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 anti- thyroid 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 , one or derivatives of 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 , sulphur and . 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 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.

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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 CH NC NH 3 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 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 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

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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 HN 4 -(NHCH3) -C5H10 N Br µW CN + 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. C6H5, 4-NO2-C6H4 , 2-C4H3O 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-(-2-yl)-1-phenyl-1H-pyrazol-4-yl)-4- ethoxyacrylate, independently with thiourea. chloro-1,2-dihydro-2-thioxopyrimidine-5- carbonitrile

(21) by reaction of 2-thiouracil derivative 20 with O O O O POCl₃/PCl₅ in boiling water bath. EtO C OEt C NH2 aq. HN OEt Cl + NaOH O S O H S N NH2 CN CN H HN POCl / PCl N 28 3 5 aq.NaOH O O S N S N ph N ph N H H EtO C O N OEt O N NH 2 + EtO S 20 21 NH2

In 2006, Ding et al.17 reported the synthesis of a In 1964, Fissekis et al.20 reported that 5-(2- series of 6-(4-bromophenyl)-5-cyano-4-alkylamino hydroxyethyl)-2-thiouracil (29) was prepared by refluxing thiouracil derivatives 23 from 4-chloro-2-thiouracil 22 thiourea with the aqueous solution of the sodium salt of α- and different amines. formylbutyro lactone in its enolate form.

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O O In 2010, Mosaad et al.24 reported the reaction of NH2 aq. CH2CH2OH + O HN ethyl cyanoacetate with thiourea in sodium ethoxide to S NH2 NaOH prepare 6-amino-2-thioxo-2, 3-dihydro-1H-pyrimidine-4- H ONa S N H one (35). 29 O 21 CN In 2002, Omar etal. reported the reaction of 2- NH2 + Na OEt HN thiouracil-5-sulphonyl chloride (30) with a series of CH2 S COOEt NH amines giving certain sulphonamides 31. 2 S N NH2 H 34 O O SO Cl SO NH - Ar HN 2 HN 2 13 Ar NH2 In 2015, Mosaad et al. reported the reaction 6- S N S N Amino-2-thiouracil with benzene sulfonyl chloride and 4- H H 30 31 toluene sulfonyl chloride in presence of as an acid binder to give sulfonamides 36. Ar = C H ,4-CH -C H ,4-Cl-C H , 6 5 3 6 4 6 4 4-Br-C H ,3-F-C H ,3,5-(Cl) -C H , 6 4 6 4 2 6 3 O O 5-Cl-C6H3-2-CH3 , 2,4-(Cl)2 - C6H3 HN HN Ar SO2Cl 1.5. 3, 5-Disubstituted thiouracils S N NHSO Ar 22 S N NH 2 In 1956, Whitehead and Traverso prepared 5- 2 H H ethoxycarbonyl-3-methyl-2-thiouracil (32) and 3-butyl-5- 36 cyano-6-methyl-2-thiouracil (33) by condensation of N- Ar = C6H5 , 4-CH3 -C6H4 methyl thiourea and its butyl homologue with diethoxycarbonyl acetaldehyde (diethyl α- 1.7. 5, 6- Disubstituted thiouracils 25 formylmalonate) or ethyl α-ethoxycarbonyl-β- In 1997, Antonello and his co-workers ethoxyacrylate to give 32 or with ethyl α-ethoxy reported the preparation of a series of 5 and 6- ethylidene cyanoacetate to give 33. disubstituted thiouracils 37 by condensation of β-oxo esters with thiourea in alcoholic sodium ethoxide. O O O O O O EtO C 1 1 OEt C R NH2 R NHMe alc. MeN OEt EtO + NaOEt HN EtOH + NaOH S 2 O H S N 2 NH S N R S NH O R 2 2 H H 37 alc . 32 1 R = H ,CH3 O O NaOH 2 R = C6H5CH3CH2,2-CH3-C6H4 , C EtO OEt 1-CH2-C10H7,2-CH2- C10 H7, NHMe C6H5 - SCH2 + EtO S 26-28 NH2 Many authors reported the formation of 5- O cyano-6-aryl-2-thiouracils 38 via cyclocondensation of O Bu CN alc. N aromatic aldehydes, thiourea, and ethylcyanoacetate in NHBu EtO CN NaOH absolute ethanol /anhy. K2CO3. + S N CH H 3 S O NH2 EtO CH CN NH 3 33 2 CN Ar -CHO + + K2CO3 HN CH2 S abs.ethanol COOEt NH2 S N Ar 1.6. 6-Substituted thiouracils H 23 In 1999, Maurizio et al. reported the synthesis 38 of thiouracil derivatives 34 via reaction of acetone Ar = C6H5 ,CH2CH2C6H5 , dicarboxylic acid diethyl ester or ethyl-γ- 4-OCH3-C6H4 ,4-Cl-C6H4, chloroacetoacetate independently with S-methyl thiourea 4-Br-C6H4 , 4-F- C6H4, hydrogen sulphate in presence of calcium hydroxide. 4-CH3- C6H4 , 3-NO2- C6H4, 3-Cl-C H ,3- Br-C H 6 4 6 4 NH 2 O O O 6-Aryl-5- cyano-2- thiouracils could be also + - Ca(OH) HN R CH - S NH HSO 14,15,29 EtO + 3 2 4 obtained by the reaction of ethyl cyanoacetate, H O / EtOH R 2 CH3 S N O 25 C 34 thiourea and aromatic aldehyde in ethanol using sodium

