Multiple Physicochemical Properties Close to Benzamide, Conformational Orientation Closer to Sulfonamide: The Dual Bioisosteric Design Value of 3-Aryl-3-aminooxetanes

1. The Key to Amide Bioisostere Design: Property Retention and Conformational Fit Are Equally Important

Amides are among the most common functional groups in drug molecules. They can provide hydrogen-bonding interactions, connect different structural fragments, and help molecules maintain specific conformations through their relatively strong planarity. However, an amide is not always the optimal linking unit. Its C–N bond has partial double-bond character and a relatively high rotational barrier, so molecules containing amides often display pronounced planarity. This feature is beneficial for conformational fixation, but it may also restrict the three-dimensional direction in which a molecule can extend. In some lead-optimization programs, amide fragments may also be associated with insufficient aqueous solubility, limited opportunities for structural modification, or suboptimal pharmacokinetic properties.

Amide bioisostere design should not stop at judging two-dimensional structural similarity. It is also necessary to assess whether physicochemical properties are retained, whether key interactions are maintained, whether the conformational orientation is suitable, and whether the replacement creates new opportunities for optimization.

A recent study published in the Journal of Medicinal Chemistry systematically compared the properties and structures of 3-aryl-3-aminooxetanes and benzamides using 12 matched molecular pairs, also known as Matched Molecular Pair Analysis, or MMPA. The results showed that, within this dataset of 12 benzamide matched molecular pairs, 3-aryl-3-aminooxetanes were broadly comparable to their corresponding benzamides in terms of lipophilicity, pH stability, metabolic stability, permeability, and hydrogen-bonding ability. At the same time, their conformational preferences, torsion angles, and exit vectors were closer to those of sulfonamides.

2. Core Structure: Aminooxetanes Combine Amide-like Property Features with Sulfonamide-like Conformational Features

2.1 Basic Differences among the Three Structural Classes

Schematic structures of amides, 3-aryl-3-aminooxetanes, and sulfonamides are shown below:

From a structural perspective, 3-aryl-3-aminooxetanes are not direct equivalent replacements for amides. They replace the amide carbonyl-containing linkage with an oxygen-containing four-membered ring, shifting the molecule from a planar connection toward a more three-dimensional orientation.

Their dual bioisosteric design value can be summarized as follows:

Comparison Dimension	Performance of Aminooxetanes	Medicinal Design Significance
Lipophilicity	Overall close to the corresponding benzamides	Replacement is less likely to cause a significant increase in logD
Stability	Most tested matched molecular pairs show good stability under acidic, neutral, and basic conditions	Provides a basis for further structural optimization
Solubility	In the tested matched molecular pairs, aqueous solubility is better than that of the corresponding benzamides in most cases, especially under acidic conditions	Can serve as a candidate replacement fragment for improving the aqueous solubility of certain amide-containing molecules
Hydrogen-bonding ability	Retains amide-like hydrogen-bond donor and acceptor features	Helps maintain key hydrogen-bonding interactions
Amine basicity	Can lower the pKaH of an adjacent amine	Can be used to modulate the protonation tendency of amines
Conformational orientation	Conformational preferences and exit vectors are closer to those of sulfonamides	Can be used to alter the three-dimensional extension direction of a molecule

3. Study Design: 12 Matched Molecular Pairs Improve the Reliability of the Conclusions

3.1 Significance of the MMPA Comparison

The value of MMPA lies in changing only one structural fragment as far as possible, thereby allowing the true impact of that fragment replacement on molecular properties to be evaluated. In this study, 12 matched molecular pairs of 3-aryl-3-aminooxetanes and benzamides were constructed. The comparison included the following aspects:

Comparison Item	Evaluation Purpose
Distribution coefficient, logD	To determine whether lipophilicity changes significantly
pH stability	To determine whether the structure is stable under acidic, neutral, and basic conditions
Aqueous solubility	To determine whether the replacement improves solubility
Human hepatocyte clearance, abbreviated as HHEPG	To evaluate metabolic stability
Ralph Russ Canine Kidney, abbreviated as RRCK, permeability	To evaluate transmembrane permeability
pKaH, the acid dissociation constant of the conjugate acid	To evaluate changes in the basicity of an adjacent amine
Crystal structures and computed conformations	To determine differences in conformation, torsion angle, and exit vector

The study molecules included two series. One series used a para-methoxyphenyl, or PMP, core while varying the amine component; the other used a morpholine core while varying the aryl group. The aminooxetanes were prepared through defluorosulfonylative coupling, abbreviated as deFS, while the corresponding benzamides were prepared through amidation reactions.

