Hubbry Logo
IsostereIsostereMain
Open search
Isostere
Community hub
Isostere
logo
7 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Isostere
Isostere
Isostere
View on Wikipedia
from Wikipedia

Classical Isosteres are molecules or ions with similar shape and often electronic properties. Many definitions are available.[1] but the term is usually employed in the context of bioactivity and drug development. Such biologically-active compounds containing an isostere is called a bioisostere. This is frequently used in drug design:[2] the bioisostere will still be recognized and accepted by the body, but its functions there will be altered as compared to the parent molecule.

History and additional definitions

[edit]

Non-classical isosteres do not obey the above classifications, but they still produce similar biological effects in vivo. Non-classical isosteres may be made up of similar atoms, but their structures do not follow an easily definable set of rules.

The isostere concept was formulated by Irving Langmuir in 1919,[3] and later modified by Grimm. Hans Erlenmeyer extended the concept to biological systems in 1932.[4][5][6] Classical isosteres are defined as being atoms, ions and molecules that had identical outer shells of electrons, This definition has now been broadened to include groups that produce compounds that can sometimes have similar biological activities. Some evidence for the validity of this notion was the observation that some pairs, such as benzene, thiophene, furan, and even pyridine, exhibited similarities in many physical and chemical properties.

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Isostere

View on Grokipedia
from Grokipedia
An isostere is a , , or group of atoms that has the same number of atoms and valence electrons arranged in a similar manner as another, resulting in comparable size, shape, and often electronic properties. The term was first introduced by chemist in 1919 to describe such structural mimics, such as (CO) and dinitrogen (N₂), which exhibit analogous behaviors due to their isoelectronic nature. Early examples included the azide (N₃⁻) and cyanate (NCO⁻), highlighting how isosteres can maintain molecular stability and reactivity profiles. The concept evolved through contributions from subsequent researchers, including Hugo Grimm's 1925 "hydride displacement law," which proposed that replacing a (H⁻) with the next higher element could yield isosteric analogs, such as (NH₄⁺) mimicking (Ne). Hans Erlenmeyer further broadened the definition in 1932 to encompass entities with identical peripheral electron layers, like (Cl⁻), (CN⁻), and (SCN⁻), emphasizing applications beyond pure chemistry into biological contexts. In , this led to the development of bioisosteres—a subset introduced by Harris in 1951—defined as isosteres that produce similar biological activities, enabling the modification of drug leads to enhance potency, selectivity, or pharmacokinetic properties without altering core interactions. Bioisosteric replacements are widely employed in to address developability challenges, such as improving , metabolic stability, or reducing ; for instance, tetrazoles serve as bioisosteres in angiotensin II receptor blockers like losartan, boosting potency by over tenfold compared to precursors. often acts as a hydrogen bioisostere, as seen in emtricitabine where it enhances HIV-1 inhibition by 4- to 10-fold through altered binding and . Other common types include heterocycle exchanges (e.g., phenyl to thiophenyl rings) and amide-to-alkene surrogates in peptides, which have facilitated the creation of therapeutics like for antineoplastic activity and flunarizine as a . These strategies underscore isosteres' role in optimizing while preserving therapeutic efficacy.

Definition and Principles

Core Definition

Isosteres are atoms, ions, or molecules that possess the same number of valence electrons and often similar arrangements of atoms, resulting in comparable physical and chemical properties. This concept was formally introduced by in 1919, who defined isosteres as entities in which the peripheral layers of electrons can be considered identical, emphasizing their role in exhibiting similar behaviors due to electronic equivalence. A key characteristic of isosteres is that they are typically isoelectronic, meaning they share the same total number of valence electrons. For example, gas (N₂) and (CO) are classic isosteres: both are diatomic molecules with a and 10 valence electrons (5 from each N atom in N₂; 4 from C and 6 from O in CO), leading to similar bond lengths, moments, and reactivity patterns. Another representative pair is (CH₄) and the (NH₄⁺), both featuring tetrahedral geometry around the central atom with 8 valence electrons (4 from C plus 4 from H atoms in CH₄; 5 from N plus 4 from H minus 1 for the positive charge in NH₄⁺). The mathematical basis for identifying isosteres lies in calculating the total valence electrons of a , given by the
Nv=∑vi−qN_v = \sum v_i - q
where viv_i is the number of valence electrons for each neutral atom ii (typically the group number in the periodic table), and qq is the net charge of the species (positive for cations, negative for anions). This electron count ensures structural and energetic similarities, distinguishing isosteres from isomers, which share the exact same molecular and atom counts but differ in atomic connectivity or spatial arrangement.

