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Review
. 2025 Oct 20;15(46):39235-39287.
doi: 10.1039/d5ra05123a. eCollection 2025 Oct 14.

5-Amino- and 6-amino-uracils in the synthesis of various heterocycles as therapeutic agents: a review

Ashraf A Aly  1 , Esraa M Osman  1 , Sara M Mostafa  1 , Tarek M Bedair  1 , Mohamed Abd-Elmonem  1 , Kamal Usef Sadek  1 , Asmaa H Mohamed  1
Affiliations
Review

5-Amino- and 6-amino-uracils in the synthesis of various heterocycles as therapeutic agents: a review

Ashraf A Aly et al. RSC Adv. .

Abstract

5-Amino- and 6-amino-uracil derivatives are used as precursors in the synthesis of various heterocyclic compounds, which have attracted great interest because of their potent biological activities and therapeutic uses. Multicomponent reactions (MCRs) are a quite significant green technique as they directly correlate with fewer byproducts as well as lower time and energy consumption. These benefits of MCRs expand their potential in the preparation of a variety of new catalytic systems for the synthesis of essential organic compounds in environmentally friendly reaction circumstances. Herein, we focus on some MCR sequences that evolved during the last decade, especially from 2014 to 2024, for the synthesis of target heterocycles starting from either 5-amino- or 6-amino-uracil derivatives. In addition, we discuss the mechanism by which the selected catalyst helps in the selectivity of the target molecules. Furthermore, the biological activity of the synthesized materials as therapeutic agents was reviewed.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1. Structures of 5-amino- and 6-amino-uracil derivatives 1 and 2.
Fig. 2
Fig. 2. Examples of some biologically active aminouracil-based compounds I–IV.
Scheme 1
Scheme 1. Synthesis of aminopyrazole 6. Reagents and conditions: A = neat, MW, 180 °C, 5 min. B = PhCHO, Pip, EtOH, MW. C = EtOH, MW, 130 °C, 10 min.
Scheme 2
Scheme 2. Proposed mechanism for the formation of aminopyrazole 6.
Scheme 3
Scheme 3. Synthesis of pyrazolo[5,1-c][1,2,4]triazine-3-carboxamides 15a–d.
Scheme 4
Scheme 4. Synthesis of uracil–thiazoles hybrid molecules 19a–l. Reagents and conditions: A = MeOH, reflux, Et3N, 10–12 h. B; EtOH, reflux, 6–12 h.
Fig. 3
Fig. 3. Structure of antiproliferative uracil–thiazolidin-4-one derivatives 19b, 19i and 19i.
Scheme 5
Scheme 5. Synthesis of uracil–thiazole 22a–l and 23a–e building blocks. Reagents and conditions: A = MeOH, reflux, 10–12 h. B; EtOH, Et3N, reflux.
Fig. 4
Fig. 4. Structure of antiproliferative uracil–thiazole derivatives.
Scheme 6
Scheme 6. Ultrasound irradiation synthesis of compound 25. Reagents and conditions: A = DMSO, ultrasound, 120 °C, 30 min.
Scheme 7
Scheme 7. Synthesis of tetrazole-uracil hybrid 29. Reagents and conditions: A = NaNO2, AcOH. B; HF, pyridine. C = solvent free, 90 °C, 1 h.
Fig. 5
Fig. 5. Structures of some biologically active and fused 6-aminouracil compounds V–VI.
Scheme 8
Scheme 8. Formation of bis uracils 30a–k. Reagents and conditions: A; Nano-[FSRN][H2PO4]. B; solvent-free, 120 °C.
Scheme 9
Scheme 9. Synthesis of quinoline-bis uracil compounds 32a–f and 33a–f. Reagents and conditions: A; AcOH, reflux, 3–4 h.
Fig. 6
Fig. 6. Structures of antiproliferative compounds 32c and 32f.
Scheme 10
Scheme 10. Synthesis of bispyrrolo[2,3-d]pyrimidines 37a–e and 38a–g. Reagents and conditions: A; TRAB, EtOH, reflux.
Scheme 11
Scheme 11. Three-component reaction for the formation of pyrrolo[2,3-d]pyrimidines 41a–m. Reagents and conditions: A; AcOH, MW 110 °C, 5 min.
Scheme 12
Scheme 12. Proposed mechanism for the formation of 41a–m.
Scheme 13
Scheme 13. Synthesis of uracil-fused 2-aminobenzothiazoles 47a–c. Reagents and conditions: A; (i) H2O2, rt; (ii) NaOH, rt, 1 h.