4. Physicochemical Properties: A Basis for Use as Amide Bioisosteres

4.1 Lipophilicity: No Obvious Loss of logD Control after Replacement

Lipophilicity is an important parameter for assessing whether a bioisosteric replacement is feasible. Many structural replacements can maintain activity but significantly increase lipophilicity, which may further affect solubility, metabolic clearance, and nonspecific binding.

In this study, the 10 tested aminooxetane compounds had logD values ranging from 0.33 to 3.60, with an average value of 1.68. The corresponding benzamide compounds had logD values ranging from 0.44 to 3.83, with an average value of 1.61. The two groups of compounds showed broadly similar logD distributions and average values. This indicates that, within this matched molecular pair dataset, replacing a benzamide fragment with an aminooxetane fragment did not lead to a systematic increase in lipophilicity.

4.2 pH Stability: Most Compounds Are Stable under Common Conditions

The study showed that, under acidic, neutral, and basic conditions, most tested matched molecular pairs displayed good stability over 24 hours. However, 1a showed reduced stability under neutral and basic conditions, and some degradation was also observed for matched molecular pair 7. Therefore, 3-aryl-3-aminooxetanes did not show a systematic risk of chemical instability, although structure-dependent differences still exist.

A few aminooxetane molecules showed lower remaining amounts under neutral and basic conditions. The study suggested that this was more likely related to solubility limitations rather than rapid degradation of the structural motif itself. Overall, no systematic chemical stability problem was observed for 3-aryl-3-aminooxetanes.

4.3 Metabolic Stability and Permeability: Broadly Comparable to Benzamides

The study further compared HHEPG and RRCK cell permeability. The results showed that aminooxetanes and benzamides were broadly comparable in these two dimensions, with no systematic increase in metabolic clearance or decrease in permeability observed.

This study indicates that aminooxetanes do not resemble amides in only a single property. Rather, they maintain a good overall balance among lipophilicity, stability, metabolic stability, and permeability.

5. Practical Value: Solubility Improvement and Modulation of Amine Basicity

5.1 Solubility: More Favorable Performance in Most Matched Molecular Pairs

Insufficient aqueous solubility is a common issue in the optimization of amide-containing lead compounds. This study showed that, in the tested matched molecular pairs, aminooxetanes generally displayed better aqueous solubility than the corresponding benzamides. Some differences were especially pronounced under acidic conditions. However, this advantage is structure-dependent, and not all matched molecular pairs showed improved solubility.

For example, aminooxetane 1a reached a solubility of 533 μM at pH 3, whereas the corresponding benzamide 1b had a solubility of less than 0.1 μM. This difference indicates that, in certain structural contexts, aminooxetane replacement may significantly improve aqueous solubility.

Within this MMPA dataset, aminooxetanes showed a trend toward improved aqueous solubility and may serve as candidate replacement fragments when an amide fragment contributes to solubility limitations.

5.2 Amine Basicity: Lowering the pKaH of an Adjacent Amine

Aminooxetanes also show an ability to modulate the pKaH of an adjacent amine. In the study, aminooxetane 4a had a pKaH of 4.61, while the corresponding benzylamine 18 had a pKaH of 7.25. This result shows that the oxetane structure can significantly reduce the basicity of an adjacent amine. A schematic representation of how aminooxetanes lower adjacent amine basicity is shown below.

Benzylamine analogue 18 — higher pKaH

Ar — CH2 — NR₂

Aminooxetane fragment — lower pKaH

 

In medicinal design, amine basicity affects the proportion of protonated species and can further influence tissue distribution, membrane permeability, and nonspecific interactions. Introducing an aminooxetane can lower the pKaH of an adjacent amine and may therefore serve as a structural strategy for modulating the physicochemical properties and pharmacokinetic behavior of amine-containing compounds. It should be noted that a decrease in pKaH does not necessarily mean improved safety, nor does it directly prove a reduced risk of off-target effects. Its value lies in providing a tunable structural variable for subsequent property optimization.

