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The development of novel strained spiro heterocycles (SSHs) as bioisosteres for aromatic or non‐strained aliphatic rings is highly sought after for improving drug design. Their high molecular rigidity and predictable vectorization can enhance drug‐likeness, target selectivity and clinical success. Towards this goal, 1‐oxa‐2,6‐diazaspiro[3.3]heptane (ODASE) is reported as a novel potential SSH‐bioisostere. We demonstrate through theoretical studies the potential of this strained spiro heterocycle to act as a bioisostere for piperazine. We have developed its synthesis from the highly strained azabicyclo[1.1.0]butyl intermediate through a robust and mild flow technology‐assisted two‐step protocol. Its tolerance and stability towards medicinally relevant N‐functionalisation protocols are studied, as well as its mild reduction to the C3‐aminoalkylazetidinol motif found in the anti‐cancer drug cobimetinib. [ABSTRACT FROM AUTHOR]

Considering the broad use of the trifluoromethyl functional group (−CF3) in medicinal chemistry and taking into account the recent concerns on the negative environmental effects of CF3 containing compounds, we are searching for "greener" alternatives. Thus, different chemical groups (i. e. iodide, fluoride, cyclopropyl, isopropyl, cyclobutyl, 3‐oxetyl, 2‐oxetyl, methylsulfide, pentafluorosulfide, methylsulfonyl and sulfonamide) have been considered as potential bioequivalents of −CF3 aiming to use them in compounds with therapeutic interest instead of the polyfluoride functionality. Different structural (molecular surface and volume) and physicochemical (electronic and lipophilic) aspects of the bioequivalent functionalities proposed have been theoretically calculated and compared to those of −CF3. Additionally, the corresponding phenyl derivatives carrying these functionalities have been purchased or prepared and their experimental lipophilicity (i. e. LogP) measured using shake‐flask experiments and UV‐vis spectroscopy. [ABSTRACT FROM AUTHOR]

The sulfinyl group, as one of the bioisosteres of carbonyl groups, attracts considerable attention in the field of synthetic chemistry. In particular, the asymmetric construction of chiral sulfinyl compounds and their derivatives remains in the early stages of development. Sulfinyl compounds mainly include sulfoxides, sulfinate esters and sulfinamides, according to the different functional groups connected to the sulfur atom. This Review summarizes the fascinating recent progress made over the past decade on the asymmetric synthesis of enantiopure sulfinyl derivatives. 1 Introduction 2 Asymmetric Synthesis of Chiral Sulfoxides 3 Asymmetric Synthesis of Chiral Sulfinate Esters 4 Asymmetric Synthesis of Chiral Sulfinamides 5 Conclusion and Outlook [ABSTRACT FROM AUTHOR]

Lipoxins are pro‐resolving mediators that play an important role in the resolution phase of the innate inflammatory response. However, because of their chemical and metabolic instability, the design of more stable synthetic analogues of lipoxin A4 and lipoxin B4 is an ongoing area of study. Herein we report the asymmetric synthesis of an aromatic lipoxin B4 analogue containing a conformationally rigid and potentially more metabolically resistant bicyclo[1.1.1]pentane (BCP) ring incorporated into the upper alkyl chain. This was achieved by the development of a 9‐step chiral‐pool synthesis of a novel BCP‐containing boronic ester coupling partner which could serve as a common precursor to the target analogue as well as other analogues with further modifications to the aromatic core. [ABSTRACT FROM AUTHOR]

This article explores the use of bicyclopentane (BCP) as a bioisostere in medicinal chemistry. BCP can replace phenyl rings or alkynes in molecules, altering their physical properties. The authors focus on the synthesis of BCP-sulfoxides, which can enhance the pharmacological properties of compounds. They present a new method using a BCP-sulfinate precursor that is more convenient and stable. The authors successfully synthesized a previously inaccessible methyl-substituted sulfoxide and suggest the potential for further modifications. [Extracted from the article]

The present work covers novel herbicidal lead structures that contain a 2,3-dihydro[1,3]thiazolo[4,5-b]pyridine scaffold as structural key feature carrying a substituted phenyl side chain. These new compounds show good acyl-ACP thioesterase inhibition in line with strong herbicidal activity against commercially important weeds in broadacre crops, e.g., wheat and corn. The desired substituted 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines were prepared via an optimized BH3-mediated reduction involving tris(pentafluorophenyl)borane as a strong Lewis acid. Remarkably, greenhouse trials showed that some of the target compounds outlined herein display promising control of grass weed species in preemergence application, combined with a dose response window that enables partial selectivity in certain crops.