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1 1 Ar Ar COCH 2 O 3 COCH2CH2NH - Ar CN HN ( CH O)n HN NH2 CN + 2 2 NaOC H HN Ar -NH2 Ar- CHO + CH + 2 5 S N H SO -CH OH 2 CH3 2 4 3 S N CH S abs.ethanol H 3 COOEt NH H 2 S N Ar 44 H 45 38 1 Ar = C6H5 ,4-OCH3 -C6H4,CH=CH- C6H5 Ar =C6H5 ,2-(OCH3 )C6H4 ,2-CH3-C6H4, 2 Ar = C6H5 ,4- OCH3 - C6H4 4-N(CH3)2C6H4 ,3,4-(OCH3)2C6H4 , 3,4,5(OCH ) C H , 4-FC H , 3 3 6 2 6 5 36 4-Br C H , 3 -Indolyl 6 4 Reaction of 5-ethoxycarbonyl-6-methyl-2- thiouracils 46 with sulfadiazine in DMF gave A series of pyrimidine-2-thione derivatives 40- sulphonamides 47. 42 were prepared via a Biginelli-type multicomponent reaction between aldehyde, (ethyl cyano acetate or ethyl Ar Ar COOCH2CH3 CONH HN trifluoroaceto acetate or isopropylacetoactate) and Sulfadiazine HN 30 31 S N CH3 S N N thiourea in piperidine , polyphosphate ester (PPE) or CH3 SO2NH H H 32,33 46 strontium chloride hexahydrate . 47 N

Ar = 4-OCH3-C6H4 , CH=CH-C6H5 O CN NH 2 CN Ar- CHO + + Piperidine HN CH2 abs.ethanol 2. Synthesis of fused thiouracils S 37 COOEt NH2 S N Ar In 2009, Mohamed et al , reported the reaction H of 6-aryl-5-cyano-2-thiouracil with chloroacetonitrile in 40 boiling ethanol containing triethylamine to afford 3- Ar =4-OCH3-C6H4,4-Cl- C6H4, aminothiazolo pyrimidine 48; whereas the reaction of 3-Cl-C6H4 thiouracil with dioxalyl chloride gave 2,3,5-

O trioxothiazolopyrimidine 49. O F C OH O NH2 3 PPE HN R + O Ar -CHO + R CF3 S NH O NH2 2 O THF - HCl S N Ar O NC NC H N CN ClCH2CN HN ClCOCOCl N 41 O S HS N Ar = C6H5 ,4-F-C6H4,4-OCH3-C6H4 , N R N S 2-Br-C H ,3-OH-C H ,3-CN-C H 6 4 6 4 6 4 48 49 H3CO H CO R = 2 -C4H3S, 2-C4H3O, OCH2CH3 ,OCH3 3

