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Review
. 2020 Nov 12;63(21):12290-12358.
doi: 10.1021/acs.jmedchem.0c00530. Epub 2020 Aug 4.

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

Shikha Kumari  1 , Angelica V Carmona  1 , Amit K Tiwari  2 , Paul C Trippier  1   3   4
Affiliations
Review

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

Shikha Kumari et al. J Med Chem. .

Abstract

The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, pKa, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Structures of selected clinically approved drug molecules containing an amide bond and their biological function.
Figure 2.
Figure 2.
Representative structures of the trans and cis amide mimics 1,4-disubstitued 1,2,3-triazole and 1,5-disubstitued 1,2,3-triazole respectively, highlighting their distancing and hydrogen bonding capabilities.
Figure 3.
Figure 3.
Replacement of the amide bond in RN-18 (12) with a 1,2,3-triazole moiety to afford compound 13 (1–2-methoxyphenyl)-4-(2-((4-nitrophenyl)thio)phenyl)-1H-1,2,3-triazole).
Figure 4.
Figure 4.
Example of amide versus 1,2,3-triazole bioisosterism in vismodegib (17), a potent Hh signaling pathway inhibitor.
Figure 5.
Figure 5.
Molecular structures of highly potent D3-R ligands: 20, 21, 22 containing amide; 23, a 1,2,3-triazole analog.
Figure 6.
Figure 6.
1,2,3-Triazole as an amide bond bioisostere in a TRPV1/CB1 antagonist.
Figure 7.
Figure 7.
Molecular structure of lead compound 26 and its bioisostere 27.
Figure 8.
Figure 8.
Structural transformation of parent compound 28 into 29 illustrating amide/triazole bioisosterism.
Figure 9.
Figure 9.
Replacement of an amide moiety with a 1,2,4-triazole: diazepam (30) to alprazolam (31).
Figure 10.
Figure 10.
Metabolic transformation of diazepam (30) into three active metabolites: desmethyldiazepam/nordazepam (32), oxazepam (33), and temazepam (34).
Figure 11.
Figure 11.
Different regioisomeric forms of the oxadiazole ring.
Figure 12.
Figure 12.
Amide bioisosteric replacement with an oxadiazole ring leading to a potent and selective γ-secretase inhibitor.
Figure 13.
Figure 13.
Structures of parent amide-containing α-lipoic acid analog 28 and its 1,2,4-oxadiazole bioisostere 40.
Figure 14.
Figure 14.
Structures of parent chroman analog 41 and its 1,2,4-oxadiazole bioisostere 42.
Figure 15.
Figure 15.
Structures of parent amides 43 and 44, potent mGlu7-NAMs and the 1,3,4-oxadiazole bioisostere 45.
Figure 16.
Figure 16.
Structural optimization in the development of potent DPP-4 inhibitors to treat type 2 diabetes mellitus.
Figure 17.
Figure 17.
Lead optimization journey to discover a potent and orally bioavailable DGAT-1 inhibitor.
Figure 18.
Figure 18.
Bioisosteric amide replacement via 1,3,4-oxadiazole (65) and 1,2,4-oxadiazole (66) in a series of CB2 receptor ligands.
Figure 19.
Figure 19.
Structures of diazepam and the imidazole-containing analog midazolam.
Figure 20.
Figure 20.
Lead optimization journey of telcagepant (72) to discover 77, a potent and orally bioavailable CGRP antagonist.
Figure 21.
Figure 21.
Structures of 80, 81, and imidazole bioisostere 82, potent HIV-1 integrase inhibitors.
Figure 22.
Figure 22.
Binding patterns of 81 and 82 into the active sites of PFV integrase (3S3N) wild-type (A) and Q148H/G140S mutant (B). Reproduced with permission from Bioorganic & Medicinal Chemistry Letters (https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry-letters), Volume 30, 126784, Peese, K. M.; Naidu, B. N.; Patel, M.; Li, C.; Langley, D. R.; Terry, B.; Protack, T.; Gali, V.; Lin, Z.; Samanta, H. K.; Zheng, M.; Jenkins, S.; Dicker, I. B.; Krystal, M. R.; Meanwell, N. A.; Walker, M. A., Heterocycle amide isosteres: an approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors. Copyright 2020 Elsevier.
