Squaric acid analogues in medicinal chemistry

Chasák, Jan; Šlachtová, Veronika; Urban, Milan; Brulíková, Lucie

doi:10.1016/j.ejmech.2020.112872

Cited by 34 publications

(25 citation statements)

References 108 publications

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“…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

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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.

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Section: Carboxylic Acid Bioisosteresmentioning

confidence: 99%

Carboxylic Acid Bioisosteres in Medicinal Chemistry: Synthesis and Properties

Bredael

Geurs

Clarisse

et al. 2022

Journal of Chemistry

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“…But a few investigations on the application of squaric acid derivatives and their metal complexes were prepared and published. In 2020 Chasák et al 1 published a review about the biological activity of squaric acid and its derivatives.…”

Section: Introductionmentioning

confidence: 99%

A concise review on application of squaric acid derivatives and their metal complexes in medicine

Bakalova¹,

Ruseva²,

Cherneva³

2022

Arkivoc

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In this review, we summarize the data about applications of squaric acid, its derivatives and their metal complexes in medicine. In recent years, researchers have been concentrated on the study of squaric acid and its derivatives because of their unique properties and the different possible ways to coordinate with metals and form complex compounds. Encouraging results have also been obtained for the cytotoxic activity of some squaric acid analogues and their metal complexes on various human tumor cell lines.

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Section: Introductionmentioning

confidence: 99%

“…The core structure of these molecules is derived from squaric acid (Figure 1). While a few examples of squaric acid diamides with antiplasmodial or other biological activities are known [22][23][24][25], up to now only a single 3,4-bis(indol-3-yl)cyclobut-3-ene-1,2-dione was prepared in a meager yield (0.67%) [26], and biological activity of this congener was not reported. Before synthesis methods for the production of bisindolylcyclobutenediones 2 were developed, docking studies were carried out to virtually fit the putative new inhibitors into the ATP binding pockets of exemplary plasmodial protein kinases.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antiplasmodial Activity of Bisindolylcyclobutenediones

Lande

Nasereddin²,

Alder

et al. 2021

Molecules

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Malaria is one of the most dangerous infectious diseases. Because the causative Plasmodium parasites have developed resistances against virtually all established antimalarial drugs, novel antiplasmodial agents are required. In order to target plasmodial kinases, novel N-unsubstituted bisindolylcyclobutenediones were designed as analogs to the kinase inhibitory bisindolylmaleimides. Molecular docking experiments produced favorable poses of the unsubstituted bisindolylcyclobutenedione in the ATP binding pocket of various plasmodial protein kinases. The synthesis of the title compounds was accomplished by sequential Friedel-Crafts acylation procedures. In vitro screening of the new compounds against transgenic NF54-luc P. falciparum parasites revealed a set of derivatives with submicromolar activity, of which some displayed a reasonable selectivity profile against a human cell line. Although the molecular docking studies suggested the plasmodial protein kinase PfGSK-3 as the putative biological target, the title compounds failed to inhibit the isolated enzyme in vitro. As selective submicromolar antiplasmodial agents, the N-unsubstituted bisindolylcyclobutenediones are promising starting structures in the search for antimalarial drugs, albeit for a rational development, the biological target addressed by these compounds has yet to be identified.

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Squaric acid analogues in medicinal chemistry

Cited by 34 publications

References 108 publications

Carboxylic Acid Bioisosteres in Medicinal Chemistry: Synthesis and Properties

Carboxylic Acid Bioisosteres in Medicinal Chemistry: Synthesis and Properties

A concise review on application of squaric acid derivatives and their metal complexes in medicine

Synthesis and Antiplasmodial Activity of Bisindolylcyclobutenediones

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