We have developed a general and practical approach towards 2‐oxabicyclo[2.1.1]hexanes with two and three exit vectors via an iodocyclization reaction. The obtained compounds have been easily converted into the corresponding building blocks for use in medicinal chemistry. 2‐Oxabicyclo[2.1.1]hexanes have been incorporated into the structure of five drugs and three agrochemicals, and validated biologically as bioisosteres of ortho‐ and meta‐benzenes. [ABSTRACT FROM AUTHOR]

The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) and diagnostic properties. The benzoylpiperidine fragment is metabolically stable, and it is also considered a potential bioisostere of the piperazine ring, thus making it a feasible and reliable chemical frame to be exploited in drug design. Herein, we discuss the main therapeutic and diagnostic agents presenting the benzoylpiperidine motif in their structure, covering articles reported in the literature since 2000. A specific section is focused on the synthetic strategies adopted to obtain this versatile chemical portion. [ABSTRACT FROM AUTHOR]

Cholinesterases are important in ensuring hemostasis in our body. Excessive increase in cholinesterase function causes various cholinergic dysfunctions. Alzheimer's is a disease characterized by loss of cholinergic activity, which is especially common in the elderly. One of the cholinesterase inhibitors most commonly used to stop the progression of Alzheimer's disease is donepezil. Due to some side effects of donepezil, the synthesis and design of new analogues that may be alternatives to donepezil are reported in the literature. In this study, molecular docking studies were performed to compare the in silico AChE inhibitory potential of some new structural analogs of donepezil. Molecular docking studies were performed using Autodock4.2 tools. In this study, the hypothesis emerges that especially compound 1 and compound 5 have the potential to inhibit AChE at least as much as donepezil. In silico docking studies showed that donepezil derivatives designed with bioisosteres of the piperidine ring in donepezil have high binding affinity towards acetylcholine esterase. These results need to be confirmed by synthesis of the donepezil analogues designed in the study and in vitro activity measurements. [ABSTRACT FROM AUTHOR]

The spiro[3.3]heptane core, with the non‐coplanar exit vectors, was shown to be a saturated benzene bioisostere. This scaffold was incorporated into the anticancer drug sonidegib (instead of the meta‐benzene), the anticancer drug vorinostat (instead of the phenyl ring), and the anesthetic drug benzocaine (instead of the para‐benzene). The patent‐free saturated analogs obtained showed a high potency in the corresponding biological assays. [ABSTRACT FROM AUTHOR]

Strategies commonly used for the synthesis of functionalised bicyclo[1.1.1]pentanes (BCP) rely on the reaction of [1.1.1]propellane with anionic or radical intermediates. In contrast, electrophilic activation has remained a considerable challenge due to the facile decomposition of BCP cations, which has severely limited the applications of this strategy. Herein, we report the electrophilic activation of [1.1.1]propellane in a halogen bond complex, which enables its reaction with electron-neutral nucleophiles such as anilines and azoles to give nitrogen-substituted BCPs that are prominent motifs in drug discovery. A detailed computational analysis indicates that the key halogen bonding interaction promotes nucleophilic attack without sacrificing cage stabilisation. Overall, our work rehabilitates electrophilic activation of [1.1.1]propellane as a valuable strategy for accessing functionalised BCPs.

Estradiol methyl ether (EDME) has recently been described by us as a very potent and subtype-specific inhibitor of the lysosomal cation channel TRPML1. Following the principle of bioisosteres, we worked out efficient synthetic approaches to ring-A aza-analogs of EDME, namely a methoxypyridine and a methoxypyrimidine analog. Both target compounds were obtained in good overall yields in six and eight steps starting from 19-nortestosterone via the oxidative cleavage of ring A followed over several intermediates and with the use of well-selected protective groups by re-cyclization to provide the desired hetero-analogs. The methoxypyridine analog largely retained its TRPML1-inhibitory activity, whereas the methoxypyrimidine analog significantly lost activity. [ABSTRACT FROM AUTHOR]

The pyridazine ring is endowed with unique physicochemical properties, characterized by weak basicity, a high dipole moment that subtends π-π stacking interactions and robust, dual hydrogen-bonding capacity that can be of importance in drug-target interactions. These properties contribute to unique applications in molecular recognition while the inherent polarity, low cytochrome P450 inhibitory effects and potential to reduce interaction of a molecule with the cardiac hERG potassium channel add additional value in drug discovery and development. The recent approvals of the gonadotropin-releasing hormone receptor antagonist relugolix (24) and the allosteric tyrosine kinase 2 inhibitor deucravacitinib (25) represent the first examples of FDA-approved drugs that incorporate a pyridazine ring. In this review, the properties of the pyridazine ring are summarized in comparison to the other azines and its potential in drug discovery is illustrated through vignettes that explore applications that take advantage of the inherent physicochemical properties as an approach to solving challenges associated with candidate optimization. [ABSTRACT FROM AUTHOR]

The N-acylsulfonamide functional group is a feature of the pharmacophore of several biologically active molecules, including marketed drugs. Although this acidic moiety presents multiple points of attachments that could be exploited to introduce structural diversification, depending on the circumstances, the replacement of the functional group itself with a suitable surrogate, or bioisostere, may be desirable. A number of N-acylsulfonamide bioisosteres have been developed over the years that provide opportunities to modulate both structure and physicochemical properties of this important structural motif. To enable an assessment of the relative impact on physicochemical properties that these replacements may have compared to the N-acylsulfonamide group, we conducted a structure-property relationship study based on matched molecular pairs, in which the N-acylsulfonamide moiety of common template reference structures is replaced with a series of bioisosteres. The data presented, which include an assessment of relative changes in acidity, permeability, lipophilicity and intrinsic solubility, provides a basis for informed decisions when deploying N-acylsulfonamides, or surrogates thereof, in analog design.

