(Bio)isosteres of ortho- and meta-substituted benzenes
- H. Erik Diepers and
- Johannes C. L. Walker
Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78
Graphical Abstract
Figure 1: Scaffolds commonly reported as bioisosteric replacements of para-substituted benzene and examples p...
Figure 2: 1,2-BCPs as isosteres for ortho-and meta-substituted benzenes: comparison of reported exit vector p...
Scheme 1: 1,2-Disubstituted bicyclo[1.1.1]pentanes as isosteres of ortho-substituted benzenes. A: Baran, Coll...
Scheme 2: Synthesis of 1,2-BCPs from BCP 15 by bridge C–H bromination as reported by MacMillan and co-workers ...
Figure 3: Comparative physicochemical data of telmisartan, lomitapide and their BCP isosteres [26,33]. Shake flask d...
Figure 4: 1,2-Disubstituted bicyclo[2.1.1]hexanes as isosteres of ortho-benzenes: Exit vector parameters of t...
Scheme 3: Synthesis of 1,2-disubstituted bicyclo[2.1.1]hexanes via alkene insertion into bicyclo[1.1.0]butane...
Scheme 4: Synthesis of 1,2-disubstituted bicyclo[2.1.1]hexanes via intramolecular crossed [2 + 2] cycloadditi...
Figure 5: Comparison of physicochemical data of fluxapyroxad and boscalid and their 1,2-BCH bioisosteres [36]. Sh...
Figure 6: Antifungal activity of fluxapyroxad, its 1,5-BCH bioisostere (±)-55, boscalid and its bioisostere 1...
Figure 7: 1,5-Disubstituted bicyclo[2.1.1]hexanes as isosteres of ortho-substituted benzenes. Comparison of e...
Scheme 5: Synthesis of 1,5-disubstituted bicyclo[2.1.1]hexanes as isosteres of ortho-benzenes via intramolecu...
Figure 8: Comparison of physicochemical data of fluxapyroxad and boscalid and their 1,5-BCH bioisosteres [45]. Sh...
Figure 9: Antifungal activity of fluxapyroxad, its 1,5-BCH bioisostere (±)-64, boscalid and its bioisostere 1...
Figure 10: 1,5-Disubstituted 3-oxabicylco[2.1.1]hexanes as isosteres for ortho-benzenes: Comparison of exit ve...
Scheme 6: Synthesis of 1,5-disubstituted 3-oxabicyclo[2.1.1]hexanes as isosteres for ortho-benzenes via intra...
Figure 11: Comparison of physicochemical data of fluxapyroxad and boscalid and their 3-oxa-1,5-BCH bioisostere...
Figure 12: Antifungal activity of fluxapyroxad and boscalid and their 3-oxa-1,5-BCH bioisosteres (±)-75 and (±...
Figure 13: 1,2-Disubstituted bicyclo[3.1.1]heptanes as isosteres of ortho-benzenes. Schematic representation o...
Scheme 7: Synthesis of 1,2-disubstituted bicyclo[3.1.1]heptanes as isosteres for ortho-benzenes via alkene in...
Figure 14: 1,2-Disubstituted stellanes as ortho-benzene isosteres: Comparison of selected exit vector paramete...
Scheme 8: Synthesis of 1,2-disubstituted stellanes as isosteres for ortho-benzenes reported by Ryabukhin, Vol...
Figure 15: 1,2-Disubstituted cubanes as ortho-benzene isosteres: Comparison of substituent distances and angle...
Scheme 9: Synthesis of 1,2-disubsituted cubanes as isosteres for ortho-benzenes. A: Synthesis of 1,2-cubane d...
Figure 16: 1,3-Disubstituted bicyclo[2.1.1]hexanes as isosteres of meta-benzenes: comparative exit vector para...
Scheme 10: Synthesis of 1,3-disubstituted bicyclo[2.1.1]hexanes as isosteres for meta-benzenes reported by Wal...
Figure 17: 1,4-Disubstituted bicyclo[2.1.1]hexanes as isosteres of meta-benzenes: comparative exit vector para...
Scheme 11: Synthesis of 1,4-disubstituted bicyclo[2.1.1}hexanes as isosteres for ortho-benzenes via intramolec...
Figure 18: 1,4-Disubstituted-2-oxabicyclo[2.1.1]hexanes as meta-benzene isosteres: comparison of selected exit...
Scheme 12: Synthesis of 1,4-disubstituted 2-oxabicyclo[2.1.1]hexanes as isosteres for meta-benzenes. A: Mykhai...
Figure 19: Comparative physicochemical data for 2- and 3-oxa-1,4-BCHs and para-substituted benzene equivalents...
Figure 20: 1,5-Disubstituted bicyclo[3.1.1]heptanes as isosteres of meta-benzenes: comparison of exit vector p...
Scheme 13: Synthesis of [3.1.1]propellane as a precursor for 1,5-disubsituted bicyclo[3.1.1]heptanes. A: aGass...
Scheme 14: Synthesis of iodine-substituted 1,5-disubstituted bicyclo[3.1.1]heptanes as isosteres for meta-benz...
Scheme 15: Synthesis of nitrogen-, chalcogen- and tin-substituted 1,5-disubstituted bicyclo[3.1.1]heptanes as ...
Figure 21: Comparative physicochemical data of URB597 and 1,5-BCHep isostere 146 [27]. Kinetic aqueous solubility ...
Figure 22: [2]-Ladderanes as isosteres of meta-benzenes: comparison of reported exit vector parameters [63].
Scheme 16: Synthesis of cis-2,6-disubstituted bicyclo[2.2.0]hexanes as isosteres for meta-benzenes. A: Brown a...
Figure 23: Comparative physicochemical data of meta-benzene 158 and [2]-ladderane isostere 159 [63]. Partition coe...
Figure 24: 1,3-Disubstituted cubanes as isosteres of meta-benzenes: comparison of selected exit vector paramet...
Scheme 17: Synthesis of 1,3-disubsituted cubanes as isosteres for meta-benzenes. A: MacMillan and co-workers’ ...
Figure 25: Comparative physicochemical data of lumacaftor and its 1,3-cubane bioisostere 183 [51]. Distribution co...
Figure 26: 1,3-Disubstituted cuneanes as isosteres of meta-benzenes: comparison of selected exit vector parame...
Scheme 18: Synthesis of 1,3-cuneanes as isosteres of meta-benzene. A: Synthesis of 1,3-cuneanes reported by La...
Figure 27: Comparative physicochemical data of sonidegib and its 1,3-cuneane isostere 190 [71]. aSolubility was to...
Figure 28: Exemplary polysubstituted scaffolds related to disubstituted scaffolds suggested as isosteres of or...