Figure 23.
Figure 23.
Bioisosteric replacement of the amide functional group in the identification of potent SCD1 inhibitors.
Figure 24.
Figure 24.
Structure of 92 and its bioisostere 93, potent PAD inhibitors.
Figure 25.
Figure 25.
Structures of LA amide-dopamine conjugate 96 and its tetrazole containing bioisostere 97.
Figure 26.
Figure 26.
Molecular structures of parent LA-amide analog 28 and its tetrazole bioisostere 100.
Figure 27.
Figure 27.
Amide bond bioisosteric modification in 101 with a tetrazole functionality (102).
Figure 28.
Figure 28.
Oak Ridge thermal ellipsoid plots of 101 (A) and 102 (B). Reproduced with permission from European Journal of Medicinal Chemistry (https://www.sciencedirect.com/journal/european-journal-of-medicinal-chemistry), Volume 84, pp 200–205, Beinat, C.; Reekie, T.; Hibbs, D.; Xie, T.; Olson, T. T.; Xiao, Y.; Harvey, A.; O’Connor, S.; Coles, C.; Tsanaktsidis, J.; Kassiou, M., Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333. Copyright 2014 Elsevier.
Figure 29.
Figure 29.
Bioisosteric replacement of amide (103 and 104) with pyrazole (105 and 106) to discover potent PrCP inhibitors.
Figure 30.
Figure 30.
Amide versus thiadiazole bioisosterism in search of potent CB1 agonist.
Figure 31.
Figure 31.
Superimposition modeling image of 107 (green) and 111 (orange). Reproduced with permission from Bioorganic & Medicinal Chemistry Letters (https://www.sciencedirect.com/journalbioorganic-and-medicinal-chemistry-letters/), Volume 21, pp 506–509, Morrison, A. J.; Adam, J. M.; Baker, J. A.; Campbell, R. A.; Clark, J. K.; Cottney, J. E.; Deehan, M.; Easson, A. M.; Fields, R.; Francis, S.; Jeremiah, F.; Keddie, N.; Kiyoi, T.; McArthur, D. R.; Meyer, K.; Ratcliffe, P. D.; Schulz, J.; Wishart, G.; Yoshiizumi, K., Design, synthesis, and structure-activity relationships of indole-3-heterocycles as agonists of the CB1 receptor. Copyright 2011 Elsevier.
Figure 32.
Figure 32.
General structure (112) showing the molecular template for designing MMP inhibitors, isosteric replacement of the C-terminal amide bond in 113 with 3-acyl indole (114), and the structure of marimastat, (115), a broad-spectrum MMP inhibitor.
Figure 33.
Figure 33.
Molecular structures of the parent amide 119 and pyrazine (120), thiazole (121), and pyridine (122) bioisosteres.
Figure 34.
Figure 34.
Structures of lead TYR2 inhibitor 125 and its optimized analogs 126–128.
Figure 35.
Figure 35.
Bioisosteric replacement of the amide within 132, with diketopiperazine (133, 134, and 135), to develop potent dopamine D2 receptor modulators.
Figure 36.
Figure 36.
Structures of an amide-containing baccharin analog 138, a potent but low selective AKR1C3 inhibitor, and 139, a potent and highly selective retroinverted amide bioisostere.
Figure 37.
Figure 37.
Compound 139 docked within the active site of AKR1C3 (gray, PDB code 3UG8): strong predicted hydrogen bond (green dotted line) and weak predicted hydrogen bond (white dotted line). Reproduced with permission from Journal of Medicinal Chemistry, Copyright 2019 American Chemical Society.
Figure 38.
Figure 38.
Structures of the parent amide 143 and the reverse amide bioisosteres 144 and 145, MTR ligands.
Figure 39.
Figure 39.
Structures of parent amide 147, urea bioisosteres 148, 149, and 150, and 151, a potent urea ACAT inhibitor.
Figure 40.
Figure 40.
Structures of DSG (155) and bioisosteric analogs.
Figure 41.
Figure 41.
Structures of lead compound 161 for anti-human cytomegalovirus (HCMV) and 2′-isopropoxyurea bioisostere 162.
Figure 42.
Figure 42.
Structures of 163, B13, a ceramide analog tested for in vitro cytotoxicity against five human tumor cell lines, and 164, a more potent urea bioisostere.