The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) and diagnostic properties. The benzoylpiperidine fragment is metabolically stable, and it is also considered a potential bioisostere of the piperazine ring, thus making it a feasible and reliable chemical frame to be exploited in drug design. Herein, we discuss the main therapeutic and diagnostic agents presenting the benzoylpiperidine motif in their structure, covering articles reported in the literature since 2000. A specific section is focused on the synthetic strategies adopted to obtain this versatile chemical portion.

Design, Synthese und Anwendung von Benzolbioisosteren haben in den letzten 20 Jahren viel Aufmerksamkeit erfahren. In jüngster Zeit haben sich Bicyclo[2.1.1]hexane als äußerst attraktive Bioisostere für ortho‐ und meta‐substituierte Benzole erwiesen. In diesem Artikel beschreiben wir eine milde, skalierbare und übergangsmetallfreie Methode zur Herstellung von hochsubstituierten Bicyclo[2.1.1]hexanen über eine Lewis‐Säure‐katalysierte (3+2)‐Cycloaddition von Bicyclo[1.1.0]butanketonen mit disubstituierten Ketenen. Die Reaktion zeigt eine hohe Toleranz gegenüber funktionellen Gruppen, wie die erfolgreiche Herstellung verschiedener 3‐Alkyl‐3‐Aryl‐ sowie 3,3‐Bisalkyl‐Bicyclo[2.1.1]hexan‐2‐onen belegt (26 Beispiele, bis zu 89 % Ausbeute). Die Folgechemie an der exozyklischen Ketonfunktion wird ebenfalls demonstriert. [ABSTRACT FROM AUTHOR]

Pirfenidone, an oral anti‐fibrotic and anti‐inflammatory medication used for the treatment of idiopathic pulmonary fibrosis (IPF), has been proposed to treat post‐COVID pneumonia pulmonary fibrosis (PF). However, pirfenidone displays side effects which include hepatotoxicity and anorexia. Cubane and cyclooctatetraene (COT) derivatives of pirfenidone were prepared as bioisostere/biomotif replacements of the phenyl ring to explore potential changes in activity. The key intermediate, aminocubane, enabled the synthesis of both the cubane and cyclooctatetraene (COT) derived pirfenidone analogues in 6 steps. The COT derivative was observed to display similar activity and cytotoxicity with pirfenidone in an anti‐virus and ACE2 inhibition assay, although limited effect was observed from pirfenidone and the analogues described herein. [ABSTRACT FROM AUTHOR]

Despite 80 years of progress in modern small molecule drug discovery, medicinal chemists still struggle to minimize the number and duration of design cycles required to optimize hit and lead compounds into high-quality chemical probes or safe and efficacious clinical candidates. High-impact design elements are needed to make multiparameter optimization efforts more efficient and effective. The exchange of an aromatic methine group with a nitrogen atom is a minor bioisosteric structure modification that can lead to major improvements in a variety of pharmacological parameters. These improvements can enhance the efficiency of multiparameter optimization efforts and increase the probability of success in small molecule drug discovery. In this review, we will discuss general aspects of this structure modification and then highlight twelve case studies in which this design element played a pivotal role in multiparameter optimization efforts, solving key program issues and leading to key tool compounds, pre-clinical candidates, and clinical candidates. [ABSTRACT FROM AUTHOR]

The heterocyclic tetrazole, a well‐established bioisosteric replacement of carboxylic acid, plays an important role in medicinal chemistry. To deepen the functional understanding of tetrazoles in chemical sciences, it is essential to investigate the noncovalent interactions between the tetrazole ring and aromatic rings. Here, we report synthetic, spectroscopic, structural and quantum chemical analyses on specially designed 2‐arylphenyl‐1H‐tetrazoles to study the underlying noncovalent interactions between the tetrazole ring and the neighboring aromatic ring possessing substituents at para/meta position. pKa values and proton affinities of 2‐arylphenyl‐1H‐tetrazoles correlate well with Hammett sigma values of para‐substituents at the flanking aromatic ring. Molecular orbital and energy decomposition analyses reveal that through‐space NH–π interactions and π–π interactions contribute to the trend of pKa values and proton affinities of 2‐arylphenyl‐1H‐tetrazoles. The electrostatic interaction between tetrazole/tetrazolide interacting with the aromatic rings appears responsible for the observed acidity trends. These results will be helpful for the rational design of tetrazole‐based drugs and materials. [ABSTRACT FROM AUTHOR]

Kappa opioid receptor (KOR) agonists represent promising therapeutics for pain relief due to their analgesic properties along with lower abuse potential than opioids that act at the mu opioid receptor. However, typical KOR agonists produce sedation and dysphoria. Previous studies have shown that G protein signaling-biased KOR agonists may present a means to untangle the desired analgesic properties from undesired side effects. In this paper, we report a new series of G protein signaling-biased KOR agonists entailing –S– → –CH 2 – replacement in a previously reported KOR agonist, triazole 1.1. With an optimized carbon linker in hand, further development of the scaffold was undertaken to investigate the appendages of the triazole core. The structure–activity relationship study of this series is described, including several analogues that display enhanced potency while maintaining G protein-signaling bias compared to triazole 1.1. [Display omitted] • The kappa opioid receptor (KOR) is a target for the treatment of pain and itch. • Most KOR agonists cause dysphoria, a problematic side effect. • Biased KOR agonist selective for G-protein activation reduce dysphoria. • We report carbon-substituted triazoles as biased KOR agonists and examine their SAR. • A binding mode of this class to the KOR is proposed. [ABSTRACT FROM AUTHOR]

