Potential of Xanthine Derivatives as Phosphodiesterase 9 Inhibitors (A Conceptual Research Paper)

 TITLE: Potential of Xanthine Derivatives as Phosphodiesterase 9 Inhibitors (A Conceptual Research Paper)

Author Name: Iqra Ahmad (Biochemistry)

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Abstract:

Natural plant products are being used as medicines since ancient times. Xanthines are plant alkaloids that are very popular as natural medicines. They have been extracted from plants and modified to treat various illnesses. One of the applications of Xanthine derivatives is their role in non-specific Phosphodiesterase inhibition leading to many therapeutic advantages. This study discusses the correlation of Xanthine derivatives with different phosphodiesterases. With the advances in computational drug designing changes in xanthine scaffold recently showed its novel applications. This study highlights the aspects of those recent significances of xanthine and its derivatives.

Introduction:

Natural plant and animal products have been used for a long time for drug development. With the advancement, microbes are also been used for extracting useful products. The extracts sometimes proved to be effective while sometimes they are modified to make them better. Plants alkaloids have caught attention in drug development. They are the biggest class of naturally occurring plant products and include xanthine, caffeine, quinine, and atropine, etc(Matsuura & Germano Fett-Neto, n.d.). Plant use these compounds for their use but their wide range of structure moiety enables them to attach to different targets and can inhibit a particular enzyme leading to a decrease of excessive damaging compounds in humans or animals as well as increasing useful products of a pathway(Yang & Stöckigt, 2010)

Xanthines are purine-based nitrogenous compounds discovered by German Chemist Emil Fisher in 1817 and have an eminent place in natural medicines due to their derivatives caffeine, theobromine, and theophylline as these compounds have shown visible benefits in therapeutic drug designing(Heinrich, n.d.)(McCarthy & McCarthy, 2007)(Monteiro et al., 2016). Natural sources of xanthine and xanthine derivatives (XDs) are coffee, tea and, cocoa. They are important for plants to protect themselves from predators(McCarthy & McCarthy, 2007). XDs play an important role as adenosine receptor antagonists(Fredholm & Persson, 1982). They act as a converging point of guanine and adenine and intermediates in the synthesis of GMP, GDP, and GTP by salvage pathway(Franco et al., 2013)

The structure of xanthine consists of a six-member and a five-member ring both rings are fused to each other. Among the four significant nitrogen binding sites three are three –NH groups. It shows proton transfer between N7 and N9 (annular tautomerization) and the migration of proton between N1 and N3 and oxygen of carbonyl group at the C2 position(lactim-lactam tautomerization). (Brovarets’ & Hovorun, 2013)(Petrucci et al., 2020) Xanthine resembles closely to Adenine and Guanine, the nitrogenous basis of DNA and RNA. This resemblance is an effective property of xanthine as a therapeutic entity.

Phosphodiesterases (PDEs) are the family of enzymes that degrades cyclic AMP and GMP and thus have a dominant role in the regulation of second messengers. Almost 11 families of PDEs have been identified and their differential distribution on the brain is a topic of concern as inhibiting a particular PDE cause a particular effect in brain functions. (M & J, 2007)(Maurice et al., 2014) Phosphodiesterase9A (PDE9A) is a cGMP-specific PDE distributed in the kidney, lung, liver and throughout the brain. Its inhibition cause a reduction in memory defects(F et al., 2005) and improvement in learning and cognition. (Liddie et al., 2012)(PH et al., 2011) In a study decrease in breast tumor cells with the inhibition of PDE9A is reported.(R et al., 2012). One of the hurdles in developing inhibitors for PDE9A is its structural similarity with its family members particularly PDE1 and PDE8.(Fisher et al., 1998)

Objectives of the Study:

1.      Assessment of the need for advanced inhibitors for PDE9A.

2.      To point out the change in status of Xanthine derivatives from non-selective PDE inhibitors to specific PDE9A inhibitors.