6. Structural and Conformational Analysis: The Three-Dimensional Orientation of Aminooxetanes Is Closer to That of Sulfonamides

6.1 Differences in Conformational Orientation among the Three Structural Classes

The important value of aminooxetanes is not limited to their physicochemical similarity to amides. Crystal-structure and computational analyses show that, in terms of conformational orientation, they do not replicate amides. Instead, they are closer to sulfonamides.

Structural Type	Main Conformational Features	Impact on Medicinal Design
Amide	Strong planarity and restricted C–N rotation	Helps fix conformation, but the exit direction is relatively constrained
Aminooxetane	Prefers a gauche conformation, with easier C–N rotation	Can retain partial hydrogen-bonding ability while changing three-dimensional orientation
Sulfonamide	Nonplanar orientation, with an exit vector different from that of amides	Can provide different binding conformations and spatial extension modes

The amide C–N bond has partial double-bond character, and its rotational barrier is usually high. The study noted that the rotational barrier of an amide bond can exceed 20 kcal·mol⁻¹. This causes amides to preferentially maintain planar cis or trans conformations.

By contrast, the C–N rotational barrier of aminooxetanes is below 10 kcal·mol⁻¹, making rotation easier in aqueous solution. At the same time, their crystal structures favor a gauche conformation, and their torsion angles and exit vectors are closer to those of sulfonamides rather than typical amides.

The spatial orientation differences among the three structural classes are illustrated below.

Amide: predominantly planar conformation, restricted C–N rotation, and an exit vector extending close to the plane.

Ar — C(=O) — NH — R

Aminooxetane: gauche conformation, easier C–N rotation, and an exit vector deviating from the amide plane.

 

Sulfonamide: nonplanar orientation, with an exit vector different from that of amides and closer to that of aminooxetanes.

 

This result changes how the bioisosteric attributes of aminooxetanes should be interpreted. They should not simply be regarded as direct conformational equivalents of amides. Rather, they are structural fragments that can retain some amide-like functions while providing a three-dimensional orientation closer to that of sulfonamides.

6.2 Hydrogen-Bonding Ability: Retaining Key Amide Interactions

Although aminooxetanes differ conformationally from amides, the study shows that, when an N–H is retained in the structure, they can still display amide-like hydrogen-bond donor and hydrogen-bond acceptor functions. The oxetane oxygen can act as a hydrogen-bond acceptor. The hydrogen-bond distances and angle distributions associated with this oxygen atom are similar to those of amide carbonyl oxygen atoms. This gives aminooxetanes an important feature: they can, to some extent, maintain key hydrogen-bonding interactions involving amides while altering the spatial orientation of the linking fragment. This combined feature explains the dual value of aminooxetanes:

Physicochemical properties and hydrogen-bonding ability close to amides → candidate amide replacements

Conformational orientation and exit vectors close to sulfonamides → candidate sulfonamide replacements

7. Computational Validation: Better Fit in Sulfonamide-Related Conformations

The research team further used computational chemistry simulations to evaluate how well aminooxetanes fit specific binding conformations. The conformational distortion energy discussed here can be understood as the energetic cost a molecule must pay to match a target binding conformation. The higher the conformational distortion energy, the more difficult it is for the molecule to naturally adopt that conformation.

When simulating the binding conformation of the benzamide drug ethamivan 21b, the aminooxetane analogue 21a had a conformational distortion energy of 5.1 kcal·mol⁻¹, higher than that of ethamivan itself at 2.1 kcal·mol⁻¹. This suggests that, if target binding strongly depends on the planar conformation of an amide, an aminooxetane may not necessarily be a low-cost replacement.

By contrast, when simulating the binding conformation of the sulfonamide drug amprenavir 22c, the aminooxetane analogue 22a had a conformational distortion energy of 3.4 kcal·mol⁻¹, close to that of amprenavir at 3.8 kcal·mol⁻¹. This result further supports the structural analysis: although aminooxetanes are close to amides in terms of physicochemical properties, they may be more suitable as sulfonamide replacement fragments in terms of conformational fit.