Underlying Principles

Isosteres exhibit electronic similarity primarily through isoelectronic configurations, which result in analogous molecular orbitals and comparable reactivity profiles. Molecules with the same number of valence electrons occupy similar electronic states, leading to parallel chemical behaviors. A representative example is the diatomic molecules (N₂) and (CO), which share 10 valence electrons and display similar characteristics, including bond lengths of 1.10 Å for N≡N and 1.13 Å for C≡O, as well as close moments of approximately 0 D and 0.11 D, respectively. Steric factors further underpin isosteric interchangeability by providing comparable spatial occupancy, achieved through similar van der Waals radii and molecular volumes that facilitate mimicry in three-dimensional arrangements. For instance, the tetrahedral geometries of (CH₄) and (Ne) or the ion (NH₄⁺) demonstrate near-equivalent effective sizes around the central atom, minimizing steric clashes in molecular assemblies. These attributes are often quantified computationally; software such as the (MOE) employs algorithms to compute molecular volume overlaps and alignment scores, confirming high steric congruence (e.g., root-mean-square deviation < 0.5 Å for well-matched isosteres). Physical property parallels among isosteres arise from their akin intermolecular forces, influencing attributes like boiling points, solubilities, and lattice energies. (CH₄), with a of -161.5°C, exemplifies this alongside the cation (NH₄⁺) in crystalline salts, where both display efficient packing densities around 0.74 (close to ideal close-packing) due to tetrahedral geometries and comparable polarizabilities, leading to similar cohesive energies in condensed phases. At the quantum mechanical level, the rationale for isosteric similarity is rooted in , which predicts small energy perturbations (typically < 5% change in total energy) upon replacement, as the Hamiltonian alterations are minor for isoelectronic systems. For π-conjugated systems, Hückel approximations reinforce this by yielding nearly identical eigenvalue spectra and orbital symmetries for isosteric variants, such as and its azaisosteres, ensuring preserved delocalization energies within 0.1 β (where β is the resonance integral).

Types of Isosteres

Classical Isosteres

Classical isosteres are categorized based on the number of atoms and their electronic configurations, focusing on structural and electronic mimicry in inorganic and organic contexts. Monatomic classical isosteres include pairs such as the hydride (H⁻) and (He), which share identical electron counts and spherical symmetry. Diatomic examples encompass (N₂), (CO), and the cyanide (CN⁻), all featuring a and 10 valence electrons, enabling similar bonding geometries. Polyatomic classical isosteres, such as (BF₃) and the (CO₃²⁻), exhibit trigonal planar structures with 24 valence electrons, allowing for comparable coordination environments. In 1925, Hugo Grimm formulated the hydride displacement rule, which posits that replacing a hydride ion (H⁻) with an atom of higher preserves key chemical properties by maintaining counts. This rule enables sequential substitutions, such as CH₃ (methyl) to NH₂ (amino), OH (hydroxyl), and F (fluoro), each retaining 7 valence electrons in the peripheral shell. A complete series illustrates tetrahedral and 8 valence electrons across (CH₄), (NH₄⁺), (H₃O⁺), and (HF). Classical isosteres demonstrate interchangeability in crystal structures due to similar ionic radii and charges, as seen in isomorphous salts like (KCl) and (KBr), both adopting the rock salt lattice. This property facilitates formation in mixed crystals. In reactivity, classical isosteres can exhibit analogous patterns, such as the comparable nucleophilicity of CN⁻ and N₂, where N₂ acts under high-pressure or catalytic conditions to mimic CN⁻ binding in coordination complexes. Despite these similarities, classical isosteres are not always perfect mimics owing to variations in , which influence polarity; for instance, CO possesses a small dipole moment (0.11 D) arising from the electronegativity difference between C and O, contrasting with the nonpolar N₂.