Omar et al, 14,29 reported the reaction of the O CH CHO O O 3 H3C hydrazinyl derivatives 50 with ethylchloroformate in NH2 SrCl .6H O HN O + O CH + 2 2 CH3 refluxing pyridine to afford the desired triazolopyrimidine H C 3 3 S NH abs.ethanol S N 2 CH3 H derivatives 51. 42 H N N In 2011, Yan-Ping et al,34 reported the synthesis NHNH2 CN O CN of a novel dihydro-alkylsulfanyl-cyclohexyl- N ClCOOEt N Pyridine oxopyrimidines 43 through the reaction of β-keto esters S N Ar S N Ar H H and thiourea in sodium ethoxide. 50 51 Ar = 2 - (OCH3) -C6H4 ,3,4-(OCH3)2 -C6H3 O O O NH R 2 HN + NaOEt O The preparation of 7-(2-methoxyphenyl)-5- CH3 S abs.ethanol S N NH2 R H thioxo-5,6-dihydro [1,2,4] triazolo[4,3-c] - pyrimidine-8- 43 carbonitrile (53) from 4-hydrazino pyrimidine 52 and R =CH3 ,CH2CH3 ,CH(CH3)2 trimethyl orthoformate by heating under reflux was reported14. 35 In 2012, Mosaad et al. reported the synthesis of NHNH a series of mannich bases 45 via the reaction of 5-acetyl- 2 N N

6-methyl-2-thiouracils 44 with paraformaldehyde and CN CN N OCH primary aromatic amines. 3 TMOF N OCH3

S N S N H H 52 53

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In 2012, Omar et al,29 reported 3. Biological significance of 2-thiouracils and fused cyclocondensation of hydrazinyl derivative 54 with thiouracils acetyl acetone in refluxing DMF for preparation of 6-(3,4- dimethoxyphenyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)-2- 3.1. Anti-cancer activity thioxo-1,2-dihydro-pyrimidine-5-carbonitrile (55). Merbarone® 62, a topoisomerase II inhibitor acting on the catalytic site, active against both fast and CH3 slow growing cancers. Merbarone®, showed antitumor 39 N activity against the murine L1210 leukemia model as NHNH H3C 2 N well as against B16 melanoma and M5076 sarcoma22 CN CN N N (optimum dose range 50-100 mg/kg). acetylacetone,DMF

S N S N H H H O O 54 55 OCH3 OCH3 OCH C6H5 3 OCH3 HN N H S N O H 16 Magdy and associates reported the synthesis of 62 1,3,4,6-tetrahydro-3,4,6- trioxo-2H-pyrimido [2,1-c]- [1,2,4] -7-carbonitrile (57) via cyclocondensation A series of 2-S-substituted thiouracil derivatives of hydrazino pyrimidine derivative 56 with diethyloxalate has been reoported for antitumer activity40-42. For in absolute ethanol. example, methioprim 63, ethioprim 64 and benzylthioprim 65 and 66. O O O CN OH (COOC H ) O CN HN 2 5 2 NH 2 N 2 R CH2OH N H NHN N HN N 2 N ph N N N ph 1 3 H R S N OH R O N R N O N 66

1 63: R=CH 3S R = 4 -CH 2C 6H 4OCH 3 , 64: R=C 2H 5S 56 4 -CH 2C 6H 4O-CH(CH 3) 2CH 2 , 57 65: R=C H CH S 6 5 2 CH 2C(CH 3)=CH 2 , CH 2C 6H 3(3-CH 3-4-OC 3H 7-iso) 2 In 2013, Mosaad et al.38 presented that the 4- R = H,CH 3 3 hydrazinopyrimidine derivatives 58 has also been used as R = H,OCH(CH 3) 2 key starting material for the preparation of Thiouracil hybrids 67 demonstrated triazolopyrimidines 59 by the reaction with acetic 44 anhydride. chemopreventive effect against carcinogenesis on Raji cells. NHNH2 N N O CN H C CN NC N 3 N AC 2O NH N N S N Ar S N Ar N S H H 67 59 58 Cl Ar = 3,4,5(OCH3)3C6H2 , 4-FC6H4 , 4-Br C6H4 ,3 -Indolyl 2-S-alkylated thiouracil 68 selectively exhibited

