Put a ring on it: application of small aliphatic rings in medicinal chemistry

Bauer, Matthias R.; Fruscia, Paolo Di; Lucas, Simon; Michaelides, Iacovos N.; Nelson, Jennifer E.; Storer, Richard; Whitehurst, Benjamin C.

doi:10.1039/d0md00370k

Cited by 239 publications

(174 citation statements)

References 177 publications

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“…Numerous studies, including those carried out over the years by our group, show that thiazole derivatives have high antifungal activity [3,25]. The cyclopropane system, due to its unique properties, such as low molecular weight, conformational rigidity, unusual bonding and planarity, is used in drug design as a replacement for gem-dimethyl and alkene groups and phenyl rings, leading to the reduced lipophilicity and increased metabolic stability of drugs [26,27]. We have recently shown that thiazole derivatives containing a cyclopropane ring exhibit high activity against both reference strains and clinical isolates of Candida spp.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Physicochemical Characterization of Novel Dicyclopropyl-Thiazole Compounds as Nontoxic and Promising Antifungals

et al. 2021

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There is a need to search for new antifungals, especially for the treatment of the invasive Candida infections, caused mainly by C. albicans. These infections are steadily increasing at an alarming rate, mostly among immunocompromised patients. The newly synthesized compounds (3a–3k) were characterized by physicochemical parameters and investigated for antimicrobial activity using the microdilution broth method to estimate minimal inhibitory concentration (MIC). Additionally, their antibiofilm activity and mode of action together with the effect on the membrane permeability in C. albicans were investigated. Biofilm biomass and its metabolic activity were quantitatively measured using crystal violet (CV) staining and tetrazolium salt (XTT) reduction assay. The cytotoxic effect on normal human lung fibroblasts and haemolytic effect were also evaluated. The results showed differential activity of the compounds against yeasts (MIC = 0.24–500 µg/mL) and bacteria (MIC = 125–1000 µg/mL). Most compounds possessed strong antifungal activity (MIC = 0.24–7.81 µg/mL). The compounds 3b, 3c and 3e, showed no inhibitory (at 1/2 × MIC) and eradication (at 8 × MIC) effect on C. albicans biofilm. Only slight decrease in the biofilm metabolic activity was observed for compound 3b. Moreover, the studied compounds increased the permeability of the membrane/cell wall of C. albicans and their mode of action may be related to action within the fungal cell wall structure and/or within the cell membrane. It is worth noting that the compounds had no cytotoxicity effect on pulmonary fibroblasts and erythrocytes at concentrations showing anticandidal activity. The present studies in vitro confirm that these derivatives appear to be a very promising group of antifungals for further preclinical studies.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Physicochemical Characterization of Novel Dicyclopropyl-Thiazole Compounds as Nontoxic and Promising Antifungals

et al. 2021

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“…These BCP derivatives serve as bioisosteres for arenes, internal alkynes, and tert-butyl groups in medicinal chemistry settings. 35 With respect to the scope of triuoromethyl-substituted alkenes, a diverse array of DNA headpieces (DNA-HPs) led to the desired benzylic triuoromethyl-substituted products without compromising yields (Scheme 4). In general, both electron-withdrawing and electron-donating groups are well tolerated under the developed conditions.…”

Section: Discussionmentioning

confidence: 99%

“…These BCP derivatives serve as bioisosteres for arenes, internal alkynes, and tert -butyl groups in medicinal chemistry settings. 35 …”

Section: Discussionmentioning

confidence: 99%

Photoredox-mediated hydroalkylation and hydroarylation of functionalized olefins for DNA-encoded library synthesis

et al. 2021

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“…Some representative natural cyclobutenes such as cyclomegistine or β‐lumicolchicine are depicted in Scheme 1a. Due to the highly rigid backbone and the well‐defined three‐dimensional rearrangement of the substituents, these scaffolds are privileged in medicinal chemistry [1f] . They can also be considered as key building blocks for the synthesis of highly substituted cyclic, heterocyclic or acyclic derivatives, via ring expansion, ring contraction or rearrangements [2] .…”

Section: Methodsmentioning

confidence: 99%

Synthesis of Functionalized Cyclobutenes and Spirocycles via Asymmetric P(III)/P(V) Redox Catalysis

et al. 2021

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An enantioselective phosphine‐catalyzed transformation has been developed for the synthesis of chiral cyclobutene triesters and fluorinated spirocyclic compounds. The strategy involved a P(III)/P(V) redox cycling process, via in situ reduction of phosphine oxide with phenylsilane. This catalytic methodology has enabled the enantioselective synthesis of functionalized cyclobutenes (24 examples, up to 94% ee). On the occasion of the extension of this study to α‐ketoester indenone substrates, a surprising reactivity has been discovered for the synthesis of spiro‐indenone products.

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Put a ring on it: application of small aliphatic rings in medicinal chemistry

Abstract: Aliphatic small rings including cyclopropanes, cyclobutanes, oxetanes, azetidines and bicyclo[1.1.1]pentanes have been increasingly exploited in medicinal chemistry. This review summarises judicious successful application and reported limitations of these ring systems.

Cited by 239 publications

References 177 publications

Synthesis and Physicochemical Characterization of Novel Dicyclopropyl-Thiazole Compounds as Nontoxic and Promising Antifungals

Synthesis and Physicochemical Characterization of Novel Dicyclopropyl-Thiazole Compounds as Nontoxic and Promising Antifungals

Photoredox-mediated hydroalkylation and hydroarylation of functionalized olefins for DNA-encoded library synthesis

Synthesis of Functionalized Cyclobutenes and Spirocycles via Asymmetric P(III)/P(V) Redox Catalysis

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