Synthesis and Biological Activities of Some Pyrimidine Derivatives: A Review

Introduction

Because of its different intrinsic biological properties Pyrimidine it become attractive for researcher in medicinal chemistry field [1], pyrimidines are used asMycobacterium tuberculosis[2],antioxidants [3] ,antidiabetics [4] .

Heterocycles which contain  pyrimidopyrimidine have  therapeutic properties ant allergic,[5], antioxidant,[6,7], antiviral,[8], antihistaminic,[9], cytostatic, immunomodulating,[10–12] herbicidal[13], anticonvulsant,[14] activities . pyrimidines exhibit  antimicrobial  activities such as fungicidal,[15] , antitoxoplasma,[16],antimalarial,[17,18], antibacterial,[19,20], antifilerial,[21]  antileishmanial[22,23], pyrimidine (Figure 1) broxuridine (I)—antiviral, and brodimoprim (II)—respiratory tract and ear infections, trimethoprin (III)—antibacterial, antifungal flucytosine (IV),—liver disorder by orotic acid (V) [24]. Pyrimidine nucleus act as antimicrobial agent [25] so they are important chemicals in agricultural and drugs. Pyrimidines comprise important interesting group of antibacterial drugs, which have made a major impact on the field of antibacterial chemotherapy particularly in the past few years.Pyrimidine nucleus act as chemotherapeutic agents and exhibit   anticancer activities [26].

Figure 1: Pyrimidine compounds that show pharmacological activity Click here to View figure

Synthesis and Biological Activities of Pyrimidine Derivatives

Reaction of diazonium salt (1) and (2) in solution of NaOH yield the corresponding (3) which react with sulphonamide derivatives  diazonium salt give compound (4 a-c) ( scheme 1).[27], compounds (4b)and (4c ) exhibit good results against  anticancer and antifungal   efficacies , gram negative and gram positive  respectively .also  both pyrimidine derivatives azo dyes and thiazolyl azo dyes derivatives displayed good properties  on polyester fabrics, but thiazolyl azo dyes derivatives exhibit good  properties than pyrimidine derivatives azo dyes[27]. sulphonamide-diazobenzene derivatives exhibit pharmacological activities so it used as nontextile.[27].

Scheme 1: Synthesis of diazobenzene dyes (4a-c), 4a (81%), 4b (77%), 4c (79%). Click here to View scheme

Treatment paracetamol(5) with 2,3-di chlorobenzaldehyde(6)  in  solution of KOH at 298k afford  chalcones (7). Reaction of chalcones (7) with urea and potassium hydroxide  in methyl alcohol yield the corresponding (8) ,Also treatment of chalcone(7) with Thiourea and KOH in methyl alcohol give compound (9), treatment  of chalcone (7)and  hydrazine monohydrate in AcOH provide the corresponding (10), the product  recrystallized with ethanol .[28]

Scheme 2: Synthesis of pyrimidine (8) and (9). Click here to View scheme

Reaction of triazole (11) with (12 a) by using different solvent such as methanol/HCl, ethanol, acetic acid, there is no reaction but the reaction of mixture in DMF using reflux and heat in presence of  potassium carbonate anhydrous provide  triazolo pyrimidine  (15a)  or (18a). The confirmation of (18a) was performed via reaction of (19) and malononitrile at the same condition provide the same sample of (18a).

Treatment of triazole (11) with (12b) provide triazolo pyrimidine (18b). Also, mixing of (11) with (12c) give amino derivatives (18c). Another method for the preparation of (18b, c) is the reaction of benzyl cyanide and cyanoacetate with (19), compound (18d) was synthesized by reaction of (12) with triazole (11). While reaction of (12e) with triazole (11) provide unsubstituted triazolo pyrimidine (18e).Triazolo pyrimidine (22) was synthesized via reaction of compound (20) with triazole (11),the reaction proceed by reflux in presenceDMF/K₂CO₃ via cyclization of (21).