cytotoxic activity against murine leukemia cell line Triazolo[1,5-c]-pyrimidine 60 and 2-methyl (P388cell) and 1-adamantylthiopyrimidine 69 displayed triazolo[1,5-c]-pyrimidine 61 were prepared via the cytotoxic activity 4 against many cell lines. Significant reaction of hydrazino derivatives with formic acid or activity of 69 was observed against multidrug-resistant acetic acid. This reaction was reported 38,18 by Mosaad et small cell lung cancer cell line (H69AR) with the IC of al in 2013 and 2014. 50 35.0 mg/mL, whereas the control drug; etoposide showing

the IC50 of 30.0 mg/mL. N H3C NHNH O N CN 2 N N CN N CN HCOOH N HN CH3COOH N S N Ar H S N Ar S N Ar H RS N 60 H 4 - Br C H , 61 Ar = 4- F C6H4 , 6 4 68 : R=CH 2C6H5 R=1- Adam 3,4,5 (OCH3)3 C6H2, 69 : 3-indolyl http://aprh.js.iknito.com 80 ISSN: 2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Ahmad and Mohamed, 2017, 1 (2), 75-88

Functionalized S-alkylated 6-aryl-5-cyano-2- Some novel 2-thiouracil-5-carbonitrile thiouracils 70 displayed potent growth inhibitory effect 44 derivatives 80-82 showed promising anticancer activity5 toward non-small cell lung cancer (HOP-92) and against many cell lines. Compound 80 exhibited potential leukemia (MOLT-4) cell lines, respectively. Compound growth inhibition activity against most of the tested 71 may possess specific biological properties45, including subpanel tumor cell lines. It showed promising activity potent antagonist of Epac protein at therapeutic target of toward several cell lines of Non-Small Cell Lung cancer cancer and 72 displayed promising anticancer activity 28 (EKVX, HOP-62, HOP-92, NCI-H23, and NCI-H322M). against leukaemia, non-small cell lung, melanoma, and O 1 2 renal cancer. R R O N CN HN N O CN O O N Br CN NC CN CN HN NH CH3 RN S N N O O H S N CH3 N S RS N S N R 80 H 70 71 72 S N O 1 81 R 82 R = 2,6-(Cl) -C H 2 2 6 3 CH3 R 1 2 N N R= CH 3, C2H5 , 5-CH 3-C4H3S NR R = 1 2 R =R =H,Br O

6-Propylthiouracils 73, 74 are novel cytotoxic Thiouracil derivatives 83, 84 revealed agents 46, the adamantly derivative is the most potent antiproliferative activity13 against human colon (HT-29) cytotoxic against multi drug-resistant small cell lung and breast (MCF-7) cell lines. cancer cell line (H69AR). O O O O HN R HN N R N HC=NHN N NHSO - R H CS N NHSO - R 2 1 3 2 S N R CH3 83 84 H S N CH3 74 73 R = C6H5 ,4 -OCH3 - C6H4 R = CH C H 2 6 5 R = CH2C6H5 1 R = n - C H 4 9 CH2C6H11 CH3 1-Adam The fused 5-cyano-2-thiouracil derivatives 85-87 A series of trifluoromethylated-2- induced a significant growth inhibition14 towards liver thioxopyrimidines 75-77 were synthesized and They cancer (HEPG2) cell line in comparison to 5-flurouracil showed highly potent and selective anticancer activity31 after treatment with IC50 values (ranged from 3.74 to 8.48 against colon cancer cell line (COLO 320 HSR). μg/ml concentrations) for each compound while the IC 50 1 CF OEt value for 5-flurouracil was 5μg/ml concentration. R CF OEt 3 F C OH 3 3 F3C HN O HN O HN O H H O N N O N N N S N R O S N N S N H H H R CN O CN O O N OCH CN 75 O 77 3 N OCH3 76 O N OCH3

R=4-OCH3-C6H4 , S N S N S N 4-F-C H H H 6 4 H 1 85 R = 1-C4H3O 86 87 4 -C10H7 R = H ,CH3

7-Phenyl-5-(-2-carbonyl)-2-thioxo- A novel series of 5-cyano-2-thiouracil 2,3-dihydro-1H-pyrido [2,3-d] pyrimidin-4-one (78) and derivatives 88-90 were designed as potential cyclic- ethyl 7-(4-methoxyphenyl)-4-oxo-2-thioxo-1,2,3,4- dependant kinase 2 inhibitors 29 (CDK2) against human tetrahydropyrido[2,3-d]pyrimidine-5-carboxylate (79) 47 cervix carcinoma (Hela cell lines). showed moderate activity against lung carcinoma cell line (H460). CH3 O COR