Dual bioisosteric logic of aminooxetanes:

Amide

│ Similar physicochemical properties

│ Partial retention of hydrogen-bonding ability

↓

Aminooxetane

↑

│ Similar conformational orientation

│ Closer exit vectors

Sulfonamide

8. Medicinal Design Implications: Four Scenarios Worth Prioritizing

8.1 Amide Replacement: Improving Solubility while Maintaining Partial Hydrogen-Bonding Ability

When an amide fragment contributes to activity but the molecule suffers from insufficient aqueous solubility, an aminooxetane can be considered as a replacement candidate. In this MMPA dataset, aminooxetanes showed lipophilicity, stability, metabolic stability, and permeability comparable to those of benzamides, while solubility was more favorable in most cases. The focus of this application scenario is not mechanical amide replacement, but rather improving physicochemical properties while retaining partial hydrogen-bonding ability.

8.2 Sulfonamide Replacement: Maintaining a Similar Spatial Orientation while Potentially Reducing Part of the Polar Burden

Sulfonamides can provide nonplanar conformations and specific exit vectors, but their relatively high polarity may sometimes limit permeability or distribution properties. Aminooxetanes are closer to sulfonamides in terms of conformation and exit vector and may therefore serve as candidate sulfonamide replacements. This direction is particularly suitable for molecular optimization projects that aim to retain the spatial orientation of a sulfonamide while exploring reduced molecular weight, reduced acidity of a secondary sulfonamide N–H, or lower TPSA.

8.3 Modulation of Amine Basicity: Lowering the pKaH of an Adjacent Amine

When the basicity of an adjacent amine in a molecule is too high, an aminooxetane can serve as a structural modulation fragment to lower pKaH. By reducing the protonation tendency of the amine, it may further influence membrane permeability, tissue distribution, and nonspecific binding. This strategy is suitable for fine-tuning amine-containing fragments, rather than simply serving as a method to increase or decrease polarity.

8.4 Conformational Exploration: Changing Exit Vectors and Three-Dimensional Extension Direction

If the binding site of a target is sensitive to the spatial orientation of the linking fragment, aminooxetanes can be used to explore new exit vectors that differ from the planar conformation of amides. They retain a certain degree of hydrogen-bonding ability while introducing a more three-dimensional four-membered ring structure, making them suitable for conformational scanning and expansion of structural novelty.

9. Examples of Reference Compounds and Building Blocks Related to the Dual Bioisosteric Design of Aminooxetanes

Table 1. Amide and Sulfonamide Reference Compounds

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Amide reference compound	55-21-0	B118608	Benzamide	Sublimed grade, ≥99.5%	Used for comparative studies of the physicochemical properties, hydrogen-bonding ability, and conformational restriction of amide fragments
Amide reference compound	3424-93-9	M158329	4-Methoxybenzamide	≥98% (HPLC)	Used for the construction of aryl amide matched molecular pairs and reference studies of para-methoxyphenyl series
Sulfonamide reference compound	98-10-2	B113828	Benzenesulfonamide	≥98%	Used for reference studies of sulfonamide conformational orientation, hydrogen-bonding patterns, and exit vectors
Sulfonamide reference compound	70-55-3	T102875	p-Toluenesulfonamide	GR, ≥99%	Used for structural comparison of aryl sulfonamides and reference studies in sulfonamide bioisostere design

Table 2. Oxetane Core and 3-Functionalized Building Blocks

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Oxetane core	503-30-0	T162173	Trimethylene oxide	≥98% (GC)	Used for studying the chemical properties of the oxetane core and for designing oxygen-containing four-membered ring structures
3-Keto oxetane building block	6704-31-0	O129097	Oxetan-3-one	≥95%	Used for constructing 3-substituted oxetanes, reductive amination, and nucleophilic addition reactions
3-Hydroxy oxetane building block	7748-36-9	H123582	Oxetan-3-ol	≥95%	Used for oxetane etherification, esterification, sulfonate formation, and fragment derivatization
3-Carboxylic acid oxetane building block	114012-41-8	O166062	Oxetane-3-carboxylic acid	≥95%	Used for amidation, esterification, and construction of carboxylic acid derivatives
3-Cyano oxetane building block	1420800-16-3	O635615	Oxetane-3-carbonitrile	≥97%	Used for nitrile transformation, introduction of nitrogen-containing fragments, and construction of polar side chains
3-Alcohol oxetane building block	6246-06-6	O176971	Oxetane-3-methanol	≥97%	Used for introducing oxetane methanol side chains and for etherification and esterification derivatization
3-Alcohol oxetane building block	251922-46-0	O175897	2-(Oxetan-3-yl)ethan-1-ol	≥97%	Used for constructing extended-chain oxetane alcohol fragments and for side-chain modification
3-Substituted oxetane building block	3143-02-0	M104534	3-Methyl-3-oxetanemethanol	≥97%	Used for side-chain design of 3,3-disubstituted oxetanes and alcohol derivatization
3-Aldehyde oxetane building block	1305207-52-6	O173275	Oxetane-3-carbaldehyde	≥97%	Used for reductive amination, condensation reactions, and construction of oxygen-containing four-membered ring amine side chains
3-Aldehyde oxetane building block	99419-31-5	M178611	3-Methyl-3-formyl-1-oxetane	≥97%	Used for synthesis of 3,3-disubstituted oxetane derivatives and side-chain extension
Halogenated oxetane building block	4741-80-4	C176555	3-Chlorooxetane	≥97%	Used for nucleophilic substitution reactions and introduction of oxetane fragments
Halogenated oxetane building block	39267-79-3	B170097	3-Bromooxetane	≥95%	Used for constructing C–N, C–O, and C–S bonds
Halogenated oxetane building block	26272-85-5	I134383	3-Iodooxetane	≥95%	Used for highly reactive oxetane alkylation and as a precursor for coupling reactions