Refluxing of compound (22) with substituted 1, 4-benzoquinone and   acetonitrile (3eq.) via refluxing provide triazolopyrimidine (23) (Scheme3). Cyclocondensation of β-enaminones (24a–c) with 11 and acetic acid via reflux givesubstituted pyrimidines, when equimolecular amount from  compound (11) react with β-enaminones (24a) in presence of DMF/K₂CO₃ via refluxing for 2h.to provide isolated compounds (25a) and (26) in equal ratio. [29],[30].

Compounds (25b, c) were prepared via treatment of (24b, c) with compound 11 (cf. Scheme 4).

Scheme 3: Synthesis of pyrimidine 22 and 23 Click here to View scheme

Scheme 4: Synthesis of pyrimidine derivatives 25a-c and 26 Click here to View scheme

Pyrimidine derivatives (30a–n) (Table1) [31] were prepared via treatment of three component (27), (28), (29) in ethanol.

Scheme 5: Synthesis of pyrimidines (30a–n) Click here to View scheme

Scheme 6: mechanism for synthesized pyrimidines (30a–n). Click here to View scheme

Table 1: Synthesis of pyrimidines (30a–n) (30a–n) [31]. Click here to View table

The condensation of thioxopyrimidine (35) with substituted aromatic aldehydes and α chloroacetic acid afford the corresponding thiazolopyrimidine derivatives (36a–h) (Scheme 7).[32]

Treatment of 2-chloro-N-substitutedphenylacetamide (37a–c) with thioxopyrimidine 35 and dimethyl formamide, potassium carbonate, provide (38a-c), and (39) obtained via reaction of compound (35) with p-toluene in presence of K₂CO₃ and DMF in stirring resulting N-alkylation product. treatment of (35) with ethylacetoacetate and potassium carbonate anhydrous afford compound( 40)  which react  with hydrazine hydrate and ethanol provide the corresponding compound (41) (Scheme7)[32] .

Treatment of (35) with hydrazine hydrate affords hydrazino derivative (41).Treatment of (41) and arylidene provide the corresponding (42) (Scheme 11). Synthesis of compounds (42–45) appears in (Scheme 10). Compound (42) obtained via reaction of p-methoxybenzaldehyde with hydrazine derivative (41). [32]

The acetyl derivatives 43 were obtained by reaction of compound (41) and acetic anhydride under reflux. Reaction of compound (41) with cyclopentanone in ethanol provide (44). Compound (45) was obtained by reaction ofhydrazine derivative (41) with acetamide derivatives. Tetrazolopyrimidine (46) was obtained viadiazotization of compound (41). Reaction of (41) with formic acid provide pyrimidines (47) (Scheme 6). Treatment of benzoyl chloride with compound (41) affords corresponding Triazolopyrimidone derivative (48). Reaction of (41) and carbon disulfide in presence of pyridine provide triazolopyrimidone derivative (49)[32]. The synthesized compounds ofcyanothiouracil derivatives (36–49) were obtained from cyanothiouracils and dihydropyrimidine carbonitriles derivatives. Some of these compounds exhibit Potent activities, anticancer and Antimicrobial.[32]

Scheme 7: Synthetic pathway of compounds (36-41) Click here to View scheme

Table 2: The synthesis of compounds (36a-h) [32] Click here to View table

Scheme 8: mechanism for synthesis of (36a-h). Click here to View scheme

Scheme 9: mechanism for compound (41). Click here to View scheme

Scheme 10: Conversion of (41) to pyrimidine derivatives (42–45).  Click here to View scheme

Scheme 11: suggested  mechanism for  (42) Click here to View scheme

Scheme 12: preparation of triazolo and tetrazolopyrimidinone derivatives (46–49).  Click here to View scheme

Scheme 13: mechanism (49). Click here to View scheme

Synthesis of (54a-l) proceed via two-step (Scheme 14) [33], the synthesis of (54a-I) via both methods microwave and conventional.in the conventional method substituted aldehydes (50a-l) treated with, malanonitrile (51), and 1, 3 dihydroxy benzene (52) afford the corresponding pyran derivatives (53a–l). Cyclization of pyrane derivatives (53a–l) by using nano catalyst provide (54a–l) this green method and highly efficient ,Also the reaction  occur without catalysts by using reflux for 8h. [33]. 

The synthesized compounds exhibit antifungal, antioxidant and antibacterial effect [33].