Figure 43.
Figure 43.
Antitrypanosomal agent 165, an amide derivative, was further optimized to urea derivatives 166 and 167.
Figure 44.
Figure 44.
Structures of the amide (169) and urea (171) bioisostere derivatives of the triazole-based Escherichia coli PDHc-E1 inhibitor 169.
Figure 45.
Figure 45.
Graphical representation of the binding modes of 170 (A) and 171 (B) into the active site of E. coli PDHc-E1 displayed in ribbon. Ligands and residues are depicted by stick, while the hydrogen and coordination bonds are shown with dashed lines (green). Reproduced with permission from Bioorganic & Medicinal Chemistry (https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry), Volume 22, pp 3180–3186, He, J. B.; Ren, Y. L.; Sun, Q. S.; You, G. Y.; Zhang, L.; Zou, P.; Feng, L. L.; Wan, J.; He, H. W., Design, synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitors. Copyright 2014 Elsevier.
Figure 46.
Figure 46.
Potent HIV protease inhibitors incorporating carbamate bioisosteres.
Figure 47.
Figure 47.
Structures of parent amide 178, a γ-secretase inhibitor, and potent carbamate-based derivatives 179 and 180 for the treatment of AD.
Figure 48.
Figure 48.
Replacement of the amide bond in 182 with a carbamate moiety to afford compound 183, novel SP1–7 analogs as potential therapeutic agents for neuropathic pain.
Figure 49.
Figure 49.
Amidine as a bioisostere of the amide functionality in VLA-4 antagonists.
Figure 50.
Figure 50.
Anthranilic acid lead 190, advanced lead 191, and alternative thioamide bioisostere 192 as antibacterial agents.
Figure 51.
Figure 51.
Molecular structures of natural 194 and bioisosteric Ψ[CH(CF3)NH]Gly 195 and 196 peptides and (S,S) [NHCH(CF3)]-retrothiorphan diastereomer 197.
Figure 52.
Figure 52.
Structures of 200 a reversible dipeptide inhibitor of cathepsin K, 201 a neutral cathepsin K inhibitor, and 202 a potent cathepsin K inhibitor containing the trifluoroethylamine bioisostere.
Figure 53.
Figure 53.
Structures of 205, a potent hepatitis C virus (HCV) NS3 protease inhibitor, and trifluoromethylated-containing cathepsin S inhibitors 206 and 207.
Figure 54.
Figure 54.
Structures of 208, an amide-based BACE-1 inhibitor, and CF3-cyclopropane bioisostere BACE-1 inhibitor 209.
Figure 55.
Figure 55.
Structures of parent malonamide 212 and selective and potent VEGFR2 inhibitor 213.
Figure 56.
Figure 56.
Structures of amide 163 and an aromatic sulfonamido ceramide bioisostere with more potent cytotoxic activity.
Figure 57.
Figure 57.
Phenoxyphenyl farnesylcysteine 217 and sulfonamide-modified farnesylcysteine (SMFC) analog 218, as hIcmt inhibitors.
Figure 58.
Figure 58.
Capsaicin (24) and step by step development of novel capsaicin-like bioisosteric analogs 222–226.
Figure 59.
Figure 59.
Novel irreversible HIV-1 protease inhibitors encompassing sulfonamide and sulfone as amide bioisosteres.
Figure 60.
Figure 60.
Non-nucleoside NS5B inhibitors (except 233), containing the phosphonamidate group as an amide bioisostere (233, 234, and 235).
Figure 61.
Figure 61.
Ribbon structure of NS5B HCV viral polymerase. Reproduced with permission from Bioorganic & Medicinal Chemistry Letters (https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry-letters), Volume 26, pp 4536–4541, Pierra Rouviere, C.; Amador, A.; Badaroux, E.; Convard, T.; Da Costa, D.; Dukhan, D.; Griffe, L.; Griffon, J. F.; LaColla, M.; Leroy, F.; Liuzzi, M.; Loi, A. G.; McCarville, J.; Mascia, V.; Milhau, J.; Onidi, L.; Paparin, J. L.; Rahali, R.; Sais, E.; Seifer, M.; Surleraux, D.; Standring, D.; Dousson, C., Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase. Copyright 2016 Elsevier.
