Isosteric Replacement Research Articles

Pentathiepins are an understudied molecular prism of biological activities.

The pentathiepin core was first synthesized in 1971, and while synthetic techniques have progressed over subsequent decades, the biological applications of this heterocycle have received less attention and are only now becoming more apparent. The first natural product, varacin, was identified in 1991, showing cytotoxicity toward a human colon cancer cell line. More recently, the pentathiepin has acted as a surrogate to replace elemental sulfur, that was discovered as a hit in neurodegenerative animal models. A variety of other medicinal chemistryapplications have recently been disclosed. Here, we summarize these indications and highlight the main synthetic pathways to access the pentathiepin core. We offer a concise summary and future perspective of this unique sulfur isosteric replacement.

Identification of isoquinolinone DHODH inhibitor isosteres

DHODH inhibition represents an attractive approach to overcome differentiation blockade for the treatment of AML. In a previous communication, we described our efforts leading to the discovery of compound 3 (JNJ-74856665), an orally bioavailable, potent, and selective DHODH inhibitor for clinical development. Guided by the co-crystal structures bound to human DHODH, other fused six-membered constructs were explored as isosteric replacements of the isoquinolinone central core. The correct positioning of the nitrogen in these core systems proved to be essential in modulating potency. Herein is described the synthesis of these complexly functionalized cores and their profiling, leading to DHODH inhibitors that possess favorable properties suitable for further development.

Catalytic asymmetric synthesis of meta benzene isosteres.

Although aromatic rings are common elements in pharmaceutically active compounds, the presence of these motifs brings several liabilities with respect to the developability of a drug1. Nonoptimal potency, metabolic stability, solubility and lipophilicity in pharmaceutical compounds can be improved by replacing aromatic rings with non-aromatic isosteric motifs2. Moreover, whereas aromatic rings are planar and lack three-dimensionality, the binding pockets of most pharmaceutical targets are chiral. Thus, the stereochemical configuration of the isosteric replacements may offer an added opportunity to improve the affinity of derived ligands for target receptors. A notable impediment to this approach is the lack of simple and scalable catalytic enantioselective syntheses of candidate isosteres from readily available precursors. Here we present a previously unknown palladium-catalysed reaction that converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes and we show that the shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings. With chiral catalysts, the Pd-catalysed reaction can be accomplished in an enantioselective fashion and subsequent transformation of the boron group provides access to a broad array of structures. We also show that the incorporation of nortricyclanes into pharmaceutical motifs can result in improved biophysical properties along with stereochemistry-dependent activity. We anticipate that these features, coupled with the simple, inexpensive synthesis of the functionalized nortricyclane scaffold, will render this platform a useful foundation for the assembly of new biologically active agents.

Isosteric Replacement of Sulfur to Selenium in a Thiosemicarbazone: Promotion of Zn(II) Complex Dissociation and Transmetalation to Augment Anticancer Efficacy.

We implemented isosteric replacement of sulfur to selenium in a novel thiosemicarbazone (PPTP4c4mT) to create a selenosemicarbazone (PPTP4c4mSe) that demonstrates potentiated anticancer efficacy and selectivity. Their design specifically incorporated cyclohexyl and styryl moieties to sterically inhibit the approach of their Fe(III) complexes to the oxy-myoglobin heme plane. Importantly, in contrast to the Fe(III) complexes of the clinically trialed thiosemicarbazones Triapine, COTI-2, and DpC, the Fe(III) complexes of PPTP4c4mT and PPTP4c4mSe did not induce detrimental oxy-myoglobin oxidation. Furthermore, PPTP4c4mSe demonstrated more potent antiproliferative activity than the homologous thiosemicarbazone, PPTP4c4mT, with their selectivity being superior or similar, respectively, to the clinically trialed thiosemicarbazone, COTI-2. An advantageous property of the selenosemicarbazone Zn(II) complexes relative to their thiosemicarbazone analogues was their greater transmetalation to Cu(II) complexes in lysosomes. This latter effect probably promoted their antiproliferative activity. Both ligands down-regulated multiple key receptors that display inter-receptor cooperation that leads to aggressive and resistant breast cancer.

More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-a]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication.

The pyrazolo[1,5-a]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against β-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5-a]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor 53. Despite excellent in vitro metabolic stability, rapid decline in plasma concentration of 53 in vivo was observed and may be attributed to lung accumulation, although in vivo pharmacological effect was not observed. Further optimization of this novel chemotype may validate CSNK2 as an antiviral target in vivo.

Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of Chikungunya nsP2 Cysteine Protease with Anti-alphavirus Activity.

Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 (1a) is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad spectrum antiviral activity. Analogs of 1a that varied each of three regions of the molecule were synthesized to establish structure-activity relationships for inhibition of Chikungunya (CHIKV) nsP2 protease and viral replication. The covalent warhead was highly sensitive to modifications of the sulfone or vinyl substituents. However, numerous alterations to the core 5-membered heterocycle and its aryl substituent were well tolerated and several analogs were identified that enhanced CHIKV nsP2 binding. For example, the 4-cyanopyrazole analog 8d exhibited a kinact /Ki ratio >10,000 M-1s-1. 3-Arylisoxazole was identified an isosteric replacement for the 5-membered heterocycle, which circumvented the intramolecular cyclization that complicated the synthesis of pyrazole-based inhibitors like 1a. The accumulated structure-activity data was used to build a ligand-based model of the enzyme active site, which can be used to guide the design of covalent nsP2 protease inhibitors as potential therapeutics against alphaviruses.

Scaffold hopping in the oxadiazole antibiotic structure leads to more active compounds

Isosteric replacement of the oxadiazole ring by amide bond in the structure of new non-β-lactam antibiotics led to compounds with higher activity against Gram-positive pathogens of ESKAPE panel. A series of 17 compounds were synthesized by acylation of 4-(4-fluorophenoxy)aniline with various amino acids. The spirocyclic derivative with 6-methylsulfonyl-2,6-diazaspiro[3.4]octane moiety showed excellent minimum inhibitory concentrations of 0.093–0.75 μg ml−1 against a number of methicillin-resistant Staphylococcus aureus strains.

Design, synthesis and biological evaluation of novel cyclic malonamide derivatives as selective RIPK1 inhibitors

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a key role in cell death and inflammation. RIPK1 is a well-established therapeutic target, due to the presence of a unique kinase-regulating allosteric pocket, which enables selective inhibition. Herein we used GSK2982772 as our starting point in our discovery campaign. Applying isosteric replacement, we successfully identified the malonamide scaffold, instead of the well-established serine template. Further structural optimization led to the design and synthesis of a series of analog inhibitors. The enantiomers of the most promising compound were tested on 97 different kinases. The active enantiomer proved to be kinase selective.

Sulfonamido, amido heterocyclic adducts of tetrazole derivatives as BACE1 inhibitors: in silico exploration.

Alzheimer's disease is a neurodegenerative disorder accounting for 60-80% of dementia cases and is accompanied by a high mortality rate in patients above 70years of age. The formation of senile plaques composed of amyloid-β protein is a hallmark of Alzheimer's disease. Beta-site APP cleaving enzyme 1 (BACE1) is a proteolytic enzyme involved in the degradation of amyloid precursor protein, which further degrades to form toxic amyloid-β fragments. Hence, inhibition of BACE1 was stated to be an effective strategy for Alzheimer's therapeutics. Keeping in mind the structures of different BACE1 inhibitors that had reached the clinical trials, we designed a library of compounds (total 164) based on a substituted 5-amino tetrazole scaffold which was an isosteric replacement of the cyclic amidine moiety, a common component of the BACE1 inhibitors which reached the clinical trials. The scaffold was linked to different structural moieties with the aid of an amide or sulfonamide bond to design some novel molecules. Molecular docking was initially performed and the top 5 molecules were selected based on docking scores and protein-ligand interactions. Furthermore, molecular dynamic simulations were performed for these molecules (3g, 7k, 8n, 9d, 9g) for 100ns and MM-GBSA calculations were performed for each of these complexes. After critical evaluation of the obtained results, three potential molecules (9d, 8n, and 7k) were forwarded for prolonged stability studies by performing molecular dynamic simulations for 250ns and simultaneous MM-GBSA calculations. It was observed that the compounds (9d, 8n, and 7k) were forming good interactions with the amino acid residues of the catalytic site of the enzyme with multiple non-covalent interactions. In MD simulations, the compounds have shown better stability and better binding energy throughout the runtime.

Asymmetric synthesis of sulfoximines, sulfonimidoyl fluorides and sulfonimidamides enabled by an enantiopure bifunctional S(VI) reagent.

