role in biomedical applications. The isatin and its derivatives are used as bactericide, fungicide, anti-HIV, anti-epileptic, anti-instigative and so on. The isatin derivatives are useful in constraining the natural action of the urease and α-glucosidase enzymes and reduce the threats to human health like pyelonephritis, gastric problems and diabetes.

Compliance with Ethical Standards
Conflict of Interest: The authors declare that they have no conflict of interest.
Ethical Approval: This article does not contain any studies with human participants or animals performed by any of the authors.