N H C H HN 3 N N N N N CN 1 N S N N R CN N O CN N N H 1 1 R NH N R 1 1 R NH N R R NH N R 78 : R= 2 -C H S ,R = C H 4 3 6 5 88 89 90 1 79 : R= OC2H5 ,R = 4 -OCH3 -C6H4 R= C6H4-SO2NH2 1 R = 3,4-(OCH3)2-C6H3 http://aprh.js.iknito.com 81 ISSN: 2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Ahmad and Mohamed, 2017, 1 (2), 75-88

3.2. Anti-microbial activity Thiouracil derivatives 100 were found to be potent 27 In various communication articles 10,47-52, against Mycobacterium tuberculosis. thiouracils having formula (91-96) were reported to be useful as anti- infective agents as antibacterial and R antifungal. F

O NH 1 R Cl CN HN O O CN N 2 N S N R HN NH 1 2 S N 3 R S N R H R S N NH2 H N N S 92 2 91 100 CH3 F 1 CH3 1 93 , R = 2-C4H3S ,3-F-C6H4 , 2-C4H3O R = Cl, Br , CN , C6H4CH2 , SO2 NH NH2 2 R= F, NO2 2 R = C H , C H , 4-Cl-C H CH R = H,C6H5,C6H5 N,CH2CH2C6H5 ,4-OCH3 -C6H4 2 5 3 7 6 4 2 3 R = H, CH3 ,C6H5 ,4-F C6H4 Thiouracil derivatives 101 showed significant R 2 activity against staphylococcus aureus, while R 1 O O COR N compounds102, 103 displayed moderate inhibitory N 28 HN HN O activity against Candida albicans. Moreover, N 2 S N N S N R compounds 104 possessed superior antibacterial activity H H CH3 N 96 against the gram positive bacteria S.aureus and B.subtilis 94 HS N 1 compared to the reference drug Amoxicillin. Moreover, R = 2 -C 4H 2 -C 4H R = Cl ,OCH ,NO 3 2 2 -C 95 1 10 compound 105 was found to be broad spectrum R 1 2 2 R = NO R = R = C H 4-OCH - C H 44 2 , OCH3 , 6 5 , 3 6 4 antimicrobial agent and it also exhibit promising Cl OH antifungal activity against C.albicans. Thiouracil derivatives,4,6-bis-(benzyldidene- O O O amino)-1,3,4-tri-hydropyrimidine-2-thiones CN CN CN (97), revealed promising antimicrobial activity53. N N N RS N HN N H2NHN N H CH -R N 101 102 N X Br 103 Br R=Cl X= CH(CH3)2 NH Br R -CH N N SH OH 97 O R = C6H5 , 4-Cl- C 6H 4 CN HN O It is demonstrated that the thiouracil analogs 98 NH CH3 S N 46 CN is a novel antibacterial. It exerts potent activity against Br N HN H B.catarrhalis with MIC of 32 μg/mL. 105 S S N O 104 O R R = Br ,CH3 HN 4-(2-Chloro-6-fluoroquinolin-3-yl)-6-(4- R S N methoxyphenyl)-3,4-dihydropyimidine-2(1H)-thione CH3 54 98 (106) has a significant antibacterial activity against R= 1-Adam S.aureus, Klebsiella aerogenes and Proteus microbialis.

A series of 6-aryl-5-cyano-2-thiouacils 99 OCH3 exhibited moderate antibacterial activity 3 against Staphylococcus aureus and Bacillus subtilis and significant antifungal activity against Candida albicans and Asperigillus niger. O NH CN F HN N S

