Synthesis and Biological Value of Thiouracils and Fused Thiouracils ( A review )

A literature survey revealed that the thiouracil derivatives and their condensed heterocycles have occupied a marked position as synthon for various biologically active compounds. They have a wide range of therapeutic uses that include anti-cancer, anti-microbial, molluscicidal, anti-leishmanial, anti-oxidant, anti-viral as anti-HIV and anti-HCV, and antithyroid activities. Numerous methods for the synthesis of thiouracils offer enormous scope in the field of medicinal chemistry. The review article aims to review the work reported for the synthesis and the biological activities of thiouracils and fused thiouracils from the past to recent years.


INTRODUCTION
Heterocyclic compounds are those cyclic compounds whose ring contain besides carbon, one or more atoms of other elements.The non-carbon atoms such rings are referred to as hetero atoms.The most common hetero atoms are nitrogen, sulphur and oxygen.Heterocyclic compounds, bearing atoms of at least two different elements as a member of its ring have attracted considerable attention in the development of pharmacologically active molecules and advanced organic materials.Pyrimidine ring is the building unit of DNA and RNA which explains the fact that pyrimidine derivatives and related fused heterocycles exhibit diverse pharmacological activities.Another important class of pyrimidine is 2-thiopyrimidine (2-TP) and its derivatives.2-Thiouracil (TU), which is a sulfur-containing uracil, a six membered simple aromatic ring comprises of carbon, two nitrogen atoms at positions 1 and 3, sulfur and oxygen (Figure 1).

Figure 1. Structure of 2-thiouracil
There are two established antithyroid drugs, 6propyl-2-thiouracil and 6-methyl-2-thiouracil.Thio derivatives of pyrimidine bases including 2-thiouracil, 6methyl-2-thiouracil, and 2-thiocytosine are minor components of t-RNA, and furthermore, they have contributed remarkably to biological, pharmacological, and medicinal chemistry.Among the pyrimidine containing heterocycles, thiouracils are potential therapeutics as antiviral, anticancer and antimicrobial agents.For example, S-alkylation and N-alkylation products have been recently reported as novel antibacterial, cytotoxic agents and unique HIV reverse transcriptase inhibitors.Moreover, a literature survey revealed that the thiouracil derivatives and their condensed heterocycles have occupied a marked position in the design and synthesis of novel chemotherapeutic agents with remarkable antitumor, HCV inhibitors and antimicrobial activities.During the last two decades, several thiouracil derivatives have been developed as chemotherapeutic agents and have found wide clinical applications.In the light of the aforementioned facts, and in continuation for our interest in the synthesis of biologically active heterocyclic compounds, we report herein the main aspects of the synthesis and the biological value of these heterocycles from the past to recent years.
In 2011, Supaluk et al. 4 reported the synthesis of S-substituted thiouracils 5 through the alkylation of 2thiouracil with alkylating agents (R -Br) in base catalysis (Et3N or K2CO3).In 2016, Dong et al. 7 reported the synthesis of thiouracils 11 by S-alkylation of the 6-substituted 2thiouracils 10 with the appropriate substituted phenacyl halides in the presence of anhydrous K2CO3.

5, 6-Disubstituted thiouracils
In 1997, Antonello and his co-workers 25 reported the preparation of a series of 5 and 6disubstituted thiouracils 37 by condensation of β-oxo esters with thiourea in alcoholic sodium ethoxide.

Anti-cancer activity
Merbarone ® 62, a topoisomerase II inhibitor acting on the catalytic site, active against both fast and slow growing cancers.Merbarone®, showed antitumor activity 39 against the murine L1210 leukemia model as well as against B16 melanoma and M5076 sarcoma22 (optimum dose range 50-100 mg/kg).
It is demonstrated that the thiouracil analogs 98 is a novel antibacterial.It exerts potent activity 46 against B.catarrhalis with MIC of 32 μg/mL.Thiouracil derivatives 101 showed significant activity against staphylococcus aureus, while compounds102, 103 displayed moderate inhibitory activity 28 against Candida albicans.
Moreover, compounds 104 possessed superior antibacterial activity against the gram positive bacteria S.aureus and B.subtilis compared to the reference drug Amoxicillin.Moreover, compound 105 was found to be broad spectrum antimicrobial agent 44 and it also exhibit promising antifungal activity against C.albicans.Thiouracil derivatives 111 were found to have significant antimicrobial activity 55 against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and antifungal Aspergillus niger and Candida albicans comparable to the standard drugs Ciprofloxacin and Fluconazole.
4-Oxo-5-cyano thiouracils 116 showed good antimicrobial activity 57 against Escherichia coli mutant strain, NR698 and evaluated as SecA inhibitors.Protein translocation is essential for bacterial survival and the most important translocation mechanism is the secretion (Sec) pathway in which Sec A is a central core driving force.Thus targeting Sec A is a promising strategy for developing novel antibacterial therapeutics.
In 1999, Maurizio et al.23 reported the synthesis of thiouracil derivatives 34 via reaction of acetone dicarboxylic acid diethyl ester or ethyl-γchloroacetoacetate independently with S-methyl thiourea hydrogen sulphate in presence of calcium hydroxide.
-alkylated thiouracil 68 selectively exhibited cytotoxic activity against murine leukemia cell line (P388cell) and 1-adamantylthiopyrimidine 69 displayed cytotoxic activity 4 against many cell lines.Significant activity of 69 was observed against multidrug-resistant small cell lung cancer cell line (H69AR) with the IC50 of 35.0 mg/mL, whereas the control drug; etoposide showing the IC50 of 30.0 mg/mL.
Thiouracil derivatives 100 were found to be potent27 against Mycobacterium tuberculosis.
towards B. subtilis, C. albicans, and A. niger, while compounds 113 and 114 were found active against A.niger and B.cereus, respectively.Compound 115 (MIC value = 0.0524 µmol/cm3) exhibited an interesting antimicrobial profile with dual antibacterial (against S. aureus) and antifungal (against C. albicans) effects 56 .
Thiouracil derivatives are useful clinically as antithyroids.A huge number of compounds structurally related to 2-thiouracil have been evaluated for antithyroid activity but probably the most widely used compounds for the treatment of hyperthyroidism 73 are 6-propyl-2thiouracil (142) and 6-methyl-2-thiouracil (143). 3143-CH