Scheme 14: synthesis of pyrano[2,3-d]pyrimidine (54a) Click here to View scheme

Table 3: Synthesis of pyrano pyrimidine derivatives (54a–l) [33] Click here to View table

Scheme 15: mechanism for synthesis of compound (54a) Click here to View scheme

Pyrimidine (58) was prepared by treatment of methylthiopyrimidinone (55) with bromomethylacetylene  (56) in K₂CO₃ /DMF at room temperature(Scheme 16).[34]

Treatment of pyrimidine (57) and (59a) in the absence of catalyst lead to there is no formation of product formed after 3h. the reaction give maximum of the yield  when use CuI/Mg-Al-LDH catalyst [28,this method was easy ,clean reaction , short reaction time ,and high yield [34].

Scheme 16: Synthesis of compound 57 and 58. Click here to View scheme

Scheme 17: Proposed mechanism for synthesis of pyrimidine derivatives (60) Click here to View scheme

Table 4: Synthesis of pyrimidine derivatives (60a-i) [34] Click here to View table

Reaction of compound  (63) with 64,66,68 afford the corresponding thioxypyrimidine (67) and pyridinethione (69) these compounds was considered as a key for synthesis of different pyrimidine derivatives [35]. The formation of compound (63) indicated in (Scheme 18). [36].

Compound (65) (Scheme 18). [37] Was prepared by treatment of chalcone (63) with thiourea (64) compound (67) was prepared via treatment of chalcone (63) and dihydropyrimidinone (66) (Scheme 18). [38]. the compound (69) was prepared by treatment of 2-cyanoethanethioamide (68) with chalcone (63) in diaoxane and piperidine catalyst at reflux the reaction proceed via cyclocondensation reaction (Scheme 18). [39].

Reaction of (65) or (67) with the appropriate nitrilimines (71) afford the corresponding triazole compound, the nitrilimines (71) prepared by treatment of hydrazonoyl chlorides (70). [40] With triethylamine (TEA). Triazolo pyrimidine (75a) (Scheme 19) was prepared by reaction of hydrazonylchloride (70a) with pyrimidine-2(1H)-thione (65) at reflux. In addition, reaction of hydrazonyl chlorides 70b-d with compound 65 provide triazolo pyrimidines (75b-d) (Scheme 19).

Initial alkylation of (65) to provide thiohydrazonate (72) and then cyclization to provide the spiro-intermediate (73) and rearrangement occur [41] provide corresponding (75) via (74) (Scheme 19).

Also treatment  of thioxopyrido[pyrimidinone (67) with  hydrazoe(70a-c ) provide triazolopyrimidines(76a-c) (Scheme 19).[38], thienopyridine (78) (Scheme 20) was synthesized by treatment of 2-dihydropyridine-3-carbonitrile (69) with 2-chloroacetamide(77) in sodium ethoxide at reflux[42]. thienopyrimidinone derivative (80) (Scheme 20).[42] was prepared by reaction of thieno[2,3-b]pyridine-2-caboxamide derivative(78) with (79). Also, 2-carboxamide derivative (78) treated with both  (81), (83a), and (83b), to give compounds (82) and (84a,b,) (Scheme 20). pyridotpyrimidinone (86)(Scheme 21) [42] was synthesized by reaction of  thienopyrimidinone (80) and  iodomethane (85) in ethanolic sodium ethoxide. Preparation of fused triazole was proceed by treatment  of (86) with hydrazonyl chlorides (70).[43]. triazolopyrimidinone derivative (88a) was synthesized by reaction of compound (86) with hydrazonyl chloride (70a) in dioxane and triethylamine at reflux, to provide  (87) and then  loss methane thiol provide  (88a) (Scheme 21). Also, compound (86) treated with (70b-d) to provide triazolopyrimidinones (88b-d) (Scheme 21). Treatment of 2-thioxopyridothienopyrimidin-4(1H)-one derivative (80) with hydrazonyl chloride 70a in dioxane and triethylamine at reflux afford the corresponding compound (88a) (Scheme 21)[35]. the newly pyrimidines was exhibit in vitro antimicrobial activities [35]

