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Review
. 2025 Aug 6;10(32):35367-35433.
doi: 10.1021/acsomega.5c04467. eCollection 2025 Aug 19.

Advances in the Synthetic Approaches to β‑Secretase (BACE-1) Inhibitors in Countering Alzheimer's: A Comprehensive Review

Yogeesh M  1 , Nitinkumar S Shetty  1
Affiliations
Review

Advances in the Synthetic Approaches to β‑Secretase (BACE-1) Inhibitors in Countering Alzheimer's: A Comprehensive Review

Yogeesh M et al. ACS Omega. .

Abstract

Alzheimer's disease is a progressive, irreversible, neurodegenerative disease, i.e., characterized by the presence of amyloid plaques, hyperphosphorylated tau protein (hyper p-tau), neural damage, etc. β-amyloid precursor protein cleavage enzyme 1 (BACE-1) inhibition is a promising avenue for slowing AD progression. In a rate-limiting step, BACE-1 cleaves the amyloid precursor protein (APP) into soluble amyloid precursor protein β (sAPPβ) and a membrane-bound C-terminal fragment called C99. γ-secretase processes C99, resulting in neurotoxic amyloid β (Aβ). Selective and potent BACE-1 inhibitors offer promising therapeutic avenues for Alzheimer's disease. While BACE-1 inhibitors have shown significant assurance as potential treatments for Alzheimer's disease, many early compounds struggled to advance clinically due to poor brain penetration, limited selectivity, and unwanted side effects. Over the last two decades, substantial progress has been made in the development of BACE-1 inhibitors, leading to the emergence of diverse structural frameworks such as aminohydontoins, dihydropyridines, pyrimidines, and iminohydantoins, and fused heterocycles. This review provides an in-depth analysis of the synthetic strategies employed. It emphasizes the structure-activity relationship (SAR) trends that have guided their optimization and the crystal structure of the enzyme used in the inhibition study.