Scheme 14
Scheme 14. Synthesis of xanthine derivatives 50a,b. Reagents and conditions: A; NaNO2/AcOH. B; NH3/Na2S2O4. C; CS2/(DMF/EtOH), reflux.
Scheme 15
Scheme 15. Synthesis of 8,8′-disulfanediylbis(dihydro-1H-purine-2,6-diones) 53a–k. Reagents and conditions: A; NaNO2/AcOH, 70 °C, Na2S2O4, NH4OH, 70 °C. B; NaHCO3, EtOH:H2O, 65 °C, C; (i) I2, KOH, EtOH, rt. (ii) reflux, overnight.
Fig. 7
Fig. 7. Structures of sirtuin inhibitor compounds 53b and 53f.
Scheme 16
Scheme 16. Synthesis of 8,10-dimethyl-6-substituted purino[8,9-a]isoquinoline-9,11(8H,10H)-diones 55a–g. Reagents and conditions: A; DMF, CuI, reflux.
Scheme 17
Scheme 17. Suggested mechanism for the formation of 6-substituted purino[8,9-a]isoquinoline-9,11-diones 55a–g.
Scheme 18
Scheme 18. Multistep reaction for the synthesis of hybrids 64a–g. Reagents and conditions: A; (i) NBS, MeCN, 80 °C, 1 h. (ii) 4-methoxypyridine, 80 °C, overnight. B; nPr-Br, DBU, MeCN, 80 °C. C; Pd(OH)2/C, HCOONH4, EtOH, reflux. D; N-bromoalkyl phthalamide, K2CO3, DMF, 100 °C, E; N2H4·H2O, MeOH, reflux. F; SOCl2, K2CO3, dry DMF, 40 °C.
Scheme 19
Scheme 19. Synthesis of xanthine derivatives 67a–j. Reagents and conditions: A; (i) NBS, MeCN, 80°oC, 1 h. (ii) 4-methoxypyridine, 80 °C, overnight. B; R–Br, DBU, MeCN, 80 °C. C; Pd(OH)2, ammonium formate, EtOH, reflux, overnight. D; R1-Br, K2CO3, DMF, overnight.
Scheme 20
Scheme 20. Synthesis of pyrido[2,3-d]pyrimidine-6-carboxylates 69a–i. Reagents and conditions: A; AcOH, reflux.
Fig. 8
Fig. 8. Structure of compound 69e with high affinity for BRDT-1 and BRD4-1.
Scheme 21
Scheme 21. Mechanochemical reaction between 6-aminouracil 2 and propargyl alcohols 70. Reagents and conditions: A; HFIP/p-TsOH, 1–2 h.
Scheme 22
Scheme 22. Suggested mechanism for the formation of compounds 72a–k.
Scheme 23
Scheme 23. Reaction of 6-amino-5-formyluracil 77 with cyclic carbon nucleophiles. Reagents and conditions: A; DMF/DBU, reflux. 120 min.
Scheme 24
Scheme 24. Synthesis of compounds 87, 88, 90 and 91a,b. Reagents and conditions: A; DMF/DBU, reflux. 120 min.
Scheme 25
Scheme 25. Reaction of 6-amino-5-formyluracil 79 with heterocyclic compounds. Reagents and conditions: A; DMF/DBU, reflux, 30 min.
Fig. 9
Fig. 9. Structures of antimicrobial and anticancer compounds 90, 91a, 91b, 96 and 97.
Scheme 26
Scheme 26. Synthesis of dihydropyrido[2,3-d]pyrimidines 99a–k. Reagents and conditions: A; DQ, cat. K3PO4, B; toluene, rt, 20 h.
Scheme 27
Scheme 27. Suggested mechanism for the formation of compounds 99a–k.
Scheme 28
Scheme 28. Synthesis of biologically active pyridopyrimidines 108a–h. Reagents and conditions: A = EtOH/H2O, Et3N.
Fig. 10
Fig. 10. Structures of antibacterial molecules 108f–h.
Scheme 29
Scheme 29. Three-component reaction for the synthesis of 108. Reagents and conditions: A; urea, EtOH:H2O, 60 °C.
Scheme 30
Scheme 30. Green synthesis of pyridopyrimidine 108. Reagents and conditions: A; glycerol: H2O, 95 °C.
Scheme 31
Scheme 31. Mn nano catalyst-mediated synthesis of pyrido[2,3-d]pyrimidines 108. Reagents and conditions: A; Mn-Zif-8@ZnTiO3 NPs, B; EtOH:H2O.