Scheme 18: Preparation pyrimidinone (69). Click here to View scheme

Scheme 19: Preparation] triazolopyrimidines (75) and (76) . Click here to View scheme

Scheme 20: Preparation pyrimidinones (80), (82), and (84a, b). Click here to View scheme

Scheme 21: Preparation triazolopyrimidinones (88) Click here to View scheme

ethyl 3-amino-2-cyano-6-hydroxy-7, 12-dioxo-2, 7, 12, 12a-tetrahydro-1H-benzo[g]pyrimido[1, 2-a]quinoline-5-carboxylate 90 was prepared by reaction of alkylidenemalononitrile derivatives with ethyl 2-amino-4-hydroxy-5, 10-dioxo-1, 5, 10, 10a-tetrahydrobenzo [g]quinoline-3-carboxylate 89,the pyrimido quinolone derivatives have photodiode applications[44]

Scheme 22: Synthesis of pyrimido quinolone derivatives (90). Click here to View scheme

Scheme 23: Synthetic pathway for the pyrimido quinolone derivatives Click here to View scheme

Conclusion

The current study gives a portrayal of the biological and natural significance of heterocyclic related pyrimidine nucleus,these pyrimidine unit exhibited significant and assorted organic properties, the examined pyrimidine derivatives prepared by cyclocondensation reaction, also through reaction of chalcone with different 1, 3-dinucleophiles. Pyrimidine derivatives that have biological activities.

Acknowledgments

The author grateful to Jouf University, Saudi Arabia, and Aswan University, Aswan, Egypt is gratefully acknowledged.

Conflicts of Interest

The author declares no conflict of interest.