Impaired expression of GABA transporters (GATs) is closely related to the pathogenesis of among others Parkinson's disease and epilepsy. As such, lipophilic nipecotic acid analogs have been extensively studied as GAT1-addressing drugs and radioligands but suffer from limited brain uptake due to the zwitterionic properties of the nipecotic acid moiety. Bioisosteric replacement of the carboxylic acid group is a promising strategy to improve the brain uptake, though it requires knowledge on the binding of these isosteres to GAT1. To screen nipecotic acid isosteres for their affinity to GAT1 in a time- and cost-effective manner, this research aims to develop a molecular imprinted polymer (MIP) that mimics the natural binding site of GAT1 and can act as an alternative screening tool to the current radiometric and mass spectrometry cellular-based assays. To this end, a nipecotic acid MIP was created using the electropolymerization of ortho -phenylenediamine (oPD) by cyclic voltammetry (CV). The optimization of the generated receptor layer was achieved by varying the scan rate (50–250 mV/s) and number of CV cycles (5–12), yielding an optimized MIP with an average imprinting factor of 2.6, a linear range of 1–1000 n m , and a theoretical LOD of 0.05 n m , as analyzed by electrical impedance spectroscopy (EIS). Selectivity studies facilitated the investigation of major binding interactions between the MIP and the substrate, building an experimental model that compares characteristics of various analogs. Results from this model indicate that the substrate carboxylic acid group plays a more important role in binding than an amine group, after comparing the binding of cyclohexanecarboxylic acid (average IF of 1.7) and piperidine (average IF of 0.46). The research culminates in a discussion regarding the feasibility of the in vitro model, comparing the synthetic system against the biological performance of GAT1. Thus, evaluating if it is possible to generate a synthetic GAT1 mimic, and if so, provide directions for follow-up research. A nipecotic acid molecular imprinted polymer (MIP) was developed with a view to generating an artificial GAT1 mimic to allow in vitro screening of nipecotic acid bioisosteres. After selection, well-binding isosteres might be used to develop more viable GAT1-addressing drugs and radioligands. [Display omitted] • GAT1 mimic can allow time- and cost-effective screening of nipecotic acid isosteres. • A nipecotic acid molecular imprinted polymer was developed as artificial GAT1 mimic. • The developed synthetic system is compared against biological performance of GAT1. [ABSTRACT FROM AUTHOR]

Estradiol methyl ether (EDME) has recently been described by us as a very potent and subtype-specific inhibitor of the lysosomal cation channel TRPML1. Following the principle of bioisosteres, we worked out efficient synthetic approaches to ring-A aza-analogs of EDME, namely a methoxypyridine and a methoxypyrimidine analog. Both target compounds were obtained in good overall yields in six and eight steps starting from 19-nortestosterone via the oxidative cleavage of ring A followed over several intermediates and with the use of well-selected protective groups by re-cyclization to provide the desired hetero-analogs. The methoxypyridine analog largely retained its TRPML1-inhibitory activity, whereas the methoxypyrimidine analog significantly lost activity.

Considering the broad use of the trifluoromethyl functional group (-CF 3 ) in medicinal chemistry and taking into account the recent concerns on the negative environmental effects of CF 3 containing compounds, we are searching for "greener" alternatives. Thus, different chemical groups (i. e. iodide, fluoride, cyclopropyl, isopropyl, cyclobutyl, 3-oxetyl, 2-oxetyl, methylsulfide, pentafluorosulfide, methylsulfonyl and sulfonamide) have been considered as potential bioequivalents of -CF 3 aiming to use them in compounds with therapeutic interest instead of the polyfluoride functionality. Different structural (molecular surface and volume) and physicochemical (electronic and lipophilic) aspects of the bioequivalent functionalities proposed have been theoretically calculated and compared to those of -CF 3 . Additionally, the corresponding phenyl derivatives carrying these functionalities have been purchased or prepared and their experimental lipophilicity (i. e. LogP) measured using shake-flask experiments and UV-vis spectroscopy., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

In the present study, a series of novel Trp-Pro-Val containing peptides were prepared via solid-phase synthesis, and their structures were cyclized by a disulfide bridge, or modified by adding heterocycles of pyrazine, pyroglutamic acid, and 1,3,4-oxadiazoles to their N-terminus. These peptides were designed to antagonize gonadotropin-releasing hormone (GnRH)-receptor. Based on the detailed in vitro studies, incorporation of disulfide bond (peptide 1), the addition of pyroglutamate at the N-terminus (peptide 2), the addition of pyrazine at the N-terminus (peptide 3), and incorporation of GFRW to the N-terminus (peptide 5) were beneficial for inhibition of proliferation and induction of apoptosis in GnRH receptor-bearing cells including Hela and MCF-7 cell lines, whereas ineffective on Hep-G2 liver cancer and SW-48 colorectal adenocarcinoma cell lines devoiding of GnRH receptor. These results imply that the synthesized peptides 1, 2, 3, and 5 are GnRH antagonists and selective for GnRH receptors on the surface of tumor cells. [ABSTRACT FROM AUTHOR]