1 H R N N Cl 99 R 106 R = H ,4-Cl ,4-OCH3 ,3-NO2 1 N N R = SCH 3 , , Isopropyl2-(4-substitutedbenzylidene)-5- O N methyl-3-oxo-7-phenyl-3,7-diydro-2H-thiazolo[3,2-a]- CH3 http://aprh.js.iknito.com 82 ISSN: 2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Ahmad and Mohamed, 2017, 1 (2), 75-88 pyrimidine-6-carboxylate derivatives 107 showed potent Thiopyrimidine 112 showed promising antimicrobial activity 33 against Escherichia coli, antimicrobial activity towards B. subtilis, C. albicans, and Staphylococcus aureus, Pseudomonas aeruginosa, A. niger, while compounds 113 and 114 were found active Streptococcus pyogenes, Klebsiella pneumoniae, against A.niger and B.cereus, respectively. Compound Aspergillus flavus, Aspergillus fumigatus, Candida 115 (MIC value = 0.0524 µmol/cm3) exhibited an albicans, Penicillium marneffei and Trichophyton interesting antimicrobial profile with dual antibacterial mentagrophytes. (against S. aureus) and antifungal (against C. albicans) effects 56.

O O O R H3C O HN HN CH O N 3 ( ) N n S N H3C N S N 1 H3C N S R 112 O O 1 O 113 : R=CH3, R =3,4 - (OCH3)2 , n = 2 O 114 : 1 R R=CH3 , R =C7H5O2 , n = 3 107 R =CH CH , 1 115 : 2 3 R =C7H5O2 , n = 3 R = C6H4 ,4-Br-C6H4 ,4-NO2-C6H4 4-OCH3 -C6H4 ,4- N(CH3)2 -C6H4 4-Oxo-5-cyano thiouracils 116 showed good

antimicrobial activity 57 against Escherichia coli mutant Novel 2-thiouracil-5-carbonitrile derivatives strain, NR698 and evaluated as SecA inhibitors. Protein 108-110 showed broad spectrum antimicrobial activity 6 translocation is essential for bacterial survival and the against Staphylococcus aureus, Pseudomonas most important translocation mechanism is the secretion aeruginosa, Shigella flexneri and Candida albicans. (Sec) pathway in which Sec A is a central core driving

H force. Thus targeting Sec A is a promising strategy for H O O N S CH O N S 3 developing novel antibacterial therapeutics. N N N NC N3 NC H3C O O CN HN

108 109 X N Cl O 116 H O N S NH X = S ,O N NC R 3.3 Molluscicidal activity 110 Fused thiouracil 117 posses significant molluscicidal activity 37 towards Biomphalaria Thiouracil derivatives 111 were found to have alexandrina snails, the intermediate host of Schistosoma significant antimicrobial activity55 against Staphylococcus mansoni. aureus, Bacillus subtilis, Escherichia coli, and antifungal Aspergillus niger and Candida albicans comparable to the O O standard drugs Ciprofloxacin and Fluconazole. NC N CHC6H5 Cl N S 117 H CO H CO 3 3 3.4. Anti-leishmanial activity O N 3-Amino-2-carboethoxy-6-substitutedthio-4-(3- X H3C N pyridyl) thieno [2,3-d] (118) found to have a 58 111 significant antileishmanial activity against L.donovani promastigotes. X = N ,S

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COOET 2 2 R R S N N NH2 N O O N RS N N

N N 118 N

HS N H2N N 127 128 R = CH3 ,C2H5 ,CH2=CH2 1 1 R R C H CH , 4-OCH -C H CH 1 1 6 5 2 3 6 4 2 R = OH, OCH OCH3 R = 3 2 2 R = R = NO2, NO2 , Cl Cl 3.5. Antioxidant activity. The antioxidant activity of fused thiouracil Thiouracil derivatives 129 and 130 have shown derivatives was reported. Compound 119 showed good more promising antioxidant activity 64 as compared to antioxidant activity59 (DPPH Scavenging method) standard, ascorbic acid. compared to BHT (Butylated Hydroxy Toluene) as reference, IC50=234,184,132; respectively. The O O 60,61 H C CN significant antioxidant activity of compounds 120- CN 3 HN N 124 were reported because they protect DNA from damage. HS N R H2NHN N R 129 130

