Design and optimization of orally spleen tyrosine kinase (SYK) inhibitors for treatment of solid tumor

Wang, Cheng; Wang, Xin; Li, Yao; Wang, Tianqi; Huang, Zhi; Qin, Zhongxiang; Yang, Shengyong; Xiang, Rong; Fan, Yan

doi:10.1016/j.bioorg.2019.103547

Cited by 11 publications

(5 citation statements)

References 39 publications

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“…tert-Butyl 4-(4-nitrophenyl)piperazine-1-carboxylate (21): The reaction of 1-fluoro-4-nitrobenzene (988 mg (7.00 mmol)) with N-Boc-piperazine (2.69 g (14.44 mmol)) and potassium carbonate (1.94 g (14.02 mmol)) in dry DMSO yielded compound 21 as orange amorphous solid (2.07 g (96%)) which was used without further purification. NMR data were in accordance with literature data [31].…”

Section: General Procedures For the Synthesis Of Compounds 9-15supporting

confidence: 74%

New Derivatives of the Multi-Stage Active Malaria Box Compound MMV030666 and Their Antiplasmodial Potencies

et al. 2022

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MMV’s Malaria Box compound MMV030666 shows multi-stage activity against various strains of Plasmodium falciparum and lacks resistance development. To evaluate the importance of its diarylether partial structure, diarylthioethers and diphenylamines with varying substitution patterns were prepared. A number of evident structure-activity relationships were revealed. Physicochemical and pharmacokinetic parameters were determined experimentally (passive permeability) or calculated. Compared to the lead compound a diarylthioether was more active and less cytotoxic resulting in an excellent selectivity index of 850. In addition, pharmacokinetic and physicochemical parameters were improved.

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Section: General Procedures For the Synthesis Of Compounds 9-15supporting

confidence: 74%

New Derivatives of the Multi-Stage Active Malaria Box Compound MMV030666 and Their Antiplasmodial Potencies

et al. 2022

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“…tert-Butyl-4-(4-nitrophenyl)piperazine-1-carboxylate (41): The reaction of potassium carbonate (1.94 g (14.02 mmol), N-Boc-piperazine (2.69 g (14.44 mmol) and 1-fluoro-4nitrobenzene (988 mg (7.00 mmol)) in dry DMSO (40 mL) yielded compound 41 as orange solid (2.07 g (96%)) which was used without further purification. NMR data were in accordance with literature data [35].…”

Section: General Procedures For the Synthesis Of Compounds 2 9 10 And 11supporting

confidence: 74%

Synthesis and Structure-Activity Relationships of New 2-Phenoxybenzamides with Antiplasmodial Activity

et al. 2021

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The 2-phenoxybenzamide 1 from the Medicines for Malaria Venture Malaria Box Project has shown promising multi-stage activity against different strains of P. falciparum. It was successfully synthesized via a retrosynthetic approach. Subsequently, twenty-one new derivatives were prepared and tested for their in vitro activity against blood stages of the NF54 strain of P. falciparum. Several insights into structure-activity relationships were revealed. The antiplasmodial activity and cytotoxicity of compounds strongly depended on the substitution pattern of the anilino partial structure as well as on the size of substituents. The diaryl ether partial structure had further impacts on the activity. Additionally, several physicochemical and pharmacokinetic parameters were calculated (log P, log D7.4 and ligand efficiency) or determined experimentally (passive permeability and CYP3A4 inhibition). The tert-butyl-4-{4-[2-(4-fluorophenoxy)-3-(trifluoromethyl)benzamido]phenyl}piperazine-1-carboxylate possesses high antiplasmodial activity against P. falciparum NF54 (PfNF54 IC50 = 0.2690 µM) and very low cytotoxicity (L-6 cells IC50 = 124.0 µM) resulting in an excellent selectivity index of 460. Compared to the lead structure 1 the antiplasmodial activity was improved as well as the physicochemical and some pharmacokinetic parameters.

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“…In general, this building block category can be only marginally considered as emerging since many of them were introduced long ago. Hetera-substituted bicyclo[3.1.0]hexanes, bicyclo[3.3.0]octanes (except morpholine analogs), bicyclo[2.2.1]heptanes and many higher bridged homologues can be named among examples of the classical M/P/P isosteric replacements (still having wide applications in these days though [434][435][436][437][438] ) (Figure 6). In 2011, we have published a comprehensive review on bicyclic conforma- tionally restricted diamines; many (if not all) of them can be considered as the piperazine analogs.…”

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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Design and optimization of orally spleen tyrosine kinase (SYK) inhibitors for treatment of solid tumor

Cited by 11 publications

References 39 publications

New Derivatives of the Multi-Stage Active Malaria Box Compound MMV030666 and Their Antiplasmodial Potencies

New Derivatives of the Multi-Stage Active Malaria Box Compound MMV030666 and Their Antiplasmodial Potencies

Synthesis and Structure-Activity Relationships of New 2-Phenoxybenzamides with Antiplasmodial Activity

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

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