Macrocyclization presents a valuable strategy for enhancing the pharmacokinetic and pharmacodynamic profiles of short bioactive peptides. The exploration of various macrocyclic characteristics, such as crosslinking tethers, ring size, and orientation, is generally conducted during the early stages of development. Herein, starting from a potent and selective C-X-C chemokine receptor 4 (CXCR4) cyclic heptapeptide antagonist mimicking the N-terminal region of CXCL12, we demonstrated that the disulfide bridge could be successfully replaced with a side-chain to side-chain lactam bond, which is commonly not enlisted among the conventional disulfide mimetics. An extensive investigation was carried out to explore the chemical space of the resulting peptides, including macrocyclization width, stereochemical configuration, and lactam orientation, all of which were correlated with biochemical activity. We identified a novel heptapeptide that fully replicates the pharmacological profile of the parent peptide on CXCR4, including its potency, selectivity, and antagonistic activity, while demonstrating enhanced stability in a reductive environment. At this stage, computational studies were instructed to shed light on how the lactam cyclization features influenced the overall structure of 21 and, in turn, its ability to interact with the receptor. We envisage that these findings can give new momentum to the use of lactam cyclization as a disulfide bond mimetic and contribute to the enhancement of the repertoire for peptide-based drug development, thereby paving the way for novel avenues in therapeutic innovation. [Display omitted] • A novel CXCR4 antagonist was developed by substituting a disulfide bond with side-chain to side-chain macrolactamization. • The new peptide exhibited low-nanomolar affinity and high selectivity for CXCR4 over the related receptor CXCR7. • The new peptide showed enhanced stability in a reductive environment compared to the parent disulfide-bridged peptide. • Molecular docking studies revealed how the orientation of the lactam bridge affects the activity of the developed peptide. [ABSTRACT FROM AUTHOR]

A structure-based drug design approach was focused on incorporating phenyl ring heterocyclic bioisosteres into coumarin derivative 1 , previously reported as potent dual AChE-MAO B inhibitor, with the aim of improving drug-like features. Structure-activity relationships highlighted that bioisosteric rings were tolerated by h MAO B enzymatic cleft more than h AChE. Interestingly, linker homologation at the basic nitrogen enabled selectivity to switch from h AChE to h BChE. In the present work, we identified thiophene-based isosteres 7 and 15 as dual AChE-MAO B (IC 50 = 261 and 15 nM, respectively) and BChE-MAO B (IC 50 = 375 and 20 nM, respectively) inhibitors, respectively. Both 7 and 15 were moderately water-soluble and membrane-permeant agents by passive diffusion (PAMPA-HDM). Moreover, they were able to counteract oxidative damage induced by both H 2 O 2 and 6-OHDA in SH-SY5Y cells and predicted to penetrate into CNS in a cell-based model mimicking blood-brain barrier. Molecular dynamics (MD) simulations shed light on key differences in AChE and BChE recognition processes promoted by the basic chain homologation from 7 to 15. [Display omitted] • Structure-based design of MTDLs was guided by phenyl ring bioisosteric mimicry. • 7 was the most potent hAChE-hMAO B inhibitor (IC 50 = 261 and 15 nM, respectively). • Linker homologation promoted ChEs selectivity switch, improving hBChE inhibition. • 15 was the most potent hBChE-hMAO B inhibitor (IC 50 = 375 and 20 nM, respectively). • Compounds 7 and 15 were drug-like cytoprotective agents against oxidative insults. [ABSTRACT FROM AUTHOR]

Cyclometallated iridium‐PhanePhos complexes generated in situ from [Ir(cod)Cl]2 and (R)‐PhanePhos catalyze 2‐propanol‐mediated reductive couplings of 2‐substituted dienes with oxetanone and N‐acyl‐azetidinones to form branched homoallylic oxetanols and azetidinols with excellent control of regio‐ and enantioselectivity without C−C cleavage of the strained ring via enantiotopic π‐facial selection of transient allyliridium nucleophiles. This work represents the first systematic study of enantioselective additions to symmetric ketones. [ABSTRACT FROM AUTHOR]

Under superacid conditions, aromatic amines are directly and regioselectively 1,1‐difluoroethylated. Low temperature in situ NMR studies confirmed the presence of benzylic α‐fluoronium and α‐chloronium ions as key intermediates in the reaction. This method has a wide substrate scope and can be applied to the late‐stage functionalization of natural alkaloids and active pharmaceutical ingredients. [ABSTRACT FROM AUTHOR]

