Squaramides as Bioisosteres in Contemporary Drug Design

Agnew‐Francis, Kylie A.; Williams, Craig M.

doi:10.1021/acs.chemrev.0c00416

Cited by 39 publications

(37 citation statements)

References 259 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cyclobutene diketone was a kind of important fragment found in many kinase inhibitors 32 , 33 . Based on the widely biological activity of cyclobutene diketone, we introduced it into our target compounds.…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis and biological evaluation of a series of dianilinopyrimidines as EGFR inhibitors

Yan

Wang

Liu

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

This paper described our efforts to develop dianilinopyrimidines as novel EGFR inhibitors. All the target compounds were tested for inhibitory effects against wild type EGFR (EGFR wt ) and three tumour cells, including A549, PC-3, and HepG2. Some of the compounds performed well in antitumor activities. Especially, compound 4c 2-((2-((4-(3-fluorobenzamido)phenyl)amino)-5-(trifluoromethyl) pyrimidin-4-yl)amino)- N -methylthiophene-3-carboxamide showed higher anti-tumour activities than Gefitinib. The IC 50 values of compound 4c against A549, PC-3, and HepG2. reached 0.56 μM, 2.46 μM, and 2.21 μM, respectively. In addition, further studies indicated that compound 4c could induce apoptosis against A549 cells and arrest A549 cells in the G2/M phase. Molecular docking studies showed that compound 4c could closely interact with EGFR. Generally, compound 4c was the potential for developing into an anti-tumour drug.

show abstract

Section: Resultsmentioning

confidence: 99%

Design, synthesis and biological evaluation of a series of dianilinopyrimidines as EGFR inhibitors

Yan

Wang

Liu

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…e thiazolidinedione ring is hypothesized to undergo an oxidative ring-opening reaction by cytochrome P450 that results in the formation of electrophilic metabolites [3,29]. Squaric acids and their derivatives, squaramides, squaramines, and squarates, have also been successfully employed in some settings as carboxylic acid surrogates but contain a very reactive structure and therefore are usually associated with toxicity, a lack of selectivity, and thus promiscuity towards several targets [30][31][32]. Meanwhile, phosphonic, phosphinic, sulfonic, and sul nic acids are nonplanar and relatively highly acidic, leading to increased hydrophilicity and decreased permeability (Table 1) [33].…”

Section: Carboxylic Acid Bioisosteresmentioning

confidence: 99%

Carboxylic Acid Bioisosteres in Medicinal Chemistry: Synthesis and Properties

Bredael

Geurs

Clarisse

et al. 2022

Journal of Chemistry

View full text Add to dashboard Cite

Lead optimization represents the tedious process of fine-tuning lead compounds from biologically active hits to suitable drug candidates for clinical trials. By chemically modifying a hit structure, an improved compound can be obtained in terms of activity, selectivity, and pharmacokinetic ADME (absorption, distribution, metabolism, and excretion) properties. The carboxylic acid moiety is known to be a crucial functionality in many pharmaceutically active compounds. Despite its common use as a key functionality in drugs, its presence in a lead molecule is often associated with poor pharmacokinetic properties and toxicity. In this literature overview, we discuss how the shortcomings of a carboxylic acid can be circumvented by replacing this functionality with bioisosteres. In this way, the positive aspects of this moiety, such as its activity, for example, by virtue of its capacity to form hydrogen bonds, can be maintained or even improved. To that end, we provide an overview of the most promising carboxylic acid bioisosteres and discuss a selection of synthetic routes towards the main functionalities.

show abstract

“…Many small molecules in market have existed cyclobutene diketone structure. 27,28 In consideration of the widely biological activity of cyclobutene diketone, we introduced it into our molecular of the target compounds. As shown in Scheme 2, compound 3 in Scheme 1 as the starting material successfully reacted with 3,4-dimethoxy-3-cyclobutene-1,2-dione to obtain intermediate 5 in 62% yield.…”

Section: Figure 3 Design Strategy Of Egfr/src Inhibitorsmentioning

confidence: 99%

Development of 5-Trifluoromethylpyrimidine Derivatives as Dual Inhibitors of EGFR and Src for Cancer Therapy

Yan¹,

Liu²,

Wang³

et al. 2022

HETEROCYCLES

View full text Add to dashboard Cite

In this paper, we reported a new series of 5-trifluoromethylpyrimidine derivatives (4a-4f, 6a-6j) for cancer therapy. They were tested for antitumor activity in vitro on four human cancer cell lines including A549, K562, HepG2, MCF-7 and two kinase including wild type epidermal growth factor receptor tyrosine kinase (EGFR wt -TK) and c-Src. The results suggested that some of the compounds (4a, 4b, 4c, 4e, 6b, 6d, 6e, 6f, 6g, 6h) performed well activities. Especially 2-((2-((4-((2-(Cyclohexylamino)-3,4-dioxocyclobut-1-en-1-yl)amino)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (6g) showed high antitumor activities against four cancer cell lines with 1.08 μM, 2.06 μM, 1.24 μM and 2.57 μM, respectively. Furthermore, compound 6g inhibited EGFR wt and Src at the values of 0.75 μM and 0.15 μM.Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK), which plays an important role in regulating cell growth, proliferation and differentiation and other physiological activities of cancer cells. And also it is an important target for new anti-cancer drug research. [1][2][3][4] As shown in Figure 1, lots of EGFR inhibitors such as Gefitinib, Erlotinib, and Lapatinib have been approved in market, which significantly improve the clinical treatment of cancer patients. 5 However, the resistance problems of EGFR inhibitors in clinic have been made it urgent to find novel generation of EGFR kinase inhibitors. 6,7

show abstract

Squaramides as Bioisosteres in Contemporary Drug Design

Cited by 39 publications

References 259 publications

Design, synthesis and biological evaluation of a series of dianilinopyrimidines as EGFR inhibitors

Design, synthesis and biological evaluation of a series of dianilinopyrimidines as EGFR inhibitors

Carboxylic Acid Bioisosteres in Medicinal Chemistry: Synthesis and Properties

Development of 5-Trifluoromethylpyrimidine Derivatives as Dual Inhibitors of EGFR and Src for Cancer Therapy

Contact Info

Product

Resources

About