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Figures

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1
Schematic representation of amyloid precursor protein cleavage by β and γ secretases, leading to the formation of amyloid β peptides.
1
1. Synthesis of Pyridine-Amino Hydantoins 9
2
2. Synthesis of Pyrazolyl Aminohydontoins 16
3
3. Synthesis of Thionyl Aminohydontoins 21
4
4. Synthesis of Pyridinyl Amino Hydantoins 25
5
5. Synthesis of Aminohydontoins 29
6
6. Synthesis of Tetrahydronaphthalone 33 and Difluoronaphthalene 35
7
7. Synthesis of Isomers of Hexahydropyrano­[3,2-b] Chromene Aminohydontoins 46
8
8. Synthesis of Hexahydropyrano­[3,2-b] Chromene Analog 58
9
9. Synthesis of β-Methyl-8-THP Chromans 62
10
10. Synthesis of Spiro Piperidine Substituted Imino Hydantoins 65
11
11. Synthesis of Aminohydontoins 71 and 72
12
12. Synthesis of Biaryl Aminooxazoline Derivatives 77
13
13. Synthesis of 2-Amino Oxazoline Xanthene 82
14
14. Synthesis of Pyrimidine-substituted 2-Amino-oxazoline Xanthene 87
15
15. Synthesis of N-(3-((4R)-2-Amino-5-fluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl) Acetamide Derivatives 96
16
16. Synthesis of 5-Cyano-N-(4-fluorophenyl) Picolinamide Substituted Oxazine Derivatives 106
17
17. Synthesis of Trifluoromethyl-substituted Oxazine Derivatives 119
18
18. Synthesis of Oxazine Derivatives 129
19
19. Synthesis of Dimethyl Butyl and Pyrimidinyl Substituted Spirooxazolo Xanthenylamine 133
20
20. Synthesis of Oxazoline Derivatives 136, 140, and 142
21
21. Synthesis of Neopentyloxy and Spirochromenopyridine Substituted Oxazolyl Amine 150
22
22. Synthesis of 2-Fluoropyridine Substituted Aminooxazoline Derivative 156
23
23. Synthesis of 1,4-Oxazine Derivative 166
24
24. Synthesis of Amide-substituted 1,4-Oxazine Derivative 171
25
25. Synthesis of 2-Aminooxazoline 3-Azaxanthenes 179
26
26. Synthesis of Difluoro Phenyl Substituted 2-Amino-4,5-dihydrothiazole Derivatives 189
27
27. Synthesis of 3-Methylfuran Substituted 2-Amino-4,5-dihydrothiazole Derivatives 194
28
28. Synthesis of 2,4-Difluorophenyl Substituted 1,3-Thiazin-2-amine 199
29
29. Synthesis of 2,4-Difluorophenyl-1,3-thiazin-2-amine Substituted Derivative 208
30
30. Synthesis of (2,4-Difluorophenyl) Methanamine Substituted 2-Amino-4,5-dihydrothiazole Derivatives 212
31
31. Synthesis of Difluorophenyl-trifluoroethylaminomethyl-pyranothiazinylamine 216
32
32. Synthesis of Prop-1-yn-1-yl Pyridine Substituted 1,2,4-Thiadiazinane 1,1-Dioxide 225
33
33. Synthesis of Fluorophenyl-imino-dimethylhexahydropyrimidinyl-acetamide Derivative 231
34
34. Synthesis of 4-Fluoro Substituted 1,2,4-Thiadiazinan-5-ylacetamide Derivatives 238
35
35. Synthesis of 2,4-Difluorophenyl Substituted Compound 240
36
36. Synthesis of 2,4-Difluorophenyl and Pyrimidin-5-yl Substituted Compound 247
37
37. Synthesis of 2-Amino-4,5-dihydrothiazole Derivatives 252
38
38. Synthesis of N-(3-((4R,5R,6R)-2-Amino-5-fluoro-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl) Acetamide Derivatives 254
39
39. Synthesis of N-(3-((4aR,7aS)-2-Amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo­[3,4-d]­[1,3]­thiazin-7a-yl)-4-fluorophenyl)­acetamide Derivatives 256
40
40. Synthesis of Dihydropyrimidines 260
41
41. Synthesis of 1-Methyl Sulfonamide Substituted 1,4-Dihydropyridine Derivatives 267
42
42. Synthesis of 1-Alkyl Acetate Substituted 1,4-Dihydropyridine Derivatives 273
43
43. Synthesis of 1,4 1,4-Dihydropyridine Derivatives 278
44
44. Synthesis of 1,4-Dihydropyridines 284
45
45. Synthesis of Iminopyrimidinones 290
46
46. Synthesis of Amide-Substituted Iminopyrimidinones 293
47
47. Synthesis of N-Phenyl Analogues of Iminopyrimidinones 297
48
48. Synthesis of N-Phenyl 288, N-Pyridinyl 301, N-Pyrimidinyl 302 Analogs of Iminopyrimidinones
49
49. Synthesis of Thiophene Analogs of Iminopyrimidinones 307 and 310