The aim of the present study was to determine the effective dose of fosfatriclaben through a field study in sheep naturally infected with F. hepatica. Thirty crossbred sheep positive for fluke eggs were selected for inclusion in the trial. On day 0, 5 groups of 6 animals each were formed for treatments: group 1 (G1), G2, and G3 received fosfatriclaben at 4, 6, and 8 mg/kg/IM, respectively. G4 received triclabendazole at 10 mg/kg/PO, and G5 was the untreated control group. Fecal samples of the sheep were analyzed to count the number of fluke eggs to evaluate the percentage of egg reduction. Twenty-one days after treatment, all sheep were humanely euthanized to extract the flukes from the bile ducts. They were counted to assess the percentage of fluke reduction. Fosfatriclaben reduced fluke eggs by 99.6, 99.6, and 100% and flukes by 94.3, 100, and 100%, respectively. Triclabendazole reduced fluke eggs by 95.2% and flukes by 100%. The fosfatriclaben injectable prodrug showed a high fasciolicidal efficacy similar to triclabendazole, with advantages over its predecessor, since only half the dose as compared to triclabendazole was required to remove eggs and flukes in the sheep that were studied. [ABSTRACT FROM AUTHOR]

Piperine, a natural product derived from peppercorns, has a variety of biological activities that make it an attractive lead compound for medicinal chemistry. However, piperine has some problematic physicochemical properties including poor aqueous solubility and a susceptibility to UV-induced degradation. In this work, we designed an analog of piperine in which the central conjugated hydrocarbon chain is replaced with a vicinal difluoroalkane moiety. We show that this fluorinated analog of piperine has superior physicochemical properties, and it also has higher potency and selectivity towards one particular drug target, acetylcholinesterase. This work highlights the potential usefulness of the threo-difluoroalkane motif as a surrogate for E-alkenes in medicinal chemistry.

Toward human immunodeficiency virus type-1 (HIV-1) cure, cells latently infected with HIV-1 must be eliminated from people living with HIV-1. We previously developed a protein kinase C (PKC) activator, diacylglycerol (DAG)-lactone derivative 3 , with high HIV-1 latency-reversing activity, based on YSE028 ( 2 ) as a lead compound and found that the activity was correlated with binding affinity for PKC and stability against esterase-mediated hydrolysis. Here, we synthesized new DAG-lactone derivatives not only containing a tertiary ester group or an isoxazole surrogate but also several symmetric alkylidene moieties to improve HIV-1 latency reversing activity. Compound 9a , with a dimethyl group at the α-position of the ester group, exerted twice higher HIV-1 latency reversing activity than compound 3 , and compound 26 , with the isoxazole moiety, was significantly active. In addition, DAG-lactone derivatives with moderate hydrophobicity and potent biostability showed high biological activity.

Pyridachlometyl is a novel tubulin dynamics modulator fungicide developed by Sumitomo as a new agent designed to tackle fungicide resistance. Pyridachlometyl is being developed as a first-in-class molecule with an anti-tubulin mode of action, the chemical structure of which is characterized by a unique tetrasubstituted pyridazine ring. The first commercial product 'Fuseki flowable' received initial registration in 2023 in Japan. The concepts of the discovery project, optimization of chemical structures, and biological profiles are reviewed herein. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

The present minireview concerns the application of cyclic isothiourea moiety (with endocyclic sulfur atom) in drug design and includes the examples of bioisosteric replacement, conformational restriction, etc. The synthetic procedures leading to the target structures of cyclic isothioureas and their bicyclic derivatives are also discussed. The review gives multiple useful examples for the chemists searching novel heterocyclic compounds with neuroprotective, antihypotensive, antiproliferative, antiobestic, and analgetic properties. [ABSTRACT FROM AUTHOR]

Efflux pumps are one of the predominant microbial resistant mechanisms leading to the development of multidrug resistance. In Staphylococcus aureus, overexpression of NorA protein enables the efflux of antibiotics belonging to the class of fluoroquinolones and, thus, makes S. aureus resistant. Hence, NorA efflux pumps are being extensively exploited as the potential drug target to evade bacterial resistance and resensitize bacteria to the existing antibiotics. Although several molecules are reported to inhibit NorA efflux pump effectively, boronic acid derivatives were shown to have promising NorA efflux pump inhibition. In this regard, the current study exploits 6-(3-phenylpropoxy)pyridine-3-boronic acid to further improve the activity and reduce cytotoxicity using the bioisostere approach, a classical medicinal chemistry concept. Using the SWISS-Bioisostere online tool, from the parent compound, 42 compounds were obtained upon the replacement of the boronic acid. The 42 compounds were docked with modeled NorA protein, and key molecular interactions of the prominent compounds were assessed. The top hit compounds were further analyzed for their drug-like properties using ADMET studies. The identified potent lead, 5-nitro-2-(3-phenylpropoxy)pyridine (5-NPPP), was synthesized, and in vitro efficacy studies have been proven to show enhanced efflux inhibition, thus acting as a potent antibiotic breaker to resensitize S. aureus without elucidating any cytotoxic effect to the host Hep-G2 cell lines.