Bioisosteres

Bioisosteres represent a specialized subset of isosteres tailored for biological contexts, defined by Harris L. in 1951 as compounds or groups of compounds that fit the broadest definition of isosteres while eliciting the same type of . This concept extends beyond strict physicochemical equivalence to emphasize functional in , where structural variations are tolerated if they preserve pharmacological effects. Bioisosteres are categorized into classical and nonclassical subtypes: classical bioisosteres involve replacements with similar electronic and steric properties, such as (-COOH) with (-SO₃H), while nonclassical bioisosteres allow greater divergence, exemplified by methylene (-CH₂-) replaced by (-S-) to modulate without disrupting chain flexibility. Selection criteria for bioisosteres prioritize physicochemical properties that influence biological interactions, including comparable pKa values for acidity, hydrogen bonding capacity, (measured by logP), and steric bulk to ensure receptor or compatibility. For instance, 1H-tetrazole serves as a prominent bioisostere for , exhibiting a pKa of approximately 4.9 versus 4.8 for -COOH, enabling both to act as acidic donors and acceptors in binding sites while offering improved metabolic stability. Common bioisosteric replacements in molecular design include mimics such as , acylsulfonamide (pKa ~4-5, enhancing ), and phosphonic acid (pKa ~2.0 and 7.2, providing dual ionization). Heterocycle exchanges also prevail, like and , which maintain and π-electron distribution for similar stacking interactions despite differing electronegativities. Bioisosteres are evaluated primarily through retention of binding affinity in inhibition assays, where successful replacements preserve potency metrics like IC₅₀ values. For example, in (ACE) inhibitors, substituting the group in analogs with difluoromethyl (CHF₂) maintained inhibitory potency, yielding Ki values of approximately 30-40 nM comparable to the parent compound, due to preserved hydrogen bonding and van der Waals interactions at the .

Applications

In Medicinal Chemistry

In medicinal chemistry, isosteres are employed to optimize key drug properties such as metabolic stability and without substantially altering . For instance, replacing an (-CONH₂) with a (-SO₂NH₂) enhances resistance to hydrolytic metabolism, as sulfonamides are less prone to enzymatic cleavage by amidases, thereby improving overall pharmacokinetic profiles in drug candidates. Similarly, substituting a (-COOH) with a group boosts and metabolic stability; in sartans like losartan, the tetrazole mimics the acidic and hydrogen-bonding properties of -COOH while increasing aqueous due to its pKa (around 4.9) and reducing susceptibility to β-oxidation, leading to better oral . Strategies involving isosteric replacements further refine drug-like properties. Scaffold hopping, such as exchanging a ring for a , introduces polarity via the nitrogen atom, which can decrease and mitigate CYP450-mediated while preserving binding affinity to targets. Another approach is group replacement to evade or metabolic hotspots; for example, a trifluoromethyl (-CF₃) provides strong withdrawal (Hammett σ = 0.54) despite its larger size compared to methyl (-CH₃) but blocks oxidative at the aromatic ring by deactivating it toward cytochrome P450 enzymes, thus avoiding reactive metabolites. Case studies illustrate these applications in . In statins, pravastatin's dihydroxyheptanoate side chain serves as a bioisosteric mimic of the compact in , enabling competitive inhibition of while maintaining the extended conformation for enzyme binding and improving hydrophilic properties for renal excretion. For kinase inhibitors, replacing a hinge binder with a pyridone in c-Met inhibitors enhances selectivity by altering hydrogen-bonding patterns and reducing off-target interactions with other s, as seen in optimized pyridine-based analogs that retain nanomolar potency against c-Met while improving selectivity over VEGFR2. Quantitative benefits from structure-activity relationship (SAR) studies underscore the value of these replacements. Bioisosteric modifications often retain potency within 10- to 100-fold of the parent compound; for example, tetrazole replacement in losartan analogs preserved angiotensin II receptor antagonism (IC₅₀ ≈ 1-5 nM) while extending plasma from under 2 hours to over 6 hours due to reduced hepatic clearance. In amide-to-sulfonamide swaps, SAR data show similar trends, with one series exhibiting equipotent inhibition (IC₅₀ ≈ 10 nM) alongside a 5- to 6-fold increase in human liver microsome (from 10 min to 59 min), demonstrating effective property modulation.