O R = C6H5 , 3-OCH3 -C6H4 , 2,3,4 - (OCH3 )3 -C6H2 O H3C O NH H3C CH R H3C 3 N H3C S 1 NH N CH2HN R 3.6. Anti-viral activity O S N CH 119 3 O S N S H A series of 5-cyano-2-thiouracil derivatives 131 H 26 1 120 was synthesized by Ram etal and reported as antiviral R = R = H,OH 121 against herpes simplex. H S O O N H3CO H NHN O 2 N O O O N O O N CN O HN S O H2N N N N N S 1 2 122 H OCH R S N R S 124 3 H2N N 123 131 1 R = C H 2 , C6H5CH2 , n - C 4H9 A series of 2-dihydropyrimidine-2(1H)-thiones 2 R = 4-Cl -C H , 125 proved to have significant antioxidant activities 6 5 4-(CH3)2NC6H4 , compared to ascorbic acid 62. Compound 126 showed 2 - Thienyl promising antioxidant activity 63. The reverse transcriptase (RT) of human immunodeficiency Type 1(HIV-1RT) is one of the main O targets for drugs used in the treatment of AIDS, several CH3 O O RT inhibitors have been developed and approved by food H3C O NH H C NH and drug administration organization ( FDA) . A series 3 of 5-substituted-2- thiouracils of general formula 132-135 H3C N S O 65-67 H3C N S H was reported as HIV-1 inhibitor . R 125 126 NH O 1 R = 4-Cl,3-Br ,4-Br ,3-NO ,4-NO O R 2 2 HN Y CH3 HN S N S 1 2 2 R S N R R O Y A series of novel 1-(2-mercapto-6-(substituted phenyl) 133 132 1 pyrimidine-4-yl)-3-(2-substituted phenyl imino) indolin- 1 R = 2,4-F-C H , 4 -Cl -C H R =C2H5 , i-propyl 6 4 6 4 2 2-ones (127) and 1-(2 amino-6-(substituted R = CH3 , CH2OH ,C6H5 4 -OCH3- C6H4, C6H5 phenyl)pyrimidine-4-yl)-3-(2-substituted phenyl imino) 2 Y = H ,CH3 R = 2,6-F-CH2C6H4 indolin-2-ones (128) were synthesized and showed more O H C CH O 53 3 3 promising antioxidant activity in comparison to O HN standard, butylated hydroxy toluene. N HN S N CH3 O O 135 S N R 134

R = CH2C6H4 ,CH2(2,6 -F2C6H3) http://aprh.js.iknito.com 84 ISSN: 2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Ahmad and Mohamed, 2017, 1 (2), 75-88

O O A series of 5-cyano-6-aryl-2-thiouracil 1 1 17,68 R R derivatives 136 showed antiviral activity against HN HN 2 2 hepatitis C viral NS5B RNA-dependant RNA polymerase R R (anti-HCV). It’s noteworthy to mention here that this is S N S N 140 the same mechanism as the famous new Sovaldi drug. 141

O 1 R = CH(CH ) - , CH CH 1 3 2 2 3 R = I , Br 2 CN 2 R = C H CH , C H CH CH , HN R = (4 - OCH3)C6H4 COCH2 , 6 5 2 6 5 2 2 C H COCH , (OCH )C H CH 2 6 4 2 C6H4CH2 , C6H5CH2CH2 , 3 6 4 2 R 1 C H COCH S N R 6 4 2 136 3.7. Anti-thyroid agents 1 R = 4- Br C H , 2,4- F- C H , 6 4 6 3 2,4 -Cl-C6 H3 , 2-Thiouracil derivatives are useful clinically as 2- CH - C H , 2,4 -F-C H 3 6 3 4-BrC6H4, 6 4 antithyroids. A huge number of compounds structurally 2 R = 3 -NO - C H CH , related to 2-thiouracil have been evaluated for antithyroid 2 6 4 2 3,5 -OCH3- C6H3CH2 , 3 - CH3 - C6H4CH2 , 2- Br - C H CH , activity but probably the most widely used compounds for 6 4 2 73 CH (CH ) , the treatment of hyperthyroidism are 6-propyl-2- 3 2 4 2 -Br -C6H4 thiouracil (142) and 6-methyl-2-thiouracil (143). A series of 2-thiouracil nucleosides 137,138 O showed potent and selective antiviral activities 69,70 against herpes simplex virus (HSV), varicella-zoster virus HN (VZV) and human cytomegalovirus (HCMV). S N R H O NH2 R R HN R N 142 - CH2CH2 CH3 S N 143 - CH HO S N 3 O HO O Conflict of Interest: The authors declare that they don’t HO 137 HO have any conflict of interest. 138

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