Cyclopropyl Moiety Research Articles

Indolizidines from Actinomycetes: An Overview of Producers, Biosynthesis and Bioactivities.

Indolizidines have long been recognized for their valuable bioactivities, their common feature being a bicyclic structure connected via a nitrogen atom. Traditionally, plants have been identified as the primary producers. However, recent discoveries have revealed that certain bacterial strains belonging to the genus of actinomycetes also possess the ability to synthesize various indolizidine-based compounds. Among these strains, Streptomyces sp. HNA39, Saccharopolyspora sp. RL78, and Streptomyces NCIB 11649 have been identified as producers of cyclizidines, characterized by their distinctive cyclopropyl moiety. Additionally, Streptomyces griseus OS-3601 synthesizes a unique class of indolizidine derivatives known as iminimycins, distinguished by their rare imine-cation structure. Protoplast fusion of a Streptomyces griseus strain with Streptomyces tenjimariensis resulted in a new indolizidine named indolizomycin. This review aims to provide an overview of known bacterial indolizidine producers, summarize current knowledge regarding the biosynthesis of cyclizidines and iminimycins, and assess their respective bioactivities.

Efficient Transferase Engineering for SAM Analog Synthesis from Iodoalkanes.

S-Adenosyl-l-methionine (SAM) is an important cosubstrate in various biochemical processes, including selective methyl transfer reactions. Simple methods for the (re)generation of SAM analogs could expand the chemistry accessible with SAM-dependent transferases and go beyond methylation reactions. Here we present an efficient enzyme engineering strategy to synthesize different SAM analogs from "off-the-shelf" iodoalkanes through enzymatic alkylation of S-adenosyl-l-homocysteine (SAH). This was achieved by mutating multiple hydrophobic and structurally dynamic amino acids simultaneously. Combinatorial mutagenesis was guided by the natural amino acid diversity and generated a highly functional mutant library. This approach increased the speed as well as the scale of enzyme engineering by providing a panel of optimized enzymes with orders of magnitude higher activities for multiple substrates in just one round of enzyme engineering. The optimized enzymes exhibit catalytic efficiencies up to 31 M-1 s-1, convert various iodoalkanes, including substrates bearing cyclopropyl or aromatic moieties, and catalyze S-alkylation of SAH with very high stereoselectivities (>99 % de). We further report a high throughput chromatographic screening system for reliable and rapid SAM analog analysis. We believe that the methods and enzymes described herein will further advance the field of selective biocatalytic alkylation chemistry by enabling SAM analog regeneration with "off-the-shelf" reagents.

Discovery and Mechanism of a Nematicide Candidate (W3): A Novel Amide Compound Containing a Cyclopropyl Moiety.

To find novel nematicides, we screened the nematicidal activity of compounds in our laboratory compound library. Interestingly, the compound N-((1R,2R)-2-(2-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)-2-(trifluoromethyl)benzamide (W3) showed a broad spectrum and excellent nematicidal activity. The LC50 values of compound W3 against second-stage juveniles of Bursaphelenchus xylophilus (B. xylophilus), Aphelenchoides besseyi, and Ditylenchus destructor are 1.30, 1.63, and 0.72 mg/L, respectively. Nematicidal activities of compound W3 against second-stage juveniles of Meloidogyne incognita were 87.66% at 100 mg/L. Meanwhile, compound W3 can not only observably inhibit the feeding, reproduction, and egg hatching of B. xylophilus but can also effectively promote the oxidative stress adverse reactions of nematodes and cause intestinal damage. Compound W3 can promote the production of MDA and inhibit the activities of defense enzymes SOD and GST in B. xylophilus. Compound W3 can affect the transcription of genes involved in regulating the tricarboxylic acid cycle in nematodes, resulting in weakened nematode respiration and reduced nematode activity and even death. In addition, compound W3 had good inhibitory activity against five pathogenic fungi. Among them, the EC50 of compound W3 against Fusarium graminearum was 8.4 mg/L. In the future, we will devote ourselves to the toxicological and structural optimization research of the candidate nematicide W3.

