Spirocyclic Derivatives Research Articles

Design, synthesis, biological evaluation study of spirocyclic POM analogues as novel MmpL3 anti-tubercular agent

We present the development of a phenyl oxazole methyl (POM) core structure with spirocyclic derivatives as part of our efforts to discover innovative anti-tuberculosis agents. Derivatives of spirocyclic POM were synthesized and evaluated for their inhibitory effects on M.tuberculosis (M. tb) H37Rv. Notably, compound 5c displayed potent anti-tubercular activity with MIC value of 0.206 μM in culture broth medium. Furthermore MIC values of compound 5c against DS/MDR/pre-XDR clinical isolates ranged from 0.34 to 0.68 μg/mL, 0.17 to 0.68 μg/mL, and 0.17 to 0.34 μg/mL, respectively. Also, compound 5c with favorable ADME and PK properties was not cytotoxic to THP-1 human cells. Based on the spontaneous mutant generation, we have identified the target of compound 5c to be MmpL3. The computational docking study suggested its plausible binding mode against MmpL3. There is no approved drug targeting this target yet, and the outcomes of the presented research will contribute to the future discovery of novel anti-tuberculosis drugs.

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles.

In this work, we report an efficient approach to 2-oxoazetidine-3-carboxylic acid derivatives based on a thermally promoted Wolff rearrangement of diazotetramic acids in the presence of nucleophiles. The method allows easy variation of the substituent in the exocyclic acyl group by introducing different N-, O-, and S-nucleophilic reagents into the reaction. The reaction of chiral diazotetramic acids leads exclusively to trans-diastereomeric β-lactams. The use of variously substituted diazotetramic acids, including spirocyclic derivatives, as well as a wide range of nucleophiles provides access to a structural diversity of medically relevant 2-oxoazetidine-3-carboxylic acid amides and esters.

Stereoselective synthesis of spirocyclic derivatives of functionalized 2,3,4,7-tetrahydro-1H-azepines

A simple and effective stereoselective synthesis of unique azaspirocyclic 2,3,4,7-tetrahydro-1H-azepine derivatives, namely, 7-azaspiro[4.6]undec-9-ene and 8-azaspiro[5.6]- dodec-10-ene, from simple commercially available reagents was accomplished. Their key 1,2-epoxy derivatives as individual diastereomers were obtained in nine steps with 31–32% overall yields. The possibility of synthesizing a library of small spiroheterocyclic molecules was exemplified by the N-Boc-protected (1RS,2SR,6RS)-1,2-epoxy-8-aza- spiro[5.6]dodec-10-ene scaffold through simple chemical modifications of its epoxide function.

Green synthesis and anti-tumor efficacy via inducing pyroptosis of novel 1H-benzo[e]indole-2(3H)-one spirocyclic derivatives

Pyroptosis induction is anticipated to be a new approach to developing anti-tumor medications. A novel class of spirocyclic compounds was designed by hybridization of 1H-Benzo[e]indole-2(3H)-one with 1,4-dihydroquinoline and synthesized through a new green “one-pot” synthesis method using 10 wt% SDS/H2O as a solvent to screen novel tumor cell pyroptosis inducers. The anti-tumor activity of all compounds in vitro was determined by the MTT method, and a fraction of the compounds showed good cell growth inhibitory activity. The quantitative structure–activity relationship models of the compounds were established by artificial intelligence random forest algorithm (R2 = 0.9656 and 0.9747). The ideal compound A9 could, in a concentration-dependent manner, prevent ovarian cancer cells from forming colonies, migrating, and invading. Furthermore, A9 could significantly induce pyroptosis and upregulate the expression of pyroptosis-related proteins GSDME-N, in addition to inducing apoptosis and mediating the expression of apoptosis-related proteins in ovarian cancer cells. A9 (5 mg/kg) significantly reduced tumor volume and weight of ovarian cancer in vivo, decreased caspase-3 expression in tumor tissue, and induced the production of GSDME-N. This study provides a green and efficient atom-economic synthesis method for 1H-Benzo[e]indole-2(3H)-one spirocyclic derivatives and a promising pyroptosis inducer with anti-tumor activity.