In Materials Science and Other Fields

In , isosteric substitution of metal nodes in metal-organic frameworks (MOFs) enables precise tuning of pore sizes while preserving the overall framework topology. For instance, in the IRMOF-14 series, replacing nodes with larger nodes results in expanded pore volumes due to the increased of Cd²⁺ (97 pm) compared to Zn²⁺ (74 pm), maintaining the primitive cubic (pcu) topology and enhancing gas sorption capacities without altering the linker connectivity. This approach has been applied to design MOFs with tailored apertures for selective adsorption, such as in separating hydrocarbons, where the subtle pore size adjustments improve diffusion kinetics. In catalysis, isosteric ligand replacements allow electronic properties to be modulated while retaining geometric constraints like bite angles, optimizing reaction selectivity. Bidentate phosphine ligands, such as 1,2-bis(diphenylphosphino)ethane (dppe) with a bite angle of approximately 85–90°, can be replaced by N-heterocyclic carbene (NHC) analogs like bis(1,3-dimesitylimidazolin-2-ylidene)ethane, which maintain a similar ~90° bite angle but offer stronger σ-donation due to the carbene's lower π-acidity. In palladium-catalyzed cross-coupling reactions, such as Suzuki-Miyaura couplings, NHC variants enhance turnover frequencies by up to 10-fold compared to phosphine counterparts, attributed to improved stability against oxidative degradation while preserving the chelate geometry. This substitution strategy has been pivotal in developing air-stable Pd catalysts for C-C bond formation in industrial processes. Supramolecular chemistry and crystal engineering leverage isosteric mimics of hydrogen-bonding motifs to control assembly and stability in host-guest complexes and co-crystals. For example, replacing hydroxyl (-OH) groups with amino (-NH) functionalities in resorcinarene-based hosts preserves the directional H-bonding patterns, such as O-H···O or N-H···O interactions with similar donor-acceptor distances (~2.8–3.0 ), enabling tunable guest encapsulation in cavitand complexes. In co-crystal design, such substitutions facilitate polymorph control by altering lattice energies; interchanging -OH and -NH in co-formers with diamines stabilizes specific packing motifs. Emerging applications in utilize isosteric heteroatom replacements to adjust optoelectronic properties without disrupting conjugation. Substituting sulfur in units with in polythiophene analogs, such as regioregular poly(3-hexylthiophene) (P3HT) replaced by poly(3-hexylselenophene) (P3HS), lowers the band gap from ~1.9 eV to ~1.6 eV due to the larger atomic size and polarizability of , enhancing near-IR absorption while maintaining similar π-π stacking distances (~3.8 Å). This modification improves charge carrier mobility in organic field-effect transistors by 20–50% and boosts power conversion efficiencies in bulk heterojunction solar cells to over 5%, as demonstrated in selenophene- copolymers.

History and Development

Origins of the Concept

The concept of isosterism has roots in late 19th-century chemistry, particularly in Dmitri Mendeleev's development of the periodic table, where he drew analogies between elements of similar atomic properties to predict their behavior in compounds and suggest potential replacements based on shared valence characteristics. These early analogies laid groundwork for recognizing structural equivalences among elements and molecules, though without a formal term for the phenomenon. The term "isosteric" was formally introduced by in 1919, in the context of his studies on atomic and molecular electron arrangements and their implications for chemical stability and adsorption processes. Langmuir defined isosteric compounds as those possessing the same number of s and similar spatial electron configurations, often adhering to the , which posits stable outer electron shells of eight s for many atoms. This concept emerged from his investigations into surface adsorption, where molecules with equivalent electronic structures exhibited comparable physical behaviors, such as similar volumes and interaction potentials on surfaces. In his seminal paper, "Isomorphism, Isosterism and Covalence," published in the Journal of the , Langmuir formalized the equivalence of electron counts as a predictor of molecular similarity, extending it beyond (structural similarity in crystals) to broader chemical analogies. He illustrated this with examples from , such as the isosteric pairs (NO) and (CO), which share 11 valence electrons and triple-bond configurations, leading to analogous roles in coordination compounds and gas-phase reactions. These pairs demonstrated how isosterism could explain comparable stabilities and reactivities, for instance, in predicting equilibrium outcomes of reactions involving isoelectronic species. Initial applications of isosterism focused on inorganic systems, aiding predictions of compound stability in gas-phase equilibria and adsorption isotherms, where isosteric molecules showed indistinguishable thermodynamic properties under constant volume conditions. Langmuir's framework thus provided a tool for chemists to anticipate substitutions without altering core electronic properties, influencing early 20th-century understandings of valence and molecular interactions.