Scheme 32
Scheme 32. Nano-catalyzed synthesis of tetrahydropyrido[2,3-d]pyrimidine-6-carbonitriles 108. Reagents and conditions: A; Fe3O4-ZnO-NH2-PW12O40. B; H2O, 80 °C.
Scheme 33
Scheme 33. Plausible mechanism for the synthesis of compound 108.
Scheme 34
Scheme 34. MgO catalytic synthesis of pyrido[2,3-d]pyrimidine-6-carbonitriles 108. Reagents and conditions: A = MgO NPs. B = H2O, 80 °C.
Scheme 35
Scheme 35. Plausible mechanism for the formation of pyrido[2,3-d]pyrimidine-6-carbonitriles 108.
Scheme 36
Scheme 36. Synthetic pathway for compound 108. Reagents and conditions: A; SBA-Pr-SO3H, solvent-free, 60 °C.
Scheme 37
Scheme 37. Reaction of 2,6-diaminopyrimidin-4-ol (119) with active methylene compounds. Reagents and conditions: A; Fe3O4@SiO2@(CH2)3S-SO3H, neat, 100 °C.
Scheme 38
Scheme 38. Synthesis of compounds 108 and 124a–j. Reagents and conditions: A; Fe3O4@TiO2@NH2@PMo12O40, H2O, 80 °C.
Scheme 39
Scheme 39. Synthetic pathway for compound 108. Reagents and conditions: A; EtOH, reflux, nano-[Fe3O4@SiO2/N-propyl-1-(thiophen-2-yl)ethanimine][ZnCl2].
Scheme 40
Scheme 40. Synthetic pathways for compound 108 under the conditions mentioned in Schemes 28–32, 34, 36, and 39.
Scheme 41
Scheme 41. General features of the role of a catalyst in the pathways describing the formation of 108.
Scheme 42
Scheme 42. Synthesis of pyrido[2,3-d]pyrimidines 126a–n. Reagents and conditions: A = Glycerol, 80 °C.
Scheme 43
Scheme 43. Synthesis of pyrido[2,3-d]pyrimidines 128a–n. Reagents and conditions: A; EtOH, 80 °C, 8–13 min.
Scheme 44
Scheme 44. Suggested mechanism for the synthesis of compound 128.
Scheme 45
Scheme 45. Synthesis of pyridopyrimidine-indole hybrids 133a–m. Reagents and conditions: A; EtOH, Fe3O4@FAp@Ni.
Scheme 46
Scheme 46. Possible mechanistic pathway for the formation of 133a–m.
Scheme 47
Scheme 47. Formation of pyrrolo[3′,4′:5,6]pyrido[2,3-d]pyrimidine-2,4,6(3H)-triones 139a–k. Reagents and conditions: A; MgSO4, MeOH, 45 °C. B; RNH2, EtOH, Microwave, 120 °C.
Fig. 11
Fig. 11. Structure of compounds 139b–h with inhibition activity against BRDT-1.
Scheme 48
Scheme 48. P2O5-mediated synthesis of 140a–k. Reagents and conditions: A = P2O5/EtOH.
Scheme 49
Scheme 49. Reaction of 6-aminouracil 2 with 5-(substituted-1-yl-sulfonyl)indoline-2,3-diones 141a–c.
Fig. 12
Fig. 12. Structures of compounds 142a, 143b, 143d and 143e.
Scheme 50
Scheme 50. Microwave-assisted synthesis of pyridopyrimidines 146a–y. Reagents and conditions: A; MW, AcOH/H2O.
Scheme 51
Scheme 51. Synthesis of bis pyrido[2,3-d]pyrimidine scaffolds 149a,b. Reagents and conditions: A; MW, 5 min, AcOH.
Scheme 52
Scheme 52. Three-component synthesis of pyrimido[4,5-b]quinolines 151a–d. Reagents and conditions: A; choline chloride, oxalic, B = DESs, 80 °C.
Scheme 53
Scheme 53. Synthesis of naphthyridines 152a–k. Reagents and conditions: A; MIL-100(Cr)/NHEtN(CH2PO3H2)2; B; DMF, 100 °C.
Scheme 54
Scheme 54. Synthesis of naphthyridines 154a–k. Reagents and conditions: A; Cat. H2O, 70 °C.
Scheme 55
Scheme 55. Ag NP-mediated synthesis of pyrimido[4,5-b][1,6]naphthyridines 156a–h. Reagents and conditions: A; Ag NPs; B; EtOH/H2O/60 °C.
Scheme 56
Scheme 56. Reaction of 1-benzyl-6-aminouracil with compound ethyl acetoacetates 157 and 159. Reagents and conditions: A; EtOH, TEA, reflux, 12 h. B; DMF, TEA, reflux, 4 h.