Efflux pumps are one of the predominant microbial resistant mechanisms leading to the development of multidrug resistance. In Staphylococcus aureus , overexpression of NorA protein enables the efflux of antibiotics belonging to the class of fluoroquinolones and, thus, makes S. aureus resistant. Hence, NorA efflux pumps are being extensively exploited as the potential drug target to evade bacterial resistance and resensitize bacteria to the existing antibiotics. Although several molecules are reported to inhibit NorA efflux pump effectively, boronic acid derivatives were shown to have promising NorA efflux pump inhibition. In this regard, the current study exploits 6-(3-phenylpropoxy)pyridine-3-boronic acid to further improve the activity and reduce cytotoxicity using the bioisostere approach, a classical medicinal chemistry concept. Using the SWISS-Bioisostere online tool, from the parent compound, 42 compounds were obtained upon the replacement of the boronic acid. The 42 compounds were docked with modeled NorA protein, and key molecular interactions of the prominent compounds were assessed. The top hit compounds were further analyzed for their drug-like properties using ADMET studies. The identified potent lead, 5-nitro-2-(3-phenylpropoxy)pyridine (5-NPPP), was synthesized, and in vitro efficacy studies have been proven to show enhanced efflux inhibition, thus acting as a potent antibiotic breaker to resensitize S. aureus without elucidating any cytotoxic effect to the host Hep-G2 cell lines. [ABSTRACT FROM AUTHOR]

[Display omitted] Carboxylic acids are key pharmacophoric elements in many molecules. They can be seen as a problem by some, due to perceived permeability challenges, potential for high plasma protein binding and the risk of forming reactive metabolites due to acyl-glucuronidation. By others they are viewed more favorably as they can decrease lipophilicity by adding an ionizable center which can be beneficial for solubility, and can add enthalpic interactions with the target protein. However, there are many instances where the replacement of a carboxylic acid with a bioisosteric group is required. This has led to the development of a number of ionizable groups which sufficiently mimic the carboxylic acid functionality whilst improving, for example, the metabolic profile of the molecule in question. An alternative strategy involves replacement of the carboxylate by neutral functional groups. This review initially details carefully selected examples whereby tetrazoles, acyl sulfonamides or isoxazolols have been beneficially utilized as carboxylic acid bioisosteres altering physicohemical properties, interactions with the target and metabolism and/or pharmacokinetics, before delving further into the binding mode of carboxylic acid derivatives with their target proteins. This analysis highlights new ways to consider the replacement of carboxylic acids by neutral bioisosteric groups which either rely on hydrogen bonds or cation-π interactions. It should serve as a useful guide for scientists working in drug discovery. [ABSTRACT FROM AUTHOR]

To investigate the effects of bioisosteric replacement of the phenyl group with the thienyl group, N-phenylcarboxamide and three regioisomers of N-(substituted-thienyl)carboxamide were synthesized. The inhibitory activity on the succinate dehydrogenase prepared from the gray mold Botrytis cinerea as well as the fungicidal activity against B. cinerea were evaluated. Two isomers, N-(2-substituted-3-thienyl)carboxamide and N-(4-substituted-3-thienyl) carboxamide exhibited the same level of activity as the phenyl derivative, whereas N-(3-substituted-2-thienyl)carboxamide exhibited lower activity than the phenyl derivative, suggesting that the 2-substituted-3-thienyl and 4-substituted-3-thienyl groups functioned as bioisosteres of the phenyl group in N-phenylcarboxamide, but the other did not. [ABSTRACT FROM AUTHOR]

An I(I)/(III) catalysis strategy to construct an enantioenriched fluorinated isostere of the iPr group is reported. The difluorination of readily accessible α‐CF3‐styrenes is enabled by the in situ generation of a chiral ArIF2 species to forge a stereocentre with the substituents F, CH2F and CF3 (up to 95 %, >20:1 vicinal:geminal difluorination). The replacement of the metabolically labile benzylic proton results in a highly preorganised scaffold as was determined by X‐ray crystallography (π→σ* and stereoelectronic gauche σ→σ* interactions). A process of catalyst editing is disclosed in which preliminary validation of enantioselectivity is placed on a structural foundation. [ABSTRACT FROM AUTHOR]

Glycans are well established to play important roles at various stages of infection and disease, and ways to modulate these interactions have been sought as novel therapies. The use of native glycan structures has met with limited success, which can be attributed to their characteristic high polarity (e.g. low binding affinities) and inherently poor pharmacokinetic properties (e.g. short drug–target residence times, rapid renal excretion), leading to the development of ′glycomimetics′. Fluorinated drugs have become increasingly common over recent decades, with fluorinated glycomimetics offering some unique advantages. Deoxyfluorination maintains certain electrostatic interactions, while concomitantly reducing net polarity through ′polar hydrophobicity′, improving residence times and binding affinities. Fluorination destabilizes the oxocarbenium transition state associated with metabolic degradation, and can restore exo‐ and endo‐anomeric effects in C‐glycosides and carbasugars. Lastly, it has shown great utility in radiotracer development and enhancement of antigenicity in glycan‐based vaccines. Owing to synthetic challenges, fluorinated glycomimetics have been somewhat underutilized to date, but methodological improvements will advance their use in glycomimetic drugs. [ABSTRACT FROM AUTHOR]

