Advances in Pharmacology of Isatin and its Derivatives: A Review

Isatin (1H-indole-2,3-dione), an indole derivative of plant origin, is involved in many pharmacological activities like antiallergic, antimalarial, antiviral and antimicrobial; isatin and its derivatives have been found to show promising results against various cancer cell lines. Isatin is a versatile precursor for many biologically active molecules and its diversified nature makes it a versatile substrate for further modifications. This review provides a brief overview on the recent advances and future perspectives on pharmacological aspects of isatin and its derivatives reported in the last decade.


INTRODUCTION
Isatin occurs in the leaves and roots of the Strobilanthes cusia (Nees) and was first isolated from plants of the Isatis tinctoria, Couroupita guianesis and Calanthe discolor in 1840 [1]. These plants are abundant in northern and central China and are of ethnic importance in traditional therapeutics. Despite of its presence in human brain isatin can also be found in secretion from the parotid glands of Bufo frogs and other biotic like; Caribbean tumorigenic plant, Melochia tomentosa, fungi and marine mollusks.
Isatin was first synthesized by Erdmann and Laurent in 1840 [2]. Isatin and triazole containing heterocyclic compounds are reported as a cure of lethal diseases [3]. Extensive literature has been published regarding the chemistry and medicinal importance of this compound including a few reviews [4]. Synthesis of isatin and its derivatives have gained great attention in recent years due to its biological potential like anticancer, anti-protozoa, cytotoxic and DNA cleavage.
In the literature, synthesis, reactivity and pharmacology of isatin have been extensively discussed but a brief account of pharmacological developments of isatin in the last decade is required. Current work is an effort to summarize the published pharmacological data of isatin and its derivatives.

PHARMACOLOGICAL PROPERTIES OF ISATIN
Isatin can be found in rat brain (mainly in hippocampus and cerebellum) as well as in other mammalian tissues where it functions as a modulator of biochemical processes [5]. Isatin and its derivatives have been reported highly efficient during in vitro studies against genotoxic and mutagenic diseases, but during in vivo, the genotoxic and mutagenic potential of isatin is not well established and reported. Isatin was first reported as "Tribulin" and was identified as a selective inhibitor of monoamine oxidase (MAO) [6].  Figure 1). Some of the pharmacological activities exhibited by isatin are discussed in this review and are listed in (Table 1).

Anti-asthmatic activity
Asthma afflicts more than 235 million people worldwide annually [17]. Traditionally, a potent remedy for asthma is treatment by inhalation of drugs, containing corticosteroids and long-acting beta agonists; which reduce swelling and body immune response but these drugs can contribute to serious side effects [18]. Encapsulated isatin in chitosan nanoparticles has been reported effective against allergic asthma [19]. Moreover, respiratory synctial viral infections can be among the reasons of asthma in infants [20] while during in vitro and in vivo studies benzimidazole-isatin oxime derivatives have been described effective against respiratory synctial viral infection [21]. Therefore, a more comprehensive and targeted research is required to find out potential drug molecules against asthma from the isatin derivatives.

Anticancer activity
Isatin and its derivatives have been found effective against a variety of cancer cell lines [ . In another study, isatin derivatives were evaluated in vitro against three human tumor cell lines, K562, HepG2 and HT-29 by using MTT assay, the studies suggested that the combination of 1-benzyl and 5-[trans-2-(methoxycarbonyl) ethen-1-yl] substitution greatly enhances their cytotoxic potential, however, an intact carbonyl functionality on C-3 as present in the parent ring is required for such a potency [30]. A variety of isatin derivatives have been found active against various cancer cell lines, therefore, isatin has a potential for structural modifications in search of an anticancer molecule.

Antimalarial activity
In 2010, malaria epidemic caused the death 7 million children infected with Plasmodium falciparum, which is the main cause of malaria and has developed resistance against traditional Antimicrobial activity

CONCLUSION
Isatin is a synthetically versatile molecule with a diversified nature of pharmacological applications. The focus of the review was to summarize the recent literature published about isatin and its derivatives. These heterocyclic molecules are among the fastest developing areas of interest for synthetic chemists and pharmacists. We have discussed some of the properties including, antiasthamatic, anticancer, MOA-inhibitor, antiviral and antimicrobial, however, as mentioned earlier, isatin derivatives have good potential and a broad spectrum of application against various cancer cell lines, therefore, synthesis and investigation of new isatin derivatives is an active area of research and has the potential for the development of pharmacologically active molecules.