Evolution and Key Milestones

In 1925, Hugo Grimm expanded the classical concept of isosterism through his hydride displacement rule, which established isoelectronic series for replacing atoms or groups—such as the progression from CH to NH⁺, O, and F—while maintaining similar counts and applying these substitutions to organic compounds and reaction mechanisms. In 1932, Hans Erlenmeyer further broadened the definition of isosteres to encompass entities with identical peripheral electron layers, such as (Cl⁻), (CN⁻), and (SCN⁻), and emphasized their applications in biological contexts. The notion of bioisosterism emerged in 1951 when Harris Friedman defined bioisosteres as molecular fragments or compounds that elicit broadly similar biological responses despite differences in elemental composition or structure, thereby emphasizing pharmacological rather than purely physicochemical equivalence. In 1970, Alfred Burger advanced the field by classifying bioisosteres into classical types—those that are isoelectronic and of comparable size and shape—and nonclassical types, which deviate from these strict criteria but still confer analogous biological effects, thus enhancing their utility in . By the , computational approaches proliferated, with quantitative structure-activity relationship (QSAR) models enabling the screening and prediction of bioisosteric replacements to optimize ligand-target interactions without extensive synthesis. In the , bioisosteric strategies became central to lead optimization, where replacements improved pharmacokinetic profiles, potency, and selectivity, and to patent evasion, allowing structural modifications that circumvent existing while preserving activity. The 2020s have witnessed further evolution through integration, exemplified by tools like SwissBioisostere, which leverage large-scale databases to identify and predict bioisosteric replacements based on bioactivity, physicochemical properties, and contextual data from millions of molecular pairs. Key reviews shaping modern understanding include those on isosteres, such as the comprehensive analysis by Ballini et al. highlighting synthetic and pharmacological applications, and the Baran group's 2020 overview of recent trends and tactics emphasizing synthetic accessibility for diverse bioisosteric scaffolds.

References

  1. https://www.scripps.edu/baran/images/grpmtgpdf/Mitsos_Feb_06.pdf
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC7416817/
  3. https://pubs.acs.org/doi/10.1021/ja02231a009
  4. https://ocw.mit.edu/courses/5-61-physical-chemistry-fall-2007/f236323f96932627d5e916fc63fd3f55_lecture31.pdf
  5. https://www.researchgate.net/publication/244653083_Study_of_crystal_perfection_in_the_KCl-KBr_and_KCl-RbCl_systems
  6. https://pubs.acs.org/doi/10.1021/ja00009a035
  7. https://nap.nationalacademies.org/read/18474/chapter/15
  8. https://pubs.acs.org/doi/10.1021/jm1013693
  9. https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01963
  10. https://www.sciencedirect.com/science/article/pii/S0223523424004057
  11. https://pmc.ncbi.nlm.nih.gov/articles/PMC7666045/
  12. https://www.tandfonline.com/doi/full/10.4155/fmc-2019-0288
  13. https://ctppc.org/archive/volume/7/issue/1/article/1413/pdf
  14. https://pmc.ncbi.nlm.nih.gov/articles/PMC7451012/
  15. https://pmc.ncbi.nlm.nih.gov/articles/PMC12298972/
  16. https://www.researchgate.net/publication/347287822_Substitution_Effect_of_the_Trifluoromethyl_Group_on_the_Bioactivity_in_Medicinal_Chemistry_Statistical_Analysis_and_Energy_Calculations
  17. https://www.researchgate.net/figure/Statins-share-a-number-of-chemical-similarities-They-all-contain-a-dihydroxy-heptanoic_fig1_51020901
  18. https://www.sciencedirect.com/science/article/abs/pii/S096808961730319X
  19. https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2022.869860/full
  20. https://pmc.ncbi.nlm.nih.gov/articles/PMC6803051/
  21. https://pubs.rsc.org/en/content/articlehtml/2021/cs/d0cs00424c
  22. https://onlinelibrary.wiley.com/doi/10.1002/ejic.201500932
  23. https://pubs.acs.org/doi/10.1021/om0608408
  24. https://pubs.acs.org/doi/10.1021/ja9735968
  25. https://pubs.rsc.org/en/content/articlelanding/2012/jm/c2jm33735e
  26. https://www.chem.msu.ru/eng/misc/mendeleev/hyper/
  27. https://drugdesign.org/chapters/bioisosterism/
  28. https://pubs.acs.org/doi/10.1021/cr950066q
  29. https://wires.onlinelibrary.wiley.com/doi/abs/10.1002/wcms.1148
  30. https://www.researchgate.net/publication/11629160_The_use_of_bioisosteric_groups_in_lead_optimization
  31. https://academic.oup.com/nar/article/50/D1/D1382/6426059
  32. https://pubmed.ncbi.nlm.nih.gov/23361977/
  33. https://baranlab.org/wp-content/uploads/2020/11/Bioisosteres-v2-Recent-Trends-and-Tactics.pdf
Add your contribution
Related Hubs
User Avatar
No comments yet.