Synthesis and Fungicidal Activity of Novel Substituted Pyrimidine-5-carboxamides Bearing Cyclopropyl Moiety

Synthesis and Fungicidal Activity of Novel Substituted Pyrimidine-5-carboxamides Bearing Cyclopropyl Moiety

Synthesis, crystal structure studies, characterization and study of novel heterocyclic thiadiazoles as caspase 3 inhibitors for anticancer activity

In the present study we have reported the synthesis of some novel heterocyclic derivatives comprising imidazole and 1,3,4-thiadiazole containing cyclopropyl moiety. Imidazothiadiazoles are of interest because of their diverse biological activities and clinical applications. Primarily docking studies are carried out with reference structure Pdb code:2DKO. We have reported the new series of 5,6 diaryl substituted with imidazo[2,1- b], , thiadiazoles analogs to target caspase family cysteine proteases. The reaction was monitored by Thin-layer chromatography using suitable mobile phase. The Rf values were compared and determined the melting point of synthesized compounds. Further these derivatives were characterized and confirmed by IR, 1H-NMR, 13C-NMR, and Mass spectral (MS) studies. For anticancer activity, all the selected compounds submitted to National Cancer Institute (NCI) for in vitro anticancer assay were evaluated for their anticancer activity. Primary one dose anticancer assay was performed in full NCI 60 cell panel in accordance with the protocol of the NCI, USA. The compounds and showed good activity against all cancer cell lines. The synthesized drugs were monitored with Caspase 3 inhibitor kit.(CASP3C-1KT)using colorimeteric assay.

Efficient Amide Formation from Non‐Activated Cyclopropyl Ester via Acyl Fluoride Generation Using Hypervalent Iodine(III) Reagent and Selectfluor

AbstractA novel and unique activation method for esters possessing a non‐activated cyclopropyl moiety as a potential activating group is developed for acyl fluoride generation using a hypervalent iodine(III) reagent and Selectfluor. The resulting acyl fluoride, which is a versatile synthetic intermediate, was smoothly transformed into the various carbonyl compounds, in particular, amides. This protocol can be applied to the chemoselective activation of diester compounds.

Strain-Release-Controlled [4 + 2 + 1] Reaction of Cyclopropyl-Capped Diene-ynes/Diene-enes and Carbon Monoxide Catalyzed by Rhodium.

Achieving transition-metal-catalyzed reactions of diene-ynes/diene-enes and carbon monoxide (CO) to deliver [4 + 2 + 1] cycloadducts, rather than the kinetically favored [2 + 2 + 1] products, is challenging. Here, we report that this can be solved by adding a cyclopropyl (CP) cap to the diene moiety of the original substrates. The resulting CP-capped diene-ynes/diene-enes can react with CO under Rh catalysis to give [4 + 2 + 1] cycloadducts exclusively without forming [2 + 2 + 1] products. This reaction has a broad scope and can be used to synthesize useful 5/7 bicycles with a CP moiety. Of the same importance, the CP moiety in the [4 + 2 + 1] cycloadducts can act as an intermediate group for further transformations so that other challenging bicyclic 5/7 and tricyclic 5/7/5, 5/7/6, and 5/7/7 skeletons, some of which are widely found in natural products, can be accessed. The mechanism of this [4 + 2 + 1] reaction has been investigated by quantum chemical calculations, and the role of the CP group in avoiding the possible side [2 + 2 + 1] reaction has been identified, showing that the [4 + 2 + 1] is controlled by releasing the ring strain in the methylenecyclopropyl (MCP) group (about 7 kcal/mol) in the CP-capped dienes.

Cyclopropane as an Unsaturation "Effect Isostere": Lowering the Melting Points in Lipid-like Ionic Liquids.

