Recent Advances and Outlook for the Isosteric Replacement of Anilines

Sodano, Taylor; Combee, Logan A.; Stephenson, Corey R. J.

doi:10.1021/acsmedchemlett.9b00687

Cited by 52 publications

(43 citation statements)

References 18 publications

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“…[3] Accordingly,b icyclo[1.1.1]pentylamine (BCPA) has been extensively targeted as ap rominent aniline bioisostere by creating unexplored druglike chemical space with varying levels of synthetic utility (Scheme 1A). [4] From as ynthetic point of view,propellane can be efficiently aminated by ringopening functionalization at the BCP bridgehead positions, where the internal central C À Cb ond of [1.1.1]propellane [5] can be readily cleaved under an anionic strain-release approach [6] and, more recently,aradical pathway affording the requisite substituted BCPAc ompounds (Scheme 1B). [7] Baran et al disclosed the strain-release amination of propellane by employing deprotonated dialkyl amines to access monosubstituted BCPAs.…”

Section: Introductionmentioning

confidence: 99%

Visible‐Light‐Induced 1,3‐Aminopyridylation of [1.1.1]Propellane with N‐Aminopyridinium Salts

et al. 2021

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Through the formation of an electron donor–acceptor (EDA) complex, strain‐release aminopyridylation of [1.1.1]propellane with N‐aminopyridinium salts as bifunctional reagents enabled the direct installation of amino and pyridyl groups onto bicyclo[1.1.1]pentane (BCP) frameworks in the absence of an external photocatalyst. The robustness of this method to synthesize 1,3‐aminopyridylated BCPs under mild and metal‐free conditions is highlighted by the late‐stage modification of structurally complex biorelevant molecules. Moreover, the strategy was extended to P‐centered and CF3 radicals for the unprecedented incorporation of such functional groups with pyridine across the BCP core in a three‐component coupling. This practical method lays the foundation for the straightforward construction of new valuable C4‐pyridine‐functionalized BCP chemical entities, thus significantly expanding the range of accessibility of BCP‐type bioisosteres for applications in drug discovery.

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Section: Introductionmentioning

confidence: 99%

Visible‐Light‐Induced 1,3‐Aminopyridylation of [1.1.1]Propellane with N‐Aminopyridinium Salts

et al. 2021

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“…Already recognised by Eaton in the 1990s as a potential '3D phenyl bioisostere', 3 it is through the later proposed concept 'Escape from Flatland', 9 that pharmaceutical research focused on the replacement of benzene rings with 3D saturated isosteres to modulate pharmacokinetics properties (ADME), 10,11 resulting in an increasing demand for access to cubane building blocks. [12][13][14] The isosteric relationship is based on the cubane diagonal (2.72 Å) being close to that of benzene (2.79 Å) ( Figure 1c). Key examples of the study of cubane analogues of drug and agrochemical molecules include diflucuburon, the cubane analogue of diflubenzuron used as insecticidal ( Figure 1c) by Tsanaktsidis, Savage, Williams et al, and imatinib, by Nicolaou, Vourloumis, Stepan et al, which showed the highest inhibitory activity against the desired target and the greatest cytotoxicity values against cancer cell lines, compared to other saturated cycloalkyl derivatives (Figure 1c).…”

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confidence: 99%

Decagram Synthesis of Dimethyl 1,4-Cubanedicarboxylate Using Continuous-Flow Photochemistry

Collin

Jackman²,

Jouandon³

et al. 2020

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The highly strained cubane system is of great interest as a scaffold and rigid linker in both pharmaceutical and materials chemistry. A straightforward approach is reported for the scale-up of a [2+2] photocycloaddition step using convenient home-made flow photoreactors to access dimethyl 1,4-cubanedicarboxylate on decagram-scale in 33–40% yield over 8 steps. The process is demonstrated on 3.4 g·h–1 input with 30 minutes residence time, enabling to reduce the process time and to avoid the use of batch photoreactors. Completion of the characterisation of the photocycloadduct and its hydrates is reported.

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“…Furthermore, GRL-0617 contains a toxic chemical moiety, an aniline group. Nearly one-third of drugs that have been withdrawn from the market, or that have black-box warnings associated with idiosyncratic adverse drug reactions (IADRs), contain an aniline group [ 44 , 45 , 46 , 47 ]. GRL-0617 has not yet been tested in clinical trials, or in animal studies, to establish safety or side-effects.…”

Section: Introductionmentioning

confidence: 99%

Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease

2021

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The ongoing coronavirus pandemic has been a burden on the worldwide population, with mass fatalities and devastating socioeconomic consequences. It has particularly drawn attention to the lack of approved small-molecule drugs to inhibit SARS coronaviruses. Importantly, lessons learned from the SARS outbreak of 2002-2004, caused by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), can be applied to current drug discovery ventures. SARS-CoV-1 and SARS-CoV-2 both possess two cysteine proteases, the main protease (Mpro) and the papain-like protease (PLpro), which play a significant role in facilitating viral replication, and are important drug targets. The non-covalent inhibitor, GRL-0617, which was found to inhibit replication of SARS-CoV-1, and more recently SARS-CoV-2, is the only PLpro inhibitor co-crystallised with the recently solved SARS-CoV-2 PLpro crystal structure. Therefore, the GRL-0617 structural template and pharmacophore features are instrumental in the design and development of more potent PLpro inhibitors. In this work, we conducted scaffold hopping using GRL-0617 as a reference to screen over 339,000 ligands in the chemical space using the ChemDiv, MayBridge, and Enamine screening libraries. Twenty-four distinct scaffolds with structural and electrostatic similarity to GRL-0617 were obtained. These proceeded to molecular docking against PLpro using the AutoDock tools. Of two compounds that showed the most favourable predicted binding affinities to the target site, as well as comparable protein-ligand interactions to GRL-0617, one was chosen for further analogue-based work. Twenty-seven analogues of this compound were further docked against the PLpro, which resulted in two additional hits with promising docking profiles. Our in silico pipeline consisted of an integrative four-step approach: (1) ligand-based virtual screening (scaffold-hopping), (2) molecular docking, (3) an analogue search, and, (4) evaluation of scaffold drug-likeness, to identify promising scaffolds and eliminate those with undesirable properties. Overall, we present four novel, and lipophilic, scaffolds obtained from an exhaustive search of diverse and uncharted regions of chemical space, which may be further explored in vitro through structure-activity relationship (SAR) studies in the search for more potent inhibitors. Furthermore, these scaffolds were predicted to have fewer off-target interactions than GRL-0617. Lastly, to our knowledge, this work contains the largest ligand-based virtual screen performed against GRL-0617.

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Recent Advances and Outlook for the Isosteric Replacement of Anilines

Cited by 52 publications

References 18 publications

Visible‐Light‐Induced 1,3‐Aminopyridylation of [1.1.1]Propellane with N‐Aminopyridinium Salts

Visible‐Light‐Induced 1,3‐Aminopyridylation of [1.1.1]Propellane with N‐Aminopyridinium Salts

Decagram Synthesis of Dimethyl 1,4-Cubanedicarboxylate Using Continuous-Flow Photochemistry

Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease

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