The pyridazine heterocycle in molecular recognition and drug discovery

Meanwell, Nicholas A.

doi:10.1007/s00044-023-03035-9

Cited by 19 publications

(15 citation statements)

References 296 publications

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“…Chiral sulfinamide ( 32 ), an intermediate in the synthesis of a partial allosteric modulator of the α-7 nicotinic acetylcholine receptor, bears a 2-aminopyridine motif and a pyrazine. Popular pyrimidines ( 33 ) and pyridazines ( 34 ) are also tolerated under the standard reaction conditions. , We next turned our attention toward common azoles. Pyrazole ( 35 ) and isothiazole ( 36 ) were tolerated under the reaction conditions.…”

Section: Resultsmentioning

confidence: 99%

Stereoselective Amine Synthesis Mediated by a Zirconocene Hydride to Accelerate a Drug Discovery Program

Aloiau,

Bobek,

Caddell Haatveit

et al. 2024

J. Org. Chem.

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Chiral amine synthesis remains a significant challenge in accelerating the design cycle of drug discovery programs. A zirconium hydride, due to its high oxophilicity and lower reactivity, gave highly chemo-and stereoselective reductions of sulfinyl ketimines. The development of this zirconocene-mediated reduction helped to accelerate our drug discovery efforts and is applicable to several motifs commonly used in medicinal chemistry. Computational investigation supported a cyclic half-chair transition state to rationalize the high selectivity in benzyl systems.

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Section: Resultsmentioning

confidence: 99%

Stereoselective Amine Synthesis Mediated by a Zirconocene Hydride to Accelerate a Drug Discovery Program

Aloiau,

Bobek,

Caddell Haatveit

et al. 2024

J. Org. Chem.

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“…We chose pyridine and pyridazine for each heteroaromatic ring. Pyridazine benefits from its double hydrogen bonding ability, high dipole moment, and weak basicity . We also introduced methoxy at the para-position of the terminal pyridazine to stabilize the tag by mitigating the electron deficiency attributed to the heteroaromatic rings by exploiting the resonance effect.…”

Section: Resultsmentioning

confidence: 99%

Visualization of Modified Bisarylbutadiyne-Tagged Small Molecules in Live-Cell Nuclei by Stimulated Raman Scattering Microscopy

Kawaguchi,

Yonetani,

Mizuguchi

et al. 2024

Anal. Chem.

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Visualizing the distribution of small-molecule drugs in living cells is an important strategy for developing specific, effective, and minimally toxic drugs. As an alternative to fluorescence imaging using bulky fluorophores or cell fixation, stimulated Raman scattering (SRS) imaging combined with bisarylbutadiyne (BADY) tagging enables the observation of small molecules closer to their native intracellular state. However, there is evidence that the physicochemical properties of BADY-tagged analogues of small-molecule drugs differ significantly from those of their parent drugs, potentially affecting their intracellular distribution. Herein, we developed a modified BADY to reduce deviations in physicochemical properties (in particular, lipophilicity and membrane permeability) between tagged and parent drugs, while maintaining high Raman activity in live-cell SRS imaging. We highlight the practical application of this approach by revealing the nuclear distribution of a modified BADY-tagged analogue of JQ1, a bromodomain and extra-terminal motif inhibitor with applications in targeted cancer therapy, in living HeLa cells. The modified BADY, methoxypyridazyl pyrimidyl butadiyne (MPDY), revealed intranuclear JQ1, while BADY-tagged JQ1 did not show a clear nuclear signal. We anticipate that the present approach combining MPDY tagging with live-cell SRS imaging provides important insight into the behavior of intracellular drugs and represents a promising avenue for improving drug development.

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“…For example, pyridazine (SMILES: c1ccnnc1) is an aromatic heterocyclic compound. 36 It contains a six-membered ring with two adjacent nitrogen atoms. The molecule has a high dipole moment with p-p stacking interactions and dual hydrogen-bonding capacity (both as hydrogen bond donor and as acceptor).…”

Section: Attention Visualisationmentioning

confidence: 99%

Using natural language processing (NLP)-inspired molecular embedding approach to predict Hansen solubility parameters

Pang,

Pine,

Sulemana

2024

Digital Discovery

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The pyridazine heterocycle in molecular recognition and drug discovery

Cited by 19 publications

References 296 publications

Stereoselective Amine Synthesis Mediated by a Zirconocene Hydride to Accelerate a Drug Discovery Program

Stereoselective Amine Synthesis Mediated by a Zirconocene Hydride to Accelerate a Drug Discovery Program

Visualization of Modified Bisarylbutadiyne-Tagged Small Molecules in Live-Cell Nuclei by Stimulated Raman Scattering Microscopy

Using natural language processing (NLP)-inspired molecular embedding approach to predict Hansen solubility parameters

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