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ISSN: 2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Ahmad and Mohamed, 2017, 1 (2), 75-88 Journal of Advanced Pharmacy Research Synthesis and Biological Value of Thiouracils and Fused Thiouracils (A review) Naglaa Mohamed Ahmed*, Mosaad Sayed Mohamed Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Helwan University, Ein-Helwan, Cairo, Egypt, 11795. *Corresponding author: Naglaa Mohamed Ahmed, Cairo, Egypt, Tel.: +2-27633982 E-mail address: [email protected] Submitted on: 25-01-2017; Revised on: 22-02-2017; Accepted on: 26-02-2017 ABSTRACT 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. Key Words: Thiouracils, Fused thiouracils, Synthesis, Biological activities . INTRODUCTION There are two established antithyroid drugs, 6- Heterocyclic compounds are those cyclic propyl-2-thiouracil and 6-methyl-2-thiouracil. Thio compounds whose ring contain besides carbon, one or derivatives of pyrimidine bases including 2-thiouracil, 6- more atoms of other elements. The non-carbon atoms methyl-2-thiouracil, and 2-thiocytosine are minor such rings are referred to as hetero atoms. The most components of t-RNA, and furthermore, they have common hetero atoms are nitrogen, sulphur and oxygen. contributed remarkably to biological, pharmacological, Heterocyclic compounds, bearing atoms of at least two and medicinal chemistry. Among the pyrimidine different elements as a member of its ring have attracted containing heterocycles, thiouracils are potential considerable attention in the development of therapeutics as antiviral, anticancer and antimicrobial pharmacologically active molecules and advanced agents. For example, S-alkylation and N-alkylation organic materials. Pyrimidine ring is the building unit of products have been recently reported as novel DNA and RNA which explains the fact that pyrimidine antibacterial, cytotoxic agents and unique HIV reverse derivatives and related fused heterocycles exhibit diverse transcriptase inhibitors. Moreover, a literature survey pharmacological activities. Another important class of revealed that the thiouracil derivatives and their pyrimidine is 2-thiopyrimidine (2-TP) and its derivatives. condensed heterocycles have occupied a marked position 2-Thiouracil (TU), which is a sulfur-containing uracil, a in the design and synthesis of novel chemotherapeutic six membered simple aromatic ring comprises of carbon, agents with remarkable antitumor, HCV inhibitors and two nitrogen atoms at positions 1 and 3, sulfur and oxygen antimicrobial activities. During the last two decades, (Figure 1). several thiouracil derivatives have been developed as O chemotherapeutic agents and have found wide clinical applications. In the light of the aforementioned facts, and HN in continuation for our interest in the synthesis of biologically active heterocyclic compounds, we report S N herein the main aspects of the synthesis and the biological H Figure 1. Structure of 2-thiouracil value of these heterocycles from the past to recent years. http://aprh.js.iknito.com 75 ISSN: 2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Ahmad and Mohamed, 2017, 1 (2), 75-88 1. Synthesis of thiouracils O O 1.1. 2-Thiouracil HN RBr HN The thiouracil system is constructed either via Et N or K CO S N 3 2 3 RS N cyclocondensation of carbonyl compound with thiourea or H 5 by introducing thiourea residues into the structure of R = CH2C6H11 ,CH2C6H5 , s -C4H9 , carbonyl compounds, followed by cyclization of n - C H , 1 - adamantyl intermediate thio ureides. According to the first synthetic 4 9 pathway, 2-Thiouracil 1 was prepared by condensation of 5 the enol form of ethyl formyl acetate as its sodium salt In 2013, Fadi et al. reported the methylation of with thiourea. This reaction was reported 1 by Wheeler and 2-thiouracils 6 with methyl iodide, K2CO3 in dry DMF. Liddle. O O CN CN O HN HN O CH3I NH H3C 2 EtO DMF , K CO S N aq.NaOH HN S N Ar 2 3 Ar + H H S HO H -EtOH 7 NH2 S N 6 -H2O H Ar = C6H5 ,4-Cl -C6H4 1 In the same year, Ahmed et al.6 reported the 2-Thiouracil 1 can be also synthesized (with a reaction of 2-thiouracils 8 with the hydrochloride salt of 70% yield) using two-stage process, whereby Meldrum’s diethyl-aminoethyl chloride in KOH to obtain 2-(diethyl acid is heated with trimethyl orthoformate and thiourea, amino) ethy-2-thiouracil derivatives 9. after which the intermediate thio ureid 2 is subjected to 2 O thermolysis in diphenyl ether . O NC NC CH3 NH NH KOH O O O Cl CH CH N (CH CH ) .HCl N + 2 2 2 3 2 Ar N S CH3 Ar N SH H CHNHCSNH2 O 1- HC(OMe)3 O HN 9 Ph2O 8 H3C H3C 2- NH2CSNH2 Reflux S N Ar = C H , 4 -NO -C H H3C O O H3C O O 6 5 2 6 4 H 2 1 In 2016, Dong et al.7 reported the synthesis of 1. 