An increased interest to expand three-dimensional chemical space for the design of new materials and medicines has created a demand for isosteric replacement groups of commonly used molecular functionality. The structural and chemical properties of chiral S(VI) functional groups provide unique spatial and electronic features compared with their achiral sulfur- and carbon-based counterparts. Manipulation of the S(VI) centre to introduce structural variation with stereochemical control has remained a synthetic challenge. The stability of sulfonimidoyl fluorides and the efficiency of sulfur fluorine exchange chemistry has enabled the development of the enantiopure bifunctional S(VI) transfer reagent t-BuSF to overcome current synthetic limitations. Here, we disclose a reagent platform that serves as a chiral sulfur fluorine exchange template for the rapid asymmetric synthesis of over 70 sulfoximines, sulfonimidoyl fluorides and sulfonimidamides with excellent enantiomeric excess and good overall yields. Furthermore, the practical utility of the bifunctional S(VI) transfer reagent was demonstrated in the syntheses of enantiopure pharmaceutical intermediates and analogues.

Bicyclo[m.n.k]alkane Building Blocks as Promising Benzene and Cycloalkane Isosteres: Multigram Synthesis, Physicochemical and Structural Characterization.

Electrophilic double bond functionalization - intramolecular enolate alkylation sequence was used to obtain a series of bridged and fused bicyclo[m.n.k]alkane derivatives (i. e., bicyclo[4.1.1]octanes, bicyclo[2.2.1]heptanes, bicyclo[3.2.1]octanes, bicyclo[3.1.0]hexanes, and bicyclo[4.2.0]heptanes). The scope and limitations of the method were established, and applicability to the multigram synthesis of target bicyclic compounds was illustrated. Using the developed protocols, over 50 mono- and bifunctional building blocks relevant to medicinal chemistry were prepared. The synthesized compounds are promising isosteres of benzene and cycloalkane rings, which is confirmed by their physicochemical and structural characterization (pKa , LogP, and exit vector parameters (EVP)). "Rules of thumb" for the upcoming isosteric replacement studies were proposed.

Switching the regioselectivity of acid-catalyzed reactions of arylnaphtho[2,1-b]furans via a [1,2]-aryl shift.

The [1,2]-aryl shift reaction was used to synthesize naphtho[2,1-b]furans as promising fluorescent scaffolds for organic electronics. The target compounds are furan analogues of phenanthrene formally accessed by isosteric replacement of the CHCH moiety with an oxygen atom. The straightforward and robust approach involving a [1,2]-aryl shift as a key step provides easy access to a wide range of naphtho[2,1-b]furans with the possibility of late-stage functionalization. Efficient switching of the regioselectivity of acid-catalyzed reactions of arylnaphtho[2,1-b]furans via a [1,2]-aryl shift has been demonstrated. A one-pot protocol involving sequential intramolecular condensation/[1,2]-aryl shift/intermolecular oxidative aromatic coupling to provide access to binaphtho[2,1-b]furan analogues of BINOL was developed. The advantage of these compounds lies in the strong variation in chemical properties and spectral performance depending on the nature and position of the aryl substituent, which facilitates the synthesis of compounds with desired spectral characteristics and opens up prospects for their further use in electronics, biotechnologies and organic synthesis.

Molecular Pharmacology Profiling of Phenylfentanil and Its Analogues to Understand the Putative Involvement of an Adrenergic Mechanism in Fentanyl-Induced Respiratory Depression.

While there are approved therapeutics to treat opioid overdoses, the need for treatments to reverse overdoses due to ultrapotent fentanyls remains unmet. This may be due in part to an adrenergic mechanism of fentanyls in addition to their stereotypical mu-opioid receptor (MOR) effects. Herein, we report our efforts to further understanding of the functions these distinct mechanisms impart. Employing the known MOR neutral antagonist phenylfentanil as a lead, 17 analogues were designed based on the concept of isosteric replacement. To probe mechanisms of action, these analogues were pharmacologically evaluated in vitro and in vivo, while in silico modeling studies were also conducted on phenylfentanil. While it did not indicate MOR involvement in vivo, phenylfentanil yielded respiratory minute volumes similar to those caused by fentanyl. Taken together with molecular modeling studies, these results indicated that respiratory effects of fentanyls may also correlate to inhibition of both α1A- and α1B-adrenergic receptors.

Gem‐Difluoro‐3‐azabicyclo[3.n.1]alkanes and Their Derivatives – Bicyclic Fluorinated Piperidine Isosteres for Drug Discovery

AbstractAn approach to gem‐difluoro‐3‐azabicyclo[3.n.1]alkane‐ derived building blocks through double‐Mannich addition– deoxofluorination sequence is described. The scope of the method was demonstrated for a series of saturated (hetero)cyclic ketones or ketoesters (including five‐ to seven‐membered cycloalkane derivatives and N‐, O‐, S‐containing saturated heterocycles). Further transformations of functional groups produced various bifunctionalized difluorinated building blocks, namely, N‐protected aminoacids, mono‐N‐Boc‐protected diamines, and unprotected aminoalcohols in good to excellent overall yields. For the azabicyclo[3.3.1]alkane series, a potential for isosteric replacements is demonstrated by evaluation of the key physicochemical properties (i. e., pKa(H) and LogP).

