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Molecular Metaphors is the application of squaryl building blocks towards creative functional group chemistry to produce lead compounds and imaging agents. This strategy is applied to rational drug design and to various imaging agents that would normally contain conventional functional group chemistry. These, include carboxylic acids, α-amino acids...
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... Squaric acid is a symmetrical planar diprotic four-membered oxocarbon compound that possesses unique 2p-pseudo-aromaticity [21]. Consequently, squaric acid features unusual high double acidity (pK a1 ¼ 0.54; pK a2 ¼ 3.58) due to the resonance stabilized squarate dianion ( Fig. 1) [22]. ...
In this review, we summarize the published data on squaric acid analogues with a special focus on their use in medicinal chemistry and as potential drugs. Squaric acid is an interesting small molecule with an almost perfectly square shape, and its analogues have a variety of biological activities that are enabled by the presence of significant H-bond donors and acceptors. Unfortunately, most of these compounds also exhibit reactive functionalities, and this deters the majority of medicinal chemists and pharmacologists from trying to use them in drug development. However, this group of compounds is experiencing a renaissance, and large numbers of them are being tested for antiprotozoal, antibacterial, antifungal, and antiviral activities. The most useful of these compounds exhibited IC50 values in the nanomolar range, which makes them promising drug candidates. In addition to these activities, their interactions with living systems were intensively explored, revealing that squaric acid analogues inhibit various enzymes and often serve as receptor antagonists and that the squaric acid moiety may be used as a non-classical isosteric replacement for other functional groups such as carboxylate. In summary, this review is focused on squaric acid and its analogues and their use in medicinal chemistry and should serve as a guide for other researchers in the field to demonstrate the potential of these compounds based on previous research.
... 264,265 In terms of its mode of action and structure, 164 shows similarity to the GSK drug sumatriptan (165), which suggests that the squaramide is acting as a sulfonamide bioisostere. 266 ...
Squaramides represent a class of vinylogous amides that are derived from the squarate oxocarbon dianion. While they have been known since the 1950s, squaramides have only recently emerged (in the last 10-20 years) as particularly useful chemical entities in a variety of applications. They have found particular use as bioisosteric replacements of several heteroatomic functional groups, notably ureas, thioureas, guanidines, and cyanoguanidines, owing in part to their similar capacity toward hydrogen bonding and ability to reliably engender defined conformations in drug ligands. This Review aims to provide a comprehensive overview of the deployment of squaramides as bioisosteres within the drug design landscape. Their utility in this space is further rationalized through an examination of the physicochemical properties of squaramides in contrast to other functional groups. In addition, we consider the deployment of related cyclic oxocarbanion derivatives as potential bioisosteric replacements of ureas and related functional groups.
... Skuarik asitin türevleri skuarat, amid, ester, karışık skuaramat ve amik asit'lerdir (Şekil 1). Bazı skuarik asit türevleri, moleküler taklitleri açısından dikkat çekmektedirler (Kitson, 2017). Karışık skuaramatlar, skuarinlerin (SAM) sentezinde ara bileşikler (Ivanovsky ve ark., 2007) olarak ve çeşitli biyolojik uygulamalarda yer aldıkları görülmektedir (Hutchings ve ark., 1998;Lim ve ark., 2003;Xu ve ark., 2005;Marin ve ark., 2007;Charton ve ark., 2008;Kumar ve ark., 2012 Skuaramik asit türevleri (Şekil 1), literatürde skuaratların diğer türevlerinden daha az incelenmiştir. ...