Figure 62.
Figure 62.
Cocrystallization image of 235 complexed with the viral NS5B (PDB code 5CZB). Reproduced with permission from Bioorganic & Medicinal Chemistry Letters (https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry-letters), Volume 26, pp 4536–4541, Pierra Rouviere, C.; Amador, A.; Badaroux, E.; Convard, T.; Da Costa, D.; Dukhan, D.; Griffe, L.; Griffon, J. F.; LaColla, M.; Leroy, F.; Liuzzi, M.; Loi, A. G.; McCarville, J.; Mascia, V.; Milhau, J.; Onidi, L.; Paparin, J. L.; Rahali, R.; Sais, E.; Seifer, M.; Surleraux, D.; Standring, D.; Dousson, C., Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase. Copyright 2016 Elsevier.
Figure 63.
Figure 63.
Structures of peptide 238 and analogs in which the amide bond was replaced by an ester 239 or N-methylamide bond 240.
Figure 64.
Figure 64.
Amide to trans olefin bioisosteric replacement leading to the clinical candidate 242.
Figure 65.
Figure 65.
Example of the replacement of a central amide of an azaoxindole derivative (244) with an E-alkene moiety 245.
Figure 66.
Figure 66.
Structural modification of an amide linker in 249 to an E-alkene in 250 that joins A and B rings.
Figure 67.
Figure 67.
Molecular structures of amylin (20–29) 254 and its modified bioisosteric analogs.
Figure 68.
Figure 68.
Distamycin (262) and its bioisosteric analogs.
Figure 69.
Figure 69.
Amino acid sequences of bombesin (266), pseudopeptide 267, and E-alkene isostere 268.
Figure 70.
Figure 70.
Graphical representation of the modification of peptide backbone from an amide to E-olefin, which is neither a hydrogen bond donor nor acceptor.
Figure 71.
Figure 71.
Bioisosteric replacement of amide linkages from parent CCK peptides 271 and 272 to develop E-alkene isostere 273, a potent CCK-B receptor ligand.
Figure 72.
Figure 72.
Bioisosteric replacement of an amide bond at the Tyr1-Gly2 position in 238 with a fluoroalkene to produce 275 and a trifluoroethylamine moiety to produce (S)-276 and (R)-277.
Figure 73.
Figure 73.
Structures of the parent peptide 238 and its fluoroalkene isostere 283.
Figure 74.
Figure 74.
Bioisosteric replacement of the amide function in daclatasvir, 290, with a fluoro-olefin moiety to yield 291.
Figure 75.
Figure 75.
Inhibitor of Rho/MLK1 transcriptional pathway 301 and analogs with amide bioisosteric replacements 302 and 303.
Figure 76.
Figure 76.
Trisubstituted acylhydrazine as a tertiary amide bioisostere.
Scheme 1.
Scheme 1.
General Synthetic Pathway To Access Triazole Scaffold via Copper(I)-Catalyzed Azide-Alkyne Cycloaddition Click Chemistry
Scheme 2.
Scheme 2.
Synthesis of the Benzodiazepine Compound Alprazolam (31) from 7-Chloro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepine-2-thione (35)
Scheme 3.
Scheme 3.
General Synthetic Route To Obtain the 1,2,4-Oxadiazole Moiety from an Amidoxime
Scheme 4.
Scheme 4.
Synthetic Preparation of 45, a Potent and Selective mGlu7-NAM
Scheme 5.
Scheme 5.
Synthetic Preparation of 50 and 51, Potent DPP Inhibitors
Scheme 6.
Scheme 6.
General Synthetic Route for Preparing 1,3,4-Oxadiazole from Diacylhydrazine
Scheme 7.
Scheme 7.
One-Pot Synthesis of Midazolam, 67, a Short Acting Benzodiazepine
Scheme 8.
Scheme 8.
Synthetic Route for Compound 77
Scheme 9.
Scheme 9.
Synthetic Route To Access Imidazole Pyrimidinedione-Containing Derivative 82
Scheme 10.
Scheme 10.
Synthetic Route for Compound 88
Scheme 11.
Scheme 11.
Synthetic Route To Access the Biphenyl Tetrazole tert-Butyl Cl-amidine-Containing PAD Inhibitor 93
Scheme 12.
