Prologue
1.1. Introduction
Since ancient time natural products from plants, animals, microbes and minerals have been the repertoire source for drug development. In the recent time, scientific approach has progressed rapidly but still the fundamentals of these developments are rooted in traditional medicines and therapies. According to the World Health Organization (WHO) report, in recent times, about 80% of the population in developing countries depends on traditional and herbal medicines to meet their basic healthcare needs. Due to the wider implication of traditional medicines, the use of these medicines and traditional healing methods have been rapidly adapted by developed and industrialized countries as complementary and alternatives medicines (CAM). Undoubtedly, the healing ability of plants has been established by various ancient Ayurvedic therapies. Ayurvedic medicinal products and therapies are developed over the centuries. In modern era, with extensive research progress in bioinformatics, medicinal chemistry, pharmacology and clinical biology, the key medicinal components and their behaviour are being identified and are being used for treating various diseases. These components provide an attractive basis for the future drug development process. In modern medicine, root of a huge fraction of drugs have been natural sources which are either directly extracted from natural sources or synthetically modified from a lead compound of natural origin.
Alkaloids containing plants have been in wide use since the early era of medicinal development (Amirkia and Heinrich, 2014). Early 19th century was the beginning of isolation and characterization of important plant alkaloid such as xanthine (1817), atropine (1819), quinine (1820), caffeine (1820) etc, (Amirkia and Heinrich, 2014). These discoveries had
created eagerness for search of more and more such type of natural alkaloids and their sources. Alkaloids are known for their diverse roles including self preservation, inhibitors for enzymes of signal communications, feeding deterrents, autoinducer, allelochemicals, sidophore, anti-depressants, antibacterial activities, metabolic activities, quenching activities, etc (Cushnie et al., 2014; Perviz et al., 2016). They are a large and structurally diverse set of natural products. Among these alkaloids, xanthine and its natural derivatives have prominent place in traditional medicine. Natural xanthine derivatives such as caffeine, theophylline and theobromine are purine based nitrogenous compounds which are present in plants such as cocoa, tea and coffee plants (Baraldi et al., 2007). These compounds are usually known as methyl xanthine derivatives. Natural xanthine derivatives are widely known targeting cellular signaling pathways. Cell signaling pathways are required for establishing the cellular communication between various cells and their extracellular environment to coordinate myriad activities which are basis for the growth, development and functioning of any organism.
In mammalian cells, the mechanism of communication is carried out by the complex pathway which is commonly known as signal transduction pathway. Second messengers–cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) act as mediator to transmit wide varieties of external signals coming from extracellular environment through membrane bound receptors to regulate many intracellular metabolic processes (Kim and Park, 2003; Wang et al., 2010). Cyclic nucleotide phosphodiesterases (PDEs) act as a key regulator to regulate the cell signaling process by continuous involvement in breakdown of second messengers, to maintain the consistency of
pathway. PDEs are a superfamily of 11 enzymes encoded by 21 human pde genes (Conti and Beavo, 2007; Ke et al., 2011; Maurice et al., 2014; Omori and Kotera, 2007; Shao et al., 2014). Based on the substrate specificity, these phosphodiesterases are further categorized in three parts- cAMP specific PDEs, cGMP specific PDEs and dual specific PDEs.
Phosphodiesterase 9A (PDE9A) is one among them which has highest affinity towards cGMP (Francis et al., 2011; Soderling et al., 1998). PDE9A has significant role in regulating the cell signaling pathway of brain cells because of its abundance in brain. In brain, most of the cellular signaling pathways are passed through cGMP (Andreeva et al., 2001; Singh and Patra, 2014). Various pathophysiological conditions lead to lowering the level of cGMP which may affect the normal functioning of signal transduction pathway. In such conditions, normal functioning of PDE9A leads to further decreasing the level of cGMP. It gives a call to researchers to look for the development of drugs for PDE9A regulation. Inhibitors play important role in regulating the catalytic action of PDE9A maintaining the consistency of pathway to some extent by preserving the level of cGMP. Thus, ‘inhibition’ has always been a key area of consideration in PDE9A research.
Despite enormous effort given by researchers and pharmaceutical companies for more than a decade to develop PDE9A inhibitor, till date, not a single inhibitor has been marketed.
Xanthine derivatives are widely known for their non-specific inhibition properties towards phosphodiesterase enzymes (Ogawa et al., 1989). Xanthine derivatives are significant in various other pharmaceutical applications such as adenosine receptor antagonists, inducers of histone deacetylase activity, antitumor drugs, anti asthmatic drug, psycho-stimulant drug, etc.
(Allwood et al., 2007; Burbiel et al., 2006; Meskini et al., 1994; Suravajhala et al., 2014).
Due to wider pharmaceutical application of natural xanthine derivatives, it has opened enormous opportunities for synthesis of xanthine based compounds which can target PDE9A specifically. In the last few decades, based on the natural xanthine derivatives, number of xanthine based inhibitors have been synthetically developed and reported (Glennon et al., 1981; Wong and Ooi, 1985). In drug development process, one of the major challenges is deciding the lead molecule which acts as scaffold to provide avenue for achieving maximum diversity. Xanthine with versatile and structurally rigid scaffold provides highest possibility for molecular diversity in constructing xanthine derivatives for combinatorial chemistry (Heizmann and Eberle, 1997).
In this study “xanthine” has been used as a scaffold for the development of potent and selective inhibitors for PDE9A. This thesis is an attempt to explore the potential of
‘xanthine’ as a scaffold to bring diversification in drug development process for PDE9A.