50
50. Synthesis of 2,4-Difluorophenyl Analogue of Iminopyrimidinones 321
51
51. Synthesis of Fluorophenyl Analogue of Iminopyrimidinones 333
52
52. Synthesis of Aryl Quinones 335 and 336
53
53. Synthesis of Cyclic Diamino Propane 343
54
54. Synthesis of 2-Fluoro-3-methoxyphenyl Aminoindazole 351
55
55. Synthesis of Bis-carbazole 354
56
56. Synthesis of Phenyl-1,2,4-thiadiazolylurea Analogues 359
57
57. Synthesis of Indanone Derivatives 361
58
58. Synthesis of Iminomethylphenylimidazolidinyl-phenyl-carbamate 371
59
59. Synthesis of 3-(2-Imino-1-methyl-5-oxo-4-phenylimidazolidin-4-yl)­phenyl Ethyl­(methyl)­carbamate Derivatives 378
60
60. Synthesis of Substituted Pyrrolidine-3-yl Benzoate Derivatives 384
61
61. Synthesis of Benzyl Ether-Linked Pyrrolidine Derivatives 388
62
62. Synthesis of Allylidene Hydrazine Carboximidamide Derivatives 392
63
63. Synthesis of Sulfonyl-Amino-Acetamides 395
64
64. Synthesis of Hydroxy-Substituted Phenylimidazolidin-4-one Derivatives 402
65
65. Synthesis of N-(6-(2-(2-Amino-3-(3-((3,3dimethylbutyl)­amino)-3-isopropyl)­quinoline-6-yl)­phenyl)­pyridine-3-yl)-4-fluoro Benzamide 414
66
66. Synthesis of Imidazopyridines Bearing Phthalimide Moiety 422
67
67. Synthesis of 3-Methylquinazolin-4­(3H)-one-hydrazone Derivatives 426–428
68
68. Synthesis of Hydroxy-phenylpropyl-methyl-oxopiperazinyl-methylsulfonamido-phenylethyl-isophthalamide Derivatives 434
69
69. Synthesis of Oxazolidinone Derivatives 438
70
70. Synthesis of Bicyclic Acetals 441
71
71. Synthesis of 3-(2-(1H-indol-3-yl)-1H-Imidazol-5-yl)-N-phenyl Benzamides 446
72
72. Synthesis of 3-(2-(1H-Indol-3-yl)-1H-imidazol-5-yl)-N-phenyl Benzamides 446
73
73. Synthesis of 3-(5-(3-(5-Methyl-1H-imidazol-2-yl) Phenyl)-1H-imidazol-2-yl)-1H-indole Derivatives 450 and 451
74
74. Synthesis of 2-Thio-N-(thiazol-2-yl) Acetamide Derivatives 463–465
75
75. Synthesis of 2-Thio-N-(1H-imidazol-2-yl) Acetamide Derivatives 468
76
76. Synthesis of Fused Cyclopropyl-3-amino-2,4-oxazines 476
77
77. Synthesis of Donepezil Derivatives 482
78
78. Synthesis of Tetrahydrobenzo [B] Pyran Derivatives 486
79
79. Synthesis of 2-Aminodihydroquinazoline Derivatives 490
80
80. Synthesis of Tetrahydro Naphthyl-phenyl-benzimidazole Derivatives 505
81
81. Synthesis of 2-(3-(1H-Benzo­[d]­imidazol-2-yl)­phenyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline Derivatives 504
82
82. Synthesis of Thiazine Derivatives 506
83
83. Synthesis of N,1-Dibenzylpyrrolidin-3-amine Derivatives 511
84
84. Synthesis of Aminochachones 514 and (E)-2-((2-(3-(4-Chlorophenyl)­acryloyl)­phenyl)­amino) Acetic Acid 516
85
85. Synthesis of (E)-8-Argio-4-(3,5-dimethoxystyryl)-2H-furo­[2,3-h] Chromen-2-one Derivatives 520
86
86. Synthesis of (2S,3R)-Methyl 5-Oxo-3-phenylmorpholine-2-carboxylate Derivatives 523
87
87. Synthesis of Morpholine-3-thiones 533 and 3-Amino-1,4-oxazine Derivatives 527
88
88. Synthesis of 5,6,7-Trihydroxy Phenyl Substituted Chromen-4-one 529 and 530
89
89. Synthesis of Biphenyl Imidazole Derivatives 534, 535, and 536
90
90. Synthesis of (Z)-2-Benzylidene-N-(1-benzylpyrrolidin-3-yl) Hydrazine Carboxamide Derivatives 542, 543, and 544
91
91. Synthesis of 1-Benzyl-N-((5-phenyl-1,3,4-oxadiazol-2-yl) methyl) Pyrrolidin-3-amine Derivatives 548
92
92. Synthesis of Piperazine-Substituted Chalcones 551
93
93. Synthesis of Compound 562 (JNJ-67569762)
94
94. Synthesis of (S)-4-(2-Amino-6-(3-(3-fluoropropoxy)­benzyl)­quinazolin-3­(4H)-yl)-N,4-dicyclohexyl-N-methylbutanamide 573 and (S)-3-(3-((2-Amino-3-(1-cyclohexyl-4-(cyclohexyl­(methyl)­amino)-4-oxobutyl)-3,4-dihydroquinazolin-6-yl)­methyl)­phenoxy)­propyl 4-Methylbenzenesulfonate 574
95
95. Synthesis of Hydrazone Derivatives 577
96
96. Synthesis of 4-Aminoquinoline Derivatives 580
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