3.      To highlight the potential of xanthine derivatives as PDE9A inhibitors.

Significance of the Study:

This study accentuates the emerging potential of Xanthine and its derivatives as specific PDE9A inhibitors. From mentioned studies, one can understand the preferable substitutions in Xanthine scaffold for increased affinity towards PDE9A. Also, it opens a new era in the research of PDE9A inhibitors as using common scaffolds for PDE isozymes can cause serious side effects e.g. pyrozolopyrimdinone is being used for both PDE9A and PDE5 inhibitors. This study appraises the interaction between xanthine and PDE9A and the factors affecting these interactions.

Literature Review:

Clinical significances of xanthine derivatives have become dominant in previous years such as in the treatment of asthma, psychosis, and inflammations. (Rakesh et al., 2013)(Gareri et al., 2014)(I.-A. Lee et al., 2014) They have been used as the inducer of histone deacetylase and the non-specific inhibitors of phosphosphodiesterases. (RA et al., 1981)(Ito et al., 2002) XD theophylline exhibited PDE4 inhibition(Miyamoto et al., 1994) PDE3 inhibition and dual inhibition of both of these enzymes. (Franciosi et al., 2013) Also it slightly inhibited PDE5 (Wu et al., 2004) Also studies have demonstrated the relation between non-selective PDE inhibition by XD pentoxifylline and suppression of tumor necrosis factor-alpha.(Semmler et al., 1993)

The generation of optimized xanthine derivatives is widespread from the beginning by old methods such as ring closure synthesis and classical condensation methods. For example, the synthesis of 8-substituted xanthine derivative by tandem ring closure synthesis,(Bandyopadhyay et al., 2012) synthesis of  1,8-Disubstituted Xanthine Derivatives by classical condensation,(Alaa M.  Hayallah et al., 2002) 1,3,7-substituted xanthines by a safety-catch protection strategy(Allwood et al., 2007) and the synthesis of 1,3,7,8-tetrasubstituted xanthines by solid-phase synthesis.(D. Lee et al., 2015) Although these methods have shown a great potential of xanthine for substitutions these methods were not prominent for showing large-scale diversity in xanthine scaffold. Deep insight into specific variations in XDs is crucial as a slight alteration can reverse its effect. (V et al., 1998)

Recently in 2016 Singh et al reported variations in Xanthine scaffold by virtual screening and molecular dynamics resulting in increased affinity towards PDE9A. In this study increase in chain length at N1, N3 and C8 with one unsubstituted –NH group were the deciding factors for XDs and PDE9A interactions. Favorably, the chemically synthesized compounds were more stable than the virtual library. In this study Xanthine was presented both as a scaffold and reaction initiator.(Singh, 2016)

Pyrazolopyrimidine scaffold is very popular for PDE9A inhibitors(Jørgensen et al., 2013) When the same scaffold was delineated for PDE5(SD et al., 2015) In 2017 a study demanded the need for non-pyrazolopyrimindine PDE9A inhibitors and presented Xanthine derivatives as a new alternate for developing novel potential inhibitors for PDE9A. Again N1, N3 and C8 were considered the best substitution sites moreover the addition of phenyl group on C8 developed hydrophobic-hydrophobic interactions between XDs and PDE9A.(Singh et al., 2017)

In 2018 ZINC62579975 was reported as a potent candidate for PDE9A inhibition after screening 2055 XDs from the ZINC database.(Singh et al., 2018) This specific inhibition of PDE9A establishes new possibilities in the research of Xanthine scaffold. The versatility and rigid scaffold of xanthine encouraged scientists to use it as a lead for generating a wide range of compounds by using in silico methodologies.

Conclusion:

Xanthine derivatives have the potential to be used as PDE9A inhibitors. They should be taken as a suggestion in designing novel and potent PDE9A inhibitors. Utilizing new approaches to expand this review will aid in future drug development processes for cognitive and memory deficits particularly for Alzheimer’s disease.

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