Stereocontrolled access to thioisosteres of nucleoside di- and triphosphates.

Nucleoside diphosphates and triphosphates impact nearly every aspect of biochemistry; however, the use of such compounds as tools or medicinal leads for nucleotide-dependent enzymes and receptors is hampered by their rapid in vivo metabolism. Although a successful strategy to address the instability of the monophosphate moiety in oligonucleotide therapeutics has been accomplished by their isosteric replacement with phosphorothioates, no practical methods exist to rapidly and controllably access stereopure di- and triphosphate thioisosteres of both natural and unnatural nucleosides. Here we show how a modular, reagent-based platform can enable the stereocontrolled and scalable synthesis of a library of such molecules. This operationally simple approach provides access to pure stereoisomers of nucleoside α-thiodiphosphates and α-thiotriphosphates, as well as symmetrical or unsymmetrical dinucleoside thiodiphosphates and thiotriphosphates (including RNA cap reagents). We demonstrate that ligand-receptor interactions can be dramatically influenced by P-stereochemistry, showing that such thioisosteric replacements can have profound effects on the potency and stability of lead candidates.

Synthesis and spectroscopic characterization of thioparacetamol: Evidence for solvent-dependent changes in conformational equilibrium

The search for analogs of compounds with proved pharmacological activity frequently starts by obtaining those that result from simple chemical substitutions, have structural and mechanical characteristics suitable for inclusion in a formulation and close similarity with related lead compounds. With this aim, the isosteric replacement of the carbonyl functional group of paracetamol to obtain solid thioparacetamol was achieved through microwave mediated thionation of parent compound in very good yield (85 %). A thorough characterization of the compound prepared was performed by GC/MS spectrometry, FTIR and NMR (1H, 13C, COSY, HSQC and HMBC) spectroscopies and quantum chemical calculations derived from density functional theory. From the experimental and theoretical spectra, it was evidenced that the structural, vibrational and conformational properties of this compound vary whether the sample is solved in a solvent or not. The anti form (anti of the CS and NH bonds) was the preferred conformational isomer in the solid phase, while a conformational equilibrium of anti and syn forms was found for samples solved in different solvents. As polarity of solvents increased, proportion of the anti isomer increased as well.

Silver(I)-Catalyzed Synthesis of Cuneanes from Cubanes and their Investigation as Isosteres.

Bridged or caged polycyclic hydrocarbons have rigid structures that project substituents into precise regions of 3D space, making them attractive as linking groups in materials science and as building blocks for medicinal chemistry. The efficient synthesis of new or underexplored classes of such compounds is, therefore, an important objective. Herein, we describe the silver(I)-catalyzed rearrangement of 1,4-disubstituted cubanes to cuneanes, which are strained hydrocarbons that have not received much attention since they were first described in 1970. The synthesis of 2,6-disubstituted or 1,3-disubstituted cuneanes can be achieved with high regioselectivities, with the regioselectivity being dependent on the electronic character of the cubane substituents. A preliminary assessment of cuneanes as scaffolds for medicinal chemistry suggests cuneanes could serve as isosteric replacements of trans-1,4-disubstituted cyclohexanes and 1,3-disubstituted benzenes. An analogue of the anticancer drug sonidegib was synthesized, in which the 1,2,3-trisubstituted benzene was replaced with a 1,3-disubstituted cuneane.

Design, Synthesis, ADME, and Anticancer Studies of Newer N-Aryl-5-(3,4,5-Trifluorophenyl)-1,3,4-Oxadiazol-2-Amines: An Insight into Experimental and Theoretical Investigations.