The replacement of unsaturation with a cyclopropane motif as a (bio)isostere is a widespread strategy in bacteria to tune the fluidity of lipid bilayers and protect membranes when exposed to adverse environmental conditions, e.g., high temperature, low pH, etc. Inspired by this phenomenon, we herein address the relative effect of the cyclopropanation, both cis and trans configurations, on melting points, packing efficiency, and order of a series of lipid-like ionic liquids via a combination of thermophysical analysis, X-ray crystallography, and computational modeling. The data indicate there is considerable structural latitude possible when designing highly lipophilic ionic liquids that exhibit low melting points. While cyclopropanation of the lipid-like ionic liquids provides more resistance to aerobic degradation than their olefin analogs, the impact on the melting point decrease is not as pronounced. Our results demonstrate that incorporating one or more cyclopropyl moieties in long aliphatic chains of imidazolium-based ionic liquids is highly effective in lowering the melting points of such materials relative to their counterparts bearing linear, saturated, or thioether side chains. It is shown that the cyclopropane moiety effectively disrupts packing, favoring formation of gauche conformer in the side chains, resulting in enhancement of fluidity. This was irrespective of the configuration of the methylene bridge, although marked differences in the effect of cis- and trans-monocyclopropanated ILs on the melting points were observed.

Resilience of transfluthrin to oxidative attack by duplicated CYP6P9 variants known to confer pyrethroid resistance in the major malaria mosquito Anopheles funestus

Resistance to common pyrethroids, such as deltamethrin and permethrin is widespread in the malaria mosquito Anopheles funestus and mainly conferred by upregulated cytochrome P450 monooxygenases (P450s). In the pyrethroid resistant laboratory strain An. funestus FUMOZ-R the duplicated genes CYP6P9a and CYP6P9b are highly upregulated and have been shown to metabolize various pyrethroids, including deltamethrin and permethrin. Here, we recombinantly expressed CYP6P9a and CYP6P9b from An. funestus using a baculovirus expression system and evaluated the interaction of the multifluorinated benzyl pyrethroid transfluthrin with these enzymes by different approaches. First, by Michaelis-Menten kinetics in a fluorescent probe assay with the model substrate 7-benzyloxymethoxy-4-trifluoromethylcoumarin (BOMFC), we showed the inhibition of BOMFC metabolism by increasing concentrations of transfluthrin. Second, we tested the metabolic capacity of recombinantly expressed CYP6P9 variants to degrade transfluthrin utilizing UPLC-MS/MS analysis and detected low depletion rates, explaining the virtual lack of resistance of strain FUMOZ-R to transfluthrin observed in previous studies. However, as both approaches suggested an interaction of CYP6P9 variants with transfluthrin, we analyzed the oxidative metabolic fate and failed to detect hydroxylated transfluthrin, but low amounts of an M-2 transfluthrin metabolite. Based on the detected metabolite we hypothesize oxidative attack of the gem-dimethyl substituted cyclopropyl moiety, resulting in the formation of an allyl cation upon ring opening. In conclusion, these findings support the resilience of transfluthrin to P450-mediated pyrethroid resistance, and thus, reinforces its employment as an important resistance-breaking pyrethroid in resistance management strategies to control the major malaria vector An. funestus.

2-(Cyclopropylamino)-5-(4-methoxybenzylidene)thiazol-4(5H)-one

Multicomponent reactions effectively contribute to modern organic and medicinal chemistry. 4-Thiazolidinone core and cyclopropyl moiety are important structural motifs for design of potential biologically active molecules. In the present paper, the convenient step-economy and cost-effective synthesis of 2-(cyclopropylamino)-5-(4-methoxybenzylidene)thiazol-4(5H)-one (2) is described based on the application of the MCR methodology. The proposed approach includes direct one-pot interaction of 2-thioxothiazolidin-4-one (rhodanine), 4-methoxybenzaldehyde with cyclopropylamine which was used in 10% excess compare to other reagents. The structure of synthesized compound 2 was confirmed using 1H, 13C, 2D NMR, LC-MS, IR and UV spectra. The presence of prototropic amino/imino tautomerism for synthesized compound 2 was observed based on spectral analysis data. Screening of antimicrobial activity against 12 strains of Gram-positive and Gram-negative bacteria, as well as yeasts, was performed for synthesized derivative 2.