References

1. Abdel-RahmanR.; El-MahdyK.Heterocycles, 2012, 85, 2391-2414.
   CrossRef
2. Bacelar, A.H.; Carvalho, M.A.; Proença, M.F.Eur. J. Med. Chem.,2010,45 3234-3239.
   CrossRef
3. De la CruzJ. P.; CarrascoT.; OrtegaG. ; De la CuestaF. S. Lipids, 1992,27,192-194.
   CrossRef
4. FangY.; XuJ.; LiZ.; YangZ.; XiongL.; JinY.; WangQ.; XieS.; Zhu W.; ChangS.Bioorg. Med. Chem., 2018,26,4080– 4087.
5. Abu-HashemA. A.; YoussefM. M.; HusseinH. A. R.J. Chin. Chem. Soc. 2001,58, 41-84.
   CrossRef
6. Rahaman S. A.;Pasad Y. R.; Kumar P.; Kumar B.SaudiPharm. J.2009,17, 255-258.
   CrossRef
7. 7.NezuY.; MiyazakiM.;SugiyamaK.;KajiwaraI.Pestic. Sci., 1996,47,103-113.
   CrossRef
8. GuptaA. K.; KayathS. H. P.; SinghA.;SharmaG.; MishraK. C.,Indian J. Pharm.,1994,26, 227-228.
9. StocksP. A.; RaynesK. J.; BrayP. G.; ParkB. K.; NeillP. M.; WardS. A.,J. Med. Chem., 2002,45,4975-4983.
10. Abu-HashemA. A.; El-ShehryM. F.; BadriaF. A.Acta Pharm., 2010,60,311-323.
11. Gangjee A; Mavandadi F;Queener S F. J. Med .Chem.,1997,40, 1173–1177.
    CrossRef
12. TorrenceP. F.; FanX.; ZhangX.; LoiseauP. M.Bioorg. Med. Chem. Lett., 2006,16, 5047-5051.
    CrossRef
13. KatiyarS. B.; BansalI.; SaxenaJ. K.; ChauhanP. M. S., Med. Chem. Lett., 2005,3,15,.47-50.
14. RenQ.; CuiZ.; HeH.; GuY.J. Fluorine Chem., 2007,128,1369-1375.
    CrossRef
15. Saudi, M.N.S.; Gaafar, M.R.; El-Azzouni, M.Z. et al. Med Chem Res,2008, 17, 541.
    CrossRef
16. Sunduru N.; Agarwal A.; Katiyar S.B.; Nishi, Goyal N.; Gupta S.; Chauhan P.M. Bioorg Med Chem., 2006,14,7706-7715.
    CrossRef
17. Ali A.; TaylorG. E.; EllsworthK.;HarrisG.; PainterR.; SilverL. L.; YoungK. J. Med. Chem. 2003,46, 1824–1830.
    CrossRef
18. Selvam T.P.; James C.R.; Dniandev P.V.; Valzita S.K.Res Pharm, 2012,2, 1-9.
19. Patil, S.A.; Patil, R.; Pfeffer, L.M.; Miller, D.D. Future Med. Chem.2013, 5, 1647–1660.
    CrossRef
20. Kemnitzer W.; Kasibhatla S.;Jiang S.; Zhang H.; Zhao J.; Jia S.; Xu L.; Crogan-Grundy C.; Denis R.; Barriault N.; Vaillancourt L.;Charron S.; Dodd J.; Attardo G.;Labrecque D.; Lamothe S.; Gourdeau H.; Tseng B.; Drewe J.; Cai S.X. Bioorg Med Chem Lett. ,2005, 15,4745-4751.
    CrossRef
21. MallikarjunaswamyC.; MalleshaL.; BhadregowdaD.G.; Othbert P.,Arab. J. Chem., 2017,10, S484-S490.
22. Sridhar S.; Rajendra P. Y. ; Dinda S. C.IJPSR, 2011,2.2562-2565.
23. SraaA.M., Pigment & Resin Technology, 2019, 48, 397–403.
    CrossRef
24. ZaiedA. M.;AL-Qadisiyah Journal of pure Science ,2018,,23 , 141.
25. PetrichS. A.; LisaZ. Q.; SantigoM.; GuptonJ. T.; SikorskiJ. A. Tetrahedron,1994, 50, 12113.
26. SirakawaK.;J. Pharm. Soc. Japan,1960, 86, 956.
27. PriyankaT. P.; WarekarP. P.; KirtiT. P.; DattatrayaK. J.;GovindB. K.; PrashantV. A.; Res Chem Intermed, 2017, 43, 4103–4114 .
28. MohamedM. M.; AliK. K.; EslamM. A.; El-Naggar A. M. Synth. Commun, 2017, 47, 1441–1457.
    CrossRef
29. SreelakshmiP.; MahammadS. S.; MuraliS.; SubbaraoY.; VedasreeN.; ApparaoC.; SureshR. C.;J. Chin. Chem. Soc.2019, 1–16.
30. Fatemeh R.; Mohammad B.; Hossein N.‐Is.; Bahram B.; Soheila N., J. Heterocyclic Chem.2020,57,565-574.
31. Sherif M. H. S.; Ahmed A. M. A.; Ahmed E. M. M. J Heterocyclic Chem.2020, 57, 590-605.
    CrossRef
32. JainV. K.; RaoJ. T. Indian Drugs,2004, 41, 334.
33. GomhaS. M.; MohamedA. M.; ZakiY. H.; EwiesM. M., ElrobyS. A.J. Heterocyclic Chem., 2018,55,1147-1156.
34. GomhaS. M.; AbdallaM.; EL-AzizM. A.; SeragN,Turk. J. Chem., 2016,40,484-498.
    CrossRef
35. Shestopalov, A.M.; Nikishin, K.G.; Gromova, A.V.;Rodinovskaya, L.A.Russ. Chem. Bull., 2003, 52, 2203-2206.
    CrossRef
36. Farag, A. M.; Algharib, M. S. Org. Prep. Proced. Int., 1988, 20, 521-526.
    CrossRef
37. HoldenC. M.; GreaneyM. F. Chemistry A European journal, 2017,23,8992-9008.
    CrossRef
38. Litvinov, V.P.; Dotsenko, V.V.; Krivokolysko, S.G. Russ. Chem. Bull., 2005, 54, 864–904.
    CrossRef
39. AbbasI.; GomhaS.; ElneairyM. A. A.; ElaasserM.; MabroukB.Turk. J. Chem., 2015,39, 510 – 531.
    CrossRef
40. ElkanziN. A.A.; FaragA.A.M.; RoushdyN.;MansourA.M. Optik,2020, 216, 164882.
    CrossRef

---

This work is licensed under a Creative Commons Attribution 4.0 International License.