Scheme 57
Scheme 57. Synthesis of pteridines 160a–d and purine compounds 161a–f.
Scheme 58
Scheme 58. Reaction of α-azidochalcones 163 with 6-amiouracils 2. Reagents and conditions: A = DMF, Et3N; B = 50 °C, 30 min.
Scheme 59
Scheme 59. Suggested mechanism for the formation of compound 164a–s.
Scheme 60
Scheme 60. Formation of dihydropyrido[2,3-d]pyrimidines 169a–k. Reagents and conditions: A; H2O, 70 °C.
Scheme 61
Scheme 61. Reaction of 3-(3-(dimethylamino)acryloyl)-2H-chromen-2-one 170 with 6-aminouracils 2. Reagents and conditions: A; AcOH, reflux, 5–6 h.
Scheme 62
Scheme 62. Reaction of 6-aminouracils 2 with compound 173. Reagents and conditions: A = DMF, Et3N.
Scheme 63
Scheme 63. Synthesis of compound 176 using TiO2@LLs nanocatalyst. Reagent and conditions: A; EtOH:H2O, reflux, cat.
Scheme 64
Scheme 64. Proposed mechanism for the synthesis of compound 176.
Scheme 65
Scheme 65. Synthesis of pyrimido[4,5-d]pyrimidines 182a–h. Reagents and conditions: A; EtOH, AcOH, rt; B; I2, TBHP, EtOH, rt.
Scheme 66
Scheme 66. Formation of pyrazolo-pyrimido[4,5-d]pyrimidine hybrids 186a–x. Reagents and conditions: A; [Bmim]FeCl4, 80 °C.
Fig. 13
Fig. 13. Structures of antibacterial compounds 186c, 186i, 186l and 186m.
Scheme 67
Scheme 67. Suggested mechanism for the synthesis of pyrazolo-pyrimido[4,5-d]pyrimidines 186a–x.
Scheme 68
Scheme 68. Synthesis of pyrimidopyrimidine derivatives 190a–i. Reagents and conditions: A; Zn(BDC)-MOF, solvent-free; B; ultrasound.
Scheme 69
Scheme 69. One-pot multicomponent reaction for the synthesis of pyrimido[4,5-d]pyrimidines 190a–p. Reagents and conditions: A; Fe3O4@SiO2@Propyl-ANDSA, H2O/reflux.
Scheme 70
Scheme 70. Synthesis of pyrimido[4,5-d]pyrimidine 190a–i. Reagents and conditions: A; MIL-53(Fe), solvent free, 110 °C.
Scheme 71
Scheme 71. Proposed mechanism for the synthesis of compounds 190a–i catalyzed by MIL-53(Fe).
Scheme 72
Scheme 72. Synthetic pathways for compound 190 under the conditions mentioned in Schemes 28–32, 34, 36, and 39.
Scheme 73
Scheme 73. Ultrasound irradiation synthesis of pyrimidopyrimidines 196a–o. Reagents and conditions: A; BAIL@UiO-66, EtOH/r.t, US irradiation.
Scheme 74
Scheme 74. Suggested mechanism for the synthesis of 196a–o.
Scheme 75
Scheme 75. Formation of chromeno[2,3-d]pyrimidines 202a–p. Reagents and conditions: A = ChCl : α-CAA (1 : 1), 90 °C, 2 h.
Scheme 76
Scheme 76. Reaction mechanism for the synthesis of chromeno[2,3-d]pyrimidines 202a–p.
Scheme 77
Scheme 77. Synthesis of phenazine scaffold 208. Reagents and conditions: A; DMSO, 70 °C. B; CHCl3, reflux, 1 h.
Scheme 78
Scheme 78. Reaction of 5,6-diaminouracils 49 with 2,7-dibromo-9H-fluoren-9-one (209) and acenaphthoquinone 210.
Scheme 79
Scheme 79. Proposed mechanism for the synthesis of 211a–e.
Fig. 14
Fig. 14. Structures of the most anti-proliferative pteridine and purine molecules.
Scheme 80
Scheme 80. Synthesis of pyridotriazolothiazolopyridopyrimidine 216. Reagents and conditions: A; DMF/DBU, reflux, 30 min.
Scheme 81
Scheme 81. Synthesis of Schiff bases 220a–f and 222a–f. Reagents and conditions: A; POCl3.B; EtOH, pip. C; EtOH, Et3N, 9 h, rt. D; EtOH, Et3N, 6 h, rt.
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