Recent Advances in the Synthesis of Xanthines: A Short Review

Xanthine and its derivatives are considered a pharmacologically potential moiety that manifests immense biological activities. Owing to this much diversity in the biological field, this scaffold has fascinated the attention of many researchers around the globe to scrutinize its basic structure chemically as well as biologically. In recent years, xanthine derivatives have been used therapeutically in different pathological conditions due to their presence in day-to-day life. Herein, we review the recent progress in the synthesis of xanthine and its derivatives. Some of the widely used synthetic strategies such as (a) Traube's synthesis, (b) one-pot synthesis, (c) xanthine-anneleated synthesis, and (d) miscellaneous synthesis were compiled in this review paper. The results obtained from this review paper highlight the significance of various xanthine derivatives as possible leads to the development of new drugs. The data compiled in this review paper could help the medicinal chemist in designing new active compounds from the modification of the already existing compounds in the search for novel drug leads. This report concludes that the various synthetic procedures exemplified in this review paper may serve as a support system for the designing of new molecules with a xanthine scaffold. Thus, we hope that this molecule may serve as the prototype in order to find out more active xanthine derivatives.


Introduction
Xanthine or 3,7-dihydropurine-2,6-dione (see Figure 1), a unique heterocycle is a purine base containing nitrogen as a central atom and composed of a pyrimidine ring fused with an imidazole ring.
It is an essential core element of diverse natural products because their structural fragments are found in various natural and synthetic medicinally active compounds [1]. Te versatility of the xanthine moiety displays that it is the essential part of several medicinal agents and some of its derivatives have shown innumerable physiological and pharmacological activities viz. respiratory tract, heart, smooth muscle cells, CNS (central nervous system), kidney, and stomach [2]. In brief, the objective of such studies is to expose the drug-like properties of xanthine and its derivatives in order to build prospects for harnessing the full potential of this scafold.
Xanthine scafold has fascinated the attention of researchers in health sciences due to its remarkable properties either chemical or physical [3]. Over the last two decades, the compound and its derivatives have gained considerable interest [4]. Te xanthine scafold can also act as a basic framework for numerous pharmacologically active scafolds [5]. Several patent applications were also fled for xanthine derivatives as mentioned in (see Table 1), which displays the therapeutic efectiveness of this scafold.
Owing to the importance of xanthine moiety in medicinal chemistry and its broad range of biological activity [22]. Tis review article primarily focuses on the updated knowledge of synthetic methods used to access xanthine scafolds. In the present work, we have compiled the recent literature that belongs to the synthetic strategies of these derivatives.

Search Strategy
Te data has been compiled from the year 2010 to 13 July 2022. We performed an electronic search to fnd out the existing literature on xanthine derivatives. For this purpose, the compiled data has been searched from diferent search engines and databases such as Science Direct, Google Scholar, Cochrane, PubMed, Scopus, and Scientifc information databases. More than ten months were completely used to compile data for this manuscript. Te key terms used during the search were "xanthine," "xanthine derivatives" "synthesis of xanthines" and "targets of xanthine derivatives." One hundred twenty-two papers were screened and then inclusion and exclusion criteria were applied to prepare this manuscript. Out of these papers, forty-four papers were used to prepare this manuscript. Te last search was conducted on 15. March 2022.
Te results obtained from this review paper highlight the signifcance of various xanthine derivatives as possible leads to the development of new drugs. Te reactions covered in this review fall under the following categories: (a) Traube's synthesis, (b) one-pot synthesis, (c) xanthine-anneleated synthesis, and (d) miscellaneous synthesis.

Traube's Method.
Traube's synthesis is the oldest and most used synthesis method for xanthine analogs. Te method consists of the preparation of 5,6-diaminouracil (17) from urea or substituted urea. Several xanthine derivatives were synthesized by using uracil (15) as a precursor. Two methods were employed for the synthesis. According to method A-the nitrosation reaction (16) took place in presence of sodium nitrite and acetic acid followed by reduction (17) in presence of sodium dithionate and cyclisation to form substituted xanthine in presence of formic acid and sodium formate. In method B, the nitrosation reaction took place in presence of sodium nitrite, dimethyl formate, and hydrochloric acid followed by reduction and ring closure in presence of triethylorthoformate to form substituted xanthine (18). Te main disadvantage of this method is that the overall process is tedious because of the ring closure synthetic mechanism (Scheme 1). Some recently used examples of this synthesis method are discussed in this section.

Xanthine-Anneleated Synthesis.
In xanthine-anneleated synthesis, the upgradation of one more ring starting from the bicyclic xanthine scafold produces several biologically important compounds with modifed physiochemical properties. Tough, xanthine-anneleated synthesis is tedious but not widely used for the synthesis of xanthine derivatives. In this context, the synthesis of tetrahydropyrimido [ purinediones by using a convergent approach was reported. Te commercially available amines (91) were treated with 8bromo-7-(3-chloropropyl)-1,3-dialkylxanthine (90) in presence of a base in DMF (dimethyl formamide) to form the substituted xanthine derivatives (92) [35] (Scheme 14).
Another contribution to this study is based on the synthesis of 8-Benzyl-substituted tetrahydropyrazino [2,1-f] purinediones was reported. Te 1,3-dimethyl-8-hydroxymethylxanthine (93) was used as the starting material in this study. Primarily, position-7 of xanthine was alkylated    (94) with 1,2 dibromoethane. Te hydroxy group present at the 8-position was then converted into the corresponding bromide to form the resulting purinedione derivative (95) which was further treated with diferent substituted benzylamines to aford the tetrahydropyrazino derivative (96) [36] (Scheme 15).

One-Pot Method.
According to the emerging importance of xanthine and its derivatives. Te development of a novel method for access to xanthine scafold in less time, without using toxic chemicals, and improvement in yield is still in great demand. In this study, numerous functionalized xanthines were synthesized with better yield, without the use of toxic reagents, and in lower time. Based on the aforementioned information, a one-pot synthesis of xanthine was reported. Te 5,6-diaminouracil (105) was chosen as the substrate. Te substrate was refuxed with acetic anhydride in acetic acid to obtain compound (106) and heating of substrate with malononitrile gave compound (107) in good yield [39] (Scheme 18).
Another one-pot synthesis of 8-xanthine derivatives was reported. Te synthesis was done by treatment of 5,6-diaminouracil (112) with a simple aldehyde to form a xanthine derivative (113,114) through an imine intermediate (115). Furthermore, cyclisation of the intermediate yield xanthine derivative (116). All the synthesized compounds were observed for A2A adenosine receptor antagonist [41] (Scheme 20).

Reported Potent Compounds of Xanthines and Their Targets
Natural and synthetic compounds consisting of xanthine scafold showed a variety of pharmacological activities. A large number of biologically active compounds were obtained by incorporating diferent substituents at diferent places in this ring [22]. A number of reported potent compounds of xanthines along with the therapeutic disease target are discussed ( Table 2).

Conclusion
Our prime aim in writing this review paper is that the content presented in this review paper will be benefcial to the feld and will provide great help to those researchers working on this scafold. Tis review article provides a summary overview of the synthesis of xanthine structures. Te development of novel, selective and efcient methods for the formation of xanthine ring starting from commercially available substrates is a pivotal target in the current organic synthesis. In this regard, the synthesis of xanthine derivatives by traube's method is the most used approach. However, other approaches were also found attractive to researchers. Te various synthetic procedures exemplifed in this review paper may serve as a support system for the designing of new molecules with xanthine scafold. We hope that the data compiled in this review paper could help the medicinal chemist in designing new active compounds from the modifcation of the already existing compounds in the search for novel drug leads.