1,2,3-triazole is an important building block in organic chemistry. It is now well known as a bioisostere for various functions, such as the amide or the ester bond, positioning it as a key pharmacophore in medicinal chemistry and it has found applications in various fields including life sciences. Attention was first focused on the synthesis of 1,4-disubstituted 1,2,3-triazole molecules however 1,4,5-trisubstituted 1,2,3-triazoles have now emerged as valuable molecules due to the possibility to expand the structural modularity. In the last decade, methods mainly derived from the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction have been developed to access halo-triazole compounds and have been applied to nucleosides, carbohydrates, peptides and proteins. In addition, late-stage modification of halo-triazole derivatives by metal-mediated cross-coupling or halo-exchange reactions offer the possibility to access highly functionalized molecules that can be used as tools for chemical biology. This review summarizes the synthesis, the functionalization, and the applications of 1,4,5-trisubstituted halo-1,2,3-triazoles in biologically relevant molecules., (© 2024 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

The present work covers novel herbicidal lead structures that contain a 2,3-dihydro[1,3]thiazolo[4,5- b ]pyridine scaffold as structural key feature carrying a substituted phenyl side chain. These new compounds show good acyl-ACP thioesterase inhibition in line with strong herbicidal activity against commercially important weeds in broadacre crops, e.g., wheat and corn. The desired substituted 2,3-dihydro[1,3]thiazolo[4,5- b ]pyridines were prepared via an optimized BH 3 -mediated reduction involving tris(pentafluorophenyl)borane as a strong Lewis acid. Remarkably, greenhouse trials showed that some of the target compounds outlined herein display promising control of grass weed species in preemergence application, combined with a dose response window that enables partial selectivity in certain crops., (Copyright © 2024, Frackenpohl et al.)

Abstract Difluoromethylation of the C9-H site of the fluorene ring using lithium base and fluoroform (CF3H), which is one of the most cost-effective difluoromethylating reagents, is attained to give difluoromethylated fluorenes with an all-carbon quaternary center. The Ruppert–Prakash reagent (CF3TMS) can also be applied to the present reaction system, providing siladifluoromethylated fluorenes that can be utilized for sequential carbon–carbon bond-forming reactions through activation of the silyl group.

Bicyclo[1.1.1]pentanes (BCP's) have been applied in medicinal chemistry as bioisosteres for phenyl groups. In pursuit of novel BCP analogs, we reported the first synthesis of 2,2‐difluorobicyclo[1.1.1]pentanes (BCP–F2) in 2019. Herein, we detail the extension of our effort in the synthesis of BCP‐F2 analogs. [ABSTRACT FROM AUTHOR]

Rational design of new bioisosteres through introduction of high-value functional groups to bicyclo[1.1.1]pentane (BCP) is of particular use for drug discovery. Disclosed herein is the first access to valuable fluoroalkylthio(seleno)-functionalized BCPs. A range of SCF3, SCF2H, SCFH2, SeCF3, SeC4F9, and SeC8F17 groups are readily incorporated to BCPs under mild conditions. Concomitant installation of a sulfone provides a platform for incorporation of the BCP motif to bioactive molecules. This practical protocol features novel BCP scaffolds, broad substrate scope, excellent atom-economy, simple operation, and gram-scale preparation. [ABSTRACT FROM AUTHOR]

Herein we report the development of a photocatalytic strategy for the divergent preparation of functionalized bicyclo[1.1.1]pentylamines. This approach exploits, for the first time, the ability of nitrogen‐radicals to undergo strain‐release reaction with [1.1.1]propellane. This reactivity is facilitated by the electrophilic nature of these open‐shell intermediates and the presence of strong polar effects in the transition‐state for C−N bond formation/ring‐opening. With the aid of a simple reductive quenching photoredox cycle, we have successfully harnessed this novel radical strain‐release amination as part of a multicomponent cascade compatible with several external trapping agents. Overall, this radical strategy enables the rapid construction of novel amino‐functionalized building blocks with potential application in medicinal chemistry programs as p‐substituted aniline bioisosteres. [ABSTRACT FROM AUTHOR]

A new generation of saturated benzene mimetics, 2‐oxabicyclo[2.1.1]hexanes, was developed. These compounds were designed as analogues of bicyclo[1.1.1]pentane with an improved water solubility. Crystallographic analysis of 2‐oxabicyclo[2.1.1]hexanes revealed that they occupy a novel chemical space, but, at the same time, resemble the motif of meta‐disubstituted benzenes. [ABSTRACT FROM AUTHOR]

Herein we present the first synthesis of bicyclo[1.1.1]pentyl (BCP) sulfoximines from the corresponding sulfides. Both BCPs and sulfoximines are bioisosteres used in medicinal chemistry and therefore desirable motifs. The access to BCP sulfides was enabled by the thiol addition to [1.1.1]propellane as published before. A broad scope with specific limitations was discovered for the sulfoximination. To diversify the sulfoximines, N‐acylations and N‐arylations were performed. As the N‐arylation was low yielding we optimized the copper(I) catalyzed reaction. A wide range of aryl iodides could be deployed and competitive reactions showed that aryl bromides react equally fast. In a scale‐up we prepared a suitable precursor for a BCP drug analogue. In this work several molecular structures could be determined by single‐crystal X‐ray diffraction. [ABSTRACT FROM AUTHOR]