Scheme 12.
General Synthetic Route To Access Tetrazole, Nonclassical Amide Bioisostere
Scheme 13.
Scheme 13.
Synthesis of Indole Bioisostere 114, a Potent MMP Inhibitor
Scheme 14.
Scheme 14.
Synthetic Route for Obtaining the Pyrazine Bioisostere 120, a Potent A2A Receptor Antagonist
Scheme 15.
Scheme 15.
Synthetic Route To Obtain Compound 128, a Potent TYR2 Inhibitor
Scheme 16.
Scheme 16.
Diketopiperazine Bioisostere Synthesis from l-Proline To Obtain Compound 134
Scheme 17.
Scheme 17.
Synthetic Route To Access the Potent and Highly Selective AKR1C3 Inhibitor 139
Scheme 18.
Scheme 18.
Synthetic Preparation of the Melatonin-Based Compounds 144 and 145
Scheme 19.
Scheme 19.
General Synthetic Route To Prepare Urea Bioisostere via Isocyanate
Scheme 20.
Scheme 20.
Synthetic Procedure To Access 158, a Potent Immunosuppressor
Scheme 21.
Scheme 21.
Synthesis of 167, a Novel and Potential Drug for Human African Trypanosomiasis
Scheme 22.
Scheme 22.
Synthetic Route To Access the Potent Urea Derivative 171, an E. coli PDHc-E1 Inhibitor
Scheme 23.
Scheme 23.
Synthetic Route To Access 3-(S)-Tetrahydrofuranylurethane-Containing Analog 176, a Potent HIV-1 Protease Inhibitor
Scheme 24.
Scheme 24.
Synthetic Route To Access the Dibenzazepinone-Based γ-Secretase Inhibitor 180
Scheme 25.
Scheme 25.
Synthetic Route To a Carbamate-Based Dipeptide SP1–7 Analog (183)
Scheme 26.
Scheme 26.
Synthetic Route To Access Amidine Derivatives as VLA-4 Antagonists
Scheme 27.
Scheme 27.
Synthetic Route To Access Thioamide 192
Scheme 28.
Scheme 28.
Synthesis Route To Access Ψ[NHCH(CF3)]-retro-thiorphan 197
Scheme 29.
Scheme 29.
General Synthetic Route To Generate Trifluoroethylamine Bioisostere via a Trifluoroacetaldehyde Ethyl Hemiacetal
Scheme 30.
Scheme 30.
Synthetic Route To Access Compound 209, a BACE-1 Inhibitor
Scheme 31.
Scheme 31.
Synthetic Route To Access the Aromatic Alkyl Sulfonamido Ceramide Analog 214
Scheme 32.
Scheme 32.
General Synthetic Procedure To Obtain Sulfonamide Bioisostere
Scheme 33.
Scheme 33.
Synthetic Route To Access 235
Scheme 34.
Scheme 34.
Synthetic Route To Access 242, a Non-Nucleoside HCV NS5B Polymerase Inhibitor
Scheme 35.
Scheme 35.
General Synthetic Route To Access Alkene Bioisosteres
Scheme 36.
Scheme 36.
General Synthesis of E-Alkene Bioisosteres from Respective Aldehyde
Scheme 37.
Scheme 37.
Solid Phase Synthesis of an Alkene Dipeptide (255) and Alkene Dipeptidosulfonamide Isostere (256)
Scheme 38.
Scheme 38.
Synthetic Route Showing the Peptide Coupling of the Dipeptide Isostere with CCK Fragment To Obtain Target Pseudopeptide 273
Scheme 39.
Scheme 39.
Synthetic Route To Access Leu-enkephalin Analog 275
Scheme 40.
Scheme 40.
Synthetic Pathway To Obtain the Fluoroalkene Peptidomimetic Compound 283
Scheme 41.
Scheme 41.
Diastereoselective Synthesis of Fluoro-olefin Analog 291 by Chang and Co-workers
Scheme 42.
Scheme 42.
Synthetic Access To Amide Bioisostere Analog 303 of a Rho/MLK1 Transcriptional Pathway Inhibitor 301
Scheme 43.
Scheme 43.
Synthetic Route To Access 308, a HCV NS5B Thumb Site II Inhibitor
See this image and copyright information in PMC

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