Table 3. Building Blocks Related to Aryl Oxetanes and Aminooxetanes

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Aryl oxetane precursor	699-73-0	P194663	3-Phenyl-3-hydroxy-1-oxetane	≥98%	Used for synthesis of 3-aryl oxetane derivatives and studies of aryl substituent effects
Aryl oxetane precursor	26755-28-2	O633295	3-(4-Methoxyphenyl)oxetan-3-ol	≥97%	Used for constructing para-methoxyphenyl oxetane series and for matched molecular pair studies
Aminooxetane core building block	21635-88-1	O135359	3-Aminooxetane	≥97%	Used for introducing aminooxetane fragments and for amide bioisostere and amine-containing side-chain design
Aminomethyl oxetane building block	6246-05-5	A171234	3-(Aminomethyl)oxetane	≥97%	Used for constructing oxygen-containing four-membered ring amine side chains and for studies on amine basicity modulation
Amino acid-like oxetane building block	138650-24-5	A138198	3-Aminooxetane-3-carboxylic acid	≥95%	Used for amino acid mimetics, polar fragments, and conformationally restricted structural design
Protected aminooxetane building block	1363382-11-9	T173648	tert-Butyl N-[3-(hydroxymethyl)oxetan-3-yl]carbamate	≥97%	Used for synthesis of protected aminooxetane derivatives and hydroxymethyl functionalization
Protected aminooxetane building block	1802048-96-9	T175134	tert-Butyl N-[3-(aminomethyl)oxetan-3-yl]carbamate	≥97%	Used for constructing bifunctional amine-containing oxetane building blocks and for protecting-group strategies in multistep synthesis
Protected aminohalogenated oxetane building block	1802048-91-4	T630542	tert-Butyl N-[3-(bromomethyl)oxetan-3-yl]carbamate	≥97%	Used for nucleophilic substitution, side-chain extension, and diversified synthesis of protected aminooxetanes

Note: The compounds listed above are examples of representative reference compounds and synthetic building blocks related to the structural design of amides, sulfonamides, and oxetanes. This does not mean that all of them were actually used in the JMC study. For specific specifications, grades, inventory status, and COA information, it is recommended to search the Aladdin website by product name, CAS number, or catalog number.

References

[1] Ishikura H, Begg C S, Rojas J J, Blagojevic L, Smith G J, Luk J, Croft R A, Romain C, Choi C, Bull J A. Do Amino-Oxetanes Resemble Amides? A Matched Molecular Pairs Property and Structural Comparison. Journal of Medicinal Chemistry, 2026. DOI: 10.1021/acs.jmedchem.5c02614.

[2] Wuitschik G, Carreira E M, Wagner B, Fischer H, Parrilla I, Schuler F, Rogers-Evans M, Müller K. Oxetanes in Drug Discovery: Structural and Synthetic Insights. Journal of Medicinal Chemistry, 2010, 53(8): 3227–3246. DOI: 10.1021/jm9018788.

[3] Bull J A, Croft R A, Davis O A, Doran R, Morgan K F. Oxetanes: Recent Advances in Synthesis, Reactivity, and Medicinal Chemistry. Chemical Reviews, 2016, 116(19): 12150–12233. DOI: 10.1021/acs.chemrev.6b00274.

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