2. 2-Substituted thiouracils thiouracils 11 by S-alkylation of the 6-substituted 2- In 2010, Basavaraja et al.3 reported that thiouracils 10 with the appropriate substituted phenacyl piperazine and morpholine linked to thiouracil derivatives halides in the presence of anhydrous K2CO3. 4 were prepared via reaction of methylated thiouracil 3 with heterocyclic secondary amines like piperazine, N- O O 2 HN R methylpiperazine and morhpoline. K2CO3 HN 1 DMF S N R 1 O O S N R H H CN CN HN 1 HN 10 O 11 HNRR 1 H C R =CH ,NH 2 3 1 3 2 R = Cl, NO ,CH ,OCH S N Ar R RN N Ar 2 3 3 3 4 In the same year, Makaram et al. 8 reported the Ar = C H ,4 - Cl -C H , 4 -OCH - C H , 6 5 6 4 3 6 4 reaction of 4-oxo-6-phenyl-2-thioxo-1, 2, 3, 4- 3 - NO2 - C6H4 tetrahydropyrimidine-5-carbonitrile (12) with 1 N N N NRR = , , chloroacetyl chloride, 2-chlororopionyl chloride, and 3- N N O H chloropropionyl chloride in dry benzene using K2CO3 as CH3 a base to obtain S-chloro alkanethioates 13. In 2011, Supaluk et al. 4 reported the synthesis of O O S-substituted thiouracils 5 through the alkylation of 2- CN CN HN O O K CO ,Dry DMF HN thiouracil with alkylating agents (R -Br) in base catalysis + Cl 2 3 Cl S N R Cl Dry benzene ,reflux 10 h. R S N (Et3N or K2CO3). H H 12 13 R=- CH2 ,CH(CH3) , CH2CH2 Alkylation of 6-amino-2-thioxo-2,3-dihydro- pyrimidin-4(1H)-one 14 was performed using http://aprh.js.iknito.com 76 ISSN: 2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Ahmad and Mohamed, 2017, 1 (2), 75-88 F3C (bromomethyl)-cyclohexane to enable the concomitant F3C alkylation at the 2- and 4-positions. The use of microwave S heating (µW) afforded the desired product 15 in 16 min S N N RNH2 at140°C. This reaction was reported 9 by C. Daniela et al N N Cl in 2016. CN NHR Br CN 22 Br 23 R = 2 -(3 - OCH3 -C6H4) - CH2CH2 , O 2 -( 3,4 - (OCH3)2 - C6H3) - CH2CH2, O 4 -(NHCH ) -C H N HN Br CN 3 5 10 + µW heating HN S N NH2 H S N NH2 15 H In 2011, Mosaad et al. reported that a series of 13 14 4-alkylamino-2-thiouracils 25 was prepared via reaction of 4-chloro-2-thiouracils 24 with different amines. 1.3. 4-Substituted thiouracils Conversion of 2-thiouracil derivatives 16, 18 to their corresponding 4-chloro analogs 17, 19 using Cl NHR 10-13 CN CN phosphorus oxychloride has been reported or it can be N HN R NH2 performed using phosphorus oxychloride / phosphorus S N Ar S N Ar pentachloride mixture 14,15. H H 24 25 R = 4-COCH3 - C6H4, 2- COOH-C6H4, 4-antipyryl O Cl Ar = 4-F-C6H4, 4-Br-C6H4, 4-N(CH3)2 -C6H4, CN HN CN 3,4,5-(OCH3)3-C6H3 POCl3 N 1 2 R S N R 1 2 R S N R In 2014, Mosaad et al.18 reported the synthesis 16 17 of 4-hydrazino derivatives 27 by reaction of the 1 R = CH3 , C2H5 , C3H7,CH2C6H5 appropriate chloropyrimidine 26 with 99% hydrazine 2 R = 2-C4H3S , 2-C4H3O , 3-F-C6H4 , hydrate in methanol. C H , 4-NO -C H , 2-C H O 6 5 2 6 4 4 3 Cl NHNH2 O CN CN Cl N N CN NH2NH2 HN CN POCl N S N S N 3 H H S N Ar PCl N N 5 S N Ar 26 H H 27 H H 18 19 Ar = C6H5 ,2-OCH3 -C6H4 ,2-CH3-C6H4, 1.4. 5-Substituted thiouracils 3,4,5 -(OCH 3) 3 -C6H2 , 4-F-C6H4, In 1942, Ballard and Johnson 19 reported the 4-Br -C H , 4-N(CH ) -C H 6 4 3 2 6 4 formation of 5-ethoxycarbonyl-2-thiouracil (28) via the reaction of diethoxycarbonyl acetaldehyde (Diethyl α- In 2011, Magdy et al.16 reported the synthesis of formyl malonate) and ethyl α-ethoxycarbonyl-β- 6-(3-(benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)-4- ethoxyacrylate, independently with thiourea.

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