Synthesis and computational studies of potent antimicrobial and anticancer indolone scaffolds with spiro cyclopropyl moiety as a novel design element

The indolones nucleus is the central core to develop new effective anticancer agents and its substitution at the 3-position can affect antitumor activity, 3-spirocyclopropyl-2-oxindoles have attracted the scientist's community to design and develop expedition's strategies towards their construction and explore the potential of this useful scaffold with their newer derivatives in medicinal world. The present paper describes the synthesis of 3-spirocyclopropyl-2-indolone derivatives in three steps via synthesis of ylide leading to methylene-indolinones followed by the formation of the final product spirocyclopropyl oxindole derivatives with improved yields. In this milieu we considered motivating to advance exploration the biological potencies and computational studies of our newly synthesized molecules. The aimed target molecules were screened for antimicrobial and anticancer activities where they exhibited substantial effective antimicrobial activities. Amongst them, potent compound, bromospirocyclopropyl indolone, 6d displayed encouraging MIC ranging from 0.007 to 0.49 μg/mL for gram positive microbes and also substantial anticancer activity with an IC50 of 11.5 μg/mL. Finally, the computational modelling studies were performed to explore structure-activity relationship analysis. Active site of receptor protein shows docking scores of these molecules as - 5.78 kcal/mol and −5.097 kcal/mol for the docked target proteins. The binding energy of the best score is found to be −41.67 kcal/mol to −44.67 kcal/mol. Thus, the present paper efficaciously validated spirocyclopropyl indolone framework for drug candidates as potent anticancer as well as antimicrobial compounds.

Synthesis of Trisubstituted Furans via Copper(I)-Catalyzed Strain-Driving Cycloisomerization/Annulative Fragmentation.

The in situ formed furan-fused cyclobutenes via Cu(I)-catalyzed cycloisomerization of readily available allenyl ketones bearing a cyclopropyl moiety are a highly reactive and powerful species, which undergo annulative fragmentation with terminal ynones to afford a wide variety of functional furans in moderate to high yields. This ring-distortion protocol features an unprecedented strain-controlled cycloisomerization/Diels-Alder/retro-Diels-Alder (CDRD) sequence under mild conditions.

Structure-based optimizations of a necroptosis inhibitor (SZM594) as novel protective agents of acute lung injury

Targeting RIPK1 is a promising strategy for the treatment or alleviation of acute lung injury (ALI). SZM594, a benzothiazole compound previously developed by our research group, possessed good dual-targeting receptor-interacting protein kinase 1 (RIPK1) and RIPK3 activity and anti-necroptosis activity as well as acceptable in vivo efficacy. In this study, the cyclopropyl moiety of SZM594 was modified based on a structure-based design strategy. The resulting cyclohexanone-containing analogue 41 improved the selectivity toward RIPK1 over RIPK3 and the anti-necroptosis activity was also increased compared with those of SZM594. More importantly, compound 41 could inhibit the tumor necrosis factor-α (TNF-α) expression in lipopolysaccharide (LPS)-induced peritoneal macrophage cell model, and significantly alleviate LPS-induced ALI in a mouse model. This compound could significantly inhibit the expressions of the phosphorylation of RIPK1 and down-stream RIPK3 and mixed lineage kinase domain-like protein (MLKL). Thus, these cyclohexanone-containing benzothiazole analogues represent promising lead structures for the discovery of novel protective agents of ALI.

Redox‐Amphoteric 4,4’‐Dicyclopropyldiphenylnitroxyl Radical: Unexpectedly High Stability

AbstractAtom‐economy cyclopropyl group turned out to be the substituent of choice for stabilization of diphenylnitroxyl radical in solution (τ1/2=1280 h, i. e., ca. 2 months, in benzene). Though the benzylic H‐atom commonly provokes fast decomposition of nitroxides in solution and the cyclopropyl moiety is prone to the ring opening in substrates with significant spin density at the α‐position, both processes are not implemented in 4,4’‐dicyclopropyldiphenylnitroxide. Instead, the stereoelectronic properties of the cyclopropyl group lead to significant stabilization of the oxidized and reduced states of the nitroxide, making it redox‐amphoteric and suitable for practical application.

