Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies

Tzara, Ariadni; Xanthopoulos, Dimitrios; Kourounakis, Angeliki P.

doi:10.1002/cmdc.201900682

Cited by 54 publications

(32 citation statements)

References 95 publications

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“…Importance of saturated six-membered nitrogen-containing heterocyclic scaffolds (i. e. mopholine, piperazine, and piperidine, M/P/P) to medicinal chemistry is well-recognized; [430][431][432][433] it is not surprising therefore that many bicyclic mimetics thereof have been designed and validated in drug discovery. In general, this building block category can be only marginally considered as emerging since many of them were introduced long ago.…”

Section: Novel Bicyclic Mimetics Of Morpholine Piperazine Piperidine: Thinking Further In 3dmentioning

confidence: 99%

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

2021

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Current medicinal chemistry relies heavily on the quality of building blocks, i. e. reagents used to introduce chemical diversity into the target molecules. The last decade witnessed an emergence of many novel (or well-overlooked old) chemotypes for drug discovery, which is related to adapting new synthetic methodologies, designing new sp 3 -enriched bioisosteres, paying attention to previously underrated (or even unwanted) structural motifs, or combination thereof. In this review with 532 references, a survey of selected chemotypes that emerged recently in medicinal chemistry is provided, with a focus on the synthesis of the corresponding building blocks. Thus, saturated (hetero)aliphatic boronates, sulfonyl fluorides, sulfinates, non-classical sp 3 -enriched benzene isosteres, bicyclic morpholine/piperidine/piperazine analogs, as well as gemdifluorinated cycloalkanes (as an example of emerging fluorinated motifs) are discussed.

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Section: Novel Bicyclic Mimetics Of Morpholine Piperazine Piperidine: Thinking Further In 3dmentioning

confidence: 99%

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

2021

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“…[9] We selected morpholine as a subunit for our new hybrids since it is a privileged structural component of many bioactive molecules and is used in a variety of drugs, both approved and experimental. [10] Furthermore, in recent reports morpholine derivatives demonstrated very promising anti-SARS-CoV-2 properties. [11] Because of poor solubility of compound 6, we did not consider it for biological investigations.…”

Section: Resultsmentioning

confidence: 99%

Anti‐SARS‐CoV‐2 Inhibitory Profile of New Quinoline Compounds in Cell Culture‐Based Infection Models

Herrmann

Hahn

Wangen

et al. 2021

Chemistry A European J

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The presently ongoing pandemic of human SARS-CoV-2 infections (COVID-19) presents an enormous challenge in surveillance, vaccine and antiviral drug development. Here we report the synthesis of new bioactive quinoline-morpho-line hybrid compounds and their virological evaluation, which proves pronounced cell culture-based inhibitory profile against SARS-CoV-2. Thus, selected quinoline compounds may suggest specific hit-to-lead development.

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“…ERJ2-03 and -04 both have a morpholine moiety and ERJ2-11 a piperazine moiety. As morpholine and piperazine are well-known drug-like features, these moieties are unlikely to cause the reduction in cell viability, suggesting that another part of these compounds exerts the deleterious effect on MCD4 cell viability [ 45 , 46 ]. This is supported by the observation that ERJ2-12, which also has a piperazine fragment, does not affect the viability of MCD4 cells.…”

Section: Resultsmentioning

confidence: 99%

Aurora Kinase A Is Involved in Controlling the Localization of Aquaporin-2 in Renal Principal Cells

Baltzer

Bulatov

Schmied

et al. 2022

IJMS

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The cAMP-dependent aquaporin-2 (AQP2) redistribution from intracellular vesicles into the plasma membrane of renal collecting duct principal cells induces water reabsorption and fine-tunes body water homeostasis. However, the mechanisms controlling the localization of AQP2 are not understood in detail. Using immortalized mouse medullary collecting duct (MCD4) and primary rat inner medullary collecting duct (IMCD) cells as model systems, we here discovered a key regulatory role of Aurora kinase A (AURKA) in the control of AQP2. The AURKA-selective inhibitor Aurora-A inhibitor I and novel derivatives as well as a structurally different inhibitor, Alisertib, prevented the cAMP-induced redistribution of AQP2. Aurora-A inhibitor I led to a depolymerization of actin stress fibers, which serve as tracks for the translocation of AQP2-bearing vesicles to the plasma membrane. The phosphorylation of cofilin-1 (CFL1) inactivates the actin-depolymerizing function of CFL1. Aurora-A inhibitor I decreased the CFL1 phosphorylation, accounting for the removal of the actin stress fibers and the inhibition of the redistribution of AQP2. Surprisingly, Alisertib caused an increase in actin stress fibers and did not affect CFL1 phosphorylation, indicating that AURKA exerts its control over AQP2 through different mechanisms. An involvement of AURKA and CFL1 in the control of the localization of AQP2 was hitherto unknown.

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Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies

Cited by 54 publications

References 95 publications

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

Anti‐SARS‐CoV‐2 Inhibitory Profile of New Quinoline Compounds in Cell Culture‐Based Infection Models

Aurora Kinase A Is Involved in Controlling the Localization of Aquaporin-2 in Renal Principal Cells

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