Çalışmada, azo grubu taşıyan skuaramik asitlerin (bileşikler 4-6) sentezleri tek-kap içerisinde gerçekleştirildi. Bileşikler 4-6’nın sentezi için önce serbest amino grubu içeren azo boyarmaddeleri (bileşikler 1-3), diazo-kenetlenme yöntemiyle elde edildi. Bu yöntemde, çıkış bileşiği 3-hidroksi-4-metoksi-siklobut-3-en-1,2-dion, metanol ortamında, metanolün skuarik asit ile tekli yerdeğiştirmesi sonucunda elde edilmiş ve izole edilmeden bileşikler 4-6’nın sentezinde kullanılmıştır. Bileşikler 4-6, elde edilen bileşikler 1-3’ün 3-hidroksi-4-metoksi-siklobut-3-en-1,2-dion arasındaki tekli yerdeğiştirme tepkimesi sonucunda tek-kap içerisinde metanol ortamında düşük verimlerle sentezlenmiştir. Bileşikler 2, 4, 5 ve 6’nın kimyasal yapıları, spektroskopik yöntemler (FTIR, NMR) ile aydınlatılmıştır. Ayrıca, farklı çözelti ortamlarında bileşikler 4-6’nın UV-Görünür bölge absorpsiyon spektrumları alınmış ve değerlendirilmiştir. Bu sentez yönteminde, bileşikler 1-3, 3-hidroksi-4-metoksi-siklobut-3-en-1,2-dion’un -OCH3 grubu ile -OH grubuna göre bişelik 3 hariç seçimli yer değiştirdiği belirlenmiştir.
... Las escuaraínas (Kitson, 2017) son compuestos producidos por la condensación del ácido escuárico 1 con 2 moléculas ricas en electrones tales como anilinas, fenoles, pirroles e indoles, denotados como X en la Figura 1. Aunque la representación alterna del anillo central de estos compuestos zwitteriónicos (Figura 1, A) es una estructura aromática con doble carga positiva (Figura 1, B), recientemente ha sido rebatida en base a estudios teóricos que indican que la polarización de este anillo en realidad desplaza la carga positiva a los grupos sustituyentes (Divya, 2019) Figura 1. Estructura general de escuaraínas La principal característica física de estos compuestos es la intensa absorción de luz que ocasiona la emisión de fluorescencia. Estas estructuras privilegiadas tienen varias aplicaciones tecnológicas derivadas de sus propiedades ópticas (Xia y Wang, 2017), por ejemplo: conversión de luz solar (Wickramsinghe, 2019, terapia fotodinámica (Sun, 2018, Ramahia, 2002, sondas fluorescentes para la detección de cáncer (Ahn, 2012) y la detección de analitos (Liu, 2019). ...
Se prepararon bis(indolil)escuaraínas como materiales potenciales de óptica no lineal aplicados a la obtención de imagen celular por microscopia de fluorescencia, se estudiaron distintos métodos para aislar y estabilizar a los derivados de escuaraínas, de los cuales el encapsulamiento con oligosacáridos cíclicos (ciclodextrinas) resultó ser el más factible.
The design of bioisosteres represents a creative and productive approach to improve a molecule, including by enhancing potency, addressing pharmacokinetic challenges, reducing off-target liabilities, and productively modulating physicochemical properties. Bioisosterism is a principle exploited in the design of bioactive compounds of interest to both medicinal and agricultural chemists, and in this review, we provide a synopsis of applications where this kind of molecular editing has proved to be advantageous in molecule optimization. The examples selected for discussion focus on bioisosteres of carboxylic acids, applications of fluorine and fluorinated motifs in compound design, some applications of the sulfoximine functionality, the design of bioisosteres of drug-H2O complexes, and the design of bioisosteres of the phenyl ring.
A high-affinity supramolecular dye-capture system with “turn on” visible fluorescence is used to create a new assay for phospholipase-mediated liposome leakage.
Silylated tertiary alcohols from 1,2-addition of alkyllithiums to dialkyl squarates undergo alkene ozonolysis to give β-substituted-α-keto-β-(silyloxy)succinates. With 3-(triethylsilyloxy)butyllithium the methodology was applied to the 2,8-dioxabicyclo[3.2.1]octane core of the squalestatins. Enantioselective 1,2-addition to di-tert-butyl squarate using butyllithium or diethylzinc/Ti(iPrO)4 in the presence of chiral ligands (such as bisoxazolines or camphorsulfonamides, respectively) gave the corresponding tertiary alcohols in up to 67.5:32.5 er.