Gold Catalysis Enabling Furan-Fused Cyclobutenes as a Platform toward Cross Cycloadditions

The inherently strained furan-fused cyclobutenes, in situ generated via cycloisomerizations of allenyl ketones bearing cyclopropyl moiety under gold catalysis, have been utilized as reactive building blocks toward cross cycloadditions. The [4 + 2] and [3 + 2] annulations of these species with benzo[c]isoxazoles and N-iminoquinazolinium ylides furnish various three-dimensional cyclobutane-bridged polyheterocycles in good yields. A wide range of typically electron-deficient 1,3-dienes, heterodienes, and 1,3-dipoles can trap furan-fused cyclobutenes to afford several polycyclic architectures.

Synthesis of Cyclopropyl Ester and Amide Substituted Pyrimidinediones as Protoporphyrinogen Oxidase‐Inhibiting Herbicides

The protoporphyrinogen oxidase (PPO) enzyme is involved in the biosynthesis of chlorophyll and is an important target in research for development of new herbicides. In this study, new pyrimidinedione compounds with thioester tail group containing cyclopropyl moiety are synthesized from the commercially available 2‐(1‐(mercaptomethyl)cyclopropyl)acetic acid. The herbicidal activity of the synthesized compounds is also evaluated. Most of the synthesized compounds exhibit herbicidal activities against both monocot and dicot weeds. In particular, 10a showed similar activity to the control material, Saflufenacil. And when against the monocot weeds, Echinochloa crusgalli and Digitaria sanguinalis, 10a shows superior activity to Saflufenacil.

Design, synthesis, antifungal evaluation, and molecular docking of novel 1,2,4-triazole derivatives containing oxime ether and cyclopropyl moieties as potential sterol demethylase inhibitors

A series of novel triazole derivatives containing oxime ether and cyclopropyl moieties were designed and synthesized. Some compounds exhibited remarkable antifungal activities. The molecular docking of compound 5k with FgCYP51 was investigated.

Development and Scale-Up of an Improved Manufacturing Route to the ATR Inhibitor Ceralasertib

Ceralasertib is currently being evaluated in multiple phase I/II clinical trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine and an azaindole, makes it a challenging molecule to synthesize on a large scale. Several features of the medicinal chemistry and early development route make it unsuitable for the long-term commercial manufacture of the active pharmaceutical ingredient. We describe the investigation and development of a new and improved route which introduces the cyclopropyl moiety in a novel process from methyl 2,4-dibromobutyrate. Following construction of the pyrimidine ring, large-scale chlorination with phosphoryl chloride was performed with a safe and robust work-up. An SNAr reaction required an innovative work-up to remove the unwanted regio-isomer, and then a Baeyer–Villiger monooxygenase enzyme was used to enable asymmetric sulfur oxidation to a sulfoxide. A safe and scalable metal-free sulfoximine formation was developed, and then optimization of a Suzuki reaction enabled the manufacture of high-quality ceralasertib with excellent control of impurities and an overall yield of 16%.

An Efficient Substrate-Induced Method for the Synthesis of CF3-Substituted Cyclopropanes by Metal-Free Reaction of Trifluoromethyl Styrylisoxazoles with Nitromethane

AbstractA series of (trifluoromethyl)cyclopropanes (TFCPs) tolerating a broad range of functional groups, known as tert-butyl bioisosteres, have been obtained from the cyclization reaction between nitromethane­ and 5-[β-(trifluoromethyl)styryl]isoxazoles in 70–94% yields and 75:25 to 90:10 dr. This method offers practical access to this cyclopropyl moiety of pharmacological interest, employing an inorganic base under phase-transfer conditions.

Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFRL858R/T790M inhibitors.

Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFRL858R/T790M inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC50 value of 0.26nM. Moreover, 8l provided strong activity against H1975cells with IC50 value of 0.008μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFRL858R/T790M-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.