In continuance of our investigation into the anticancer activity of oxadiazoles, we report here the preparation of 10 new 1,3,4-oxadiazole analogues using the scaffold hopping technique. We have prepared the oxadiazoles having a common pharmacophoric structure (oxadiazole linked aryl nucleus) as seen in the reported anticancer agents IMC-038525 (tubulin inhibitor), IMC-094332 (tubulin inhibitor), and FATB (isosteric replacement of the S of thiadiazole with the O of oxadiazole). All of the oxadiazole analogues were predicted for their absorption, distribution, metabolism, and excretion (ADME) profiles and toxicity studies. All of the compounds were found to follow Lipinski's rule of 5 with a safe toxicity profile (Class IV compound) against immunotoxicity, mutagenicity, and toxicity. All of the compounds were synthesized and characterized using spectral data, followed by their anticancer activity tested in a single-dose assay at 10 μM as reported by the National Cancer Institute (NCI US) Protocol against nearly 59 cancer cell lines obtained from nine panels, including non-small-cell lung, ovarian, breast, central nervous system (CNS), colon, leukemia, prostate, and cancer melanoma. N-(2,4-Dimethylphenyl)-5-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-amine (6h) displayed significant anticancer activity against SNB-19, OVCAR-8, and NCI-H40 with percent growth inhibitions (PGIs) of 86.61, 85.26, and 75.99 and moderate anticancer activity against HOP-92, SNB-75, ACHN, NCI/ADR-RES, 786-O, A549/ATCC, HCT-116, MDA-MB-231, and SF-295 with PGIs of 67.55, 65.46, 59.09, 59.02, 57.88, 56.88, 56.53, 56.4, and 51.88, respectively. The compound 6h also registered better anticancer activity than Imatinib against CNS, ovarian, renal, breast, prostate, and melanoma cancers with average PGIs of 56.18, 40.41, 36.36, 27.61, 22.61, and 10.33, respectively. Molecular docking against tubulin, one of the appealing cancer targets, demonstrated an efficient binding within the binding site of combretastatin A4. The ligand 6h (docking score = -8.144 kcal/mol) interacted π-cationically with the residue Lys352 (with the oxadiazole ring). Furthermore, molecular dynamic (MD) simulation studies in complex with the tubulin-combretastatin A4 protein and ligand 6h were performed to examine the dynamic stability and conformational behavior.

Identified Isosteric Replacements of Ligands' Glycosyl Domain by Data Mining.

Biologically equivalent replacements of key moieties in molecules rationalize scaffold hopping, patent busting, or R-group enumeration. Yet, this information may depend upon the expert-defined space, and might be subjective and biased toward the chemistries they get used to. Most importantly, these practices are often informatively incomplete since they are often compromised by a try-and-error cycle, and although they depict what kind of substructures are suitable for the replacement occurrence, they fail to explain the driving forces to support such interchanges. The protein data bank (PDB) encodes a receptor-ligand interaction pattern and could be an optional source to mine structural surrogates. However, manual decoding of PDB has become almost impossible and redundant to excavate the bioisosteric know-how. Therefore, a text parsing workflow has been developed to automatically extract the local structural replacement of a specific structure from PDB by finding spatial and steric interaction overlaps between the fragments in endogenous ligands and particular ligand fragments. Taking the glycosyl domain for instance, a total of 49 520 replacements that overlap on nucleotide ribose were identified and categorized based on their SMILE codes. A predominately ring system, such as aliphatic and aromatic rings, was observed; yet, amide and sulfonamide replacements also occur. We believe these findings may enlighten medicinal chemists on the structure design and optimization of ligands using the bioisosteric replacement strategy.

Biological activities of 4H-thiochromen-4-one 1,1-dioxide derivatives against tropical disease parasites: A target-based drug design approach

A promising strategy for developing novel therapies against tropical diseases, including malaria, leishmaniasis, and trypanosomiasis, is to detect biological targets such as trypanothione reductase, a vital parasite enzyme that regulates oxidative stress. This enzyme is highly selective and conserved in the Trypanosotidae family and has an ortholog in the Plasmodium genus. Previous studies have established that an isosteric replacement of naphthoquinone's carbonyl group with a sulfone group leads to compounds with high bioactivity and selectivity (half-maximal inhibitory concentration = 3 μM against intracellular amastigotes of L. panamensis, selectivity index = 153 over monocytes U-937). In this study, we analyzed the reactive oxygen species (ROS) levels of parasites through indirect measurements of the tryparedoxin system after treatment with these isosteric compounds. This strategy proved that a significant increase in the ROS levels and strong mitochondrial perturbation led to the death of parasites due to cell homeostatic imbalance, confirming the compounds' effectiveness in disrupting this important metabolic pathway. To improve understanding of the parasite-molecule interaction, 27 new compounds were synthesized and assessed against parasites of the three principal tropical diseases (malaria, leishmaniasis, and trypanosomiasis), displaying an EC50 below 10 μM and good correlation with in-silico studies, indicating that the 4H-thiochromen-4-one 1,1-dioxide core is a special allosteric modulator. It can interact in the binding pocket through key amino acids like Ser-14, Leu-17, Trp-21, Ser-109, Tyr-110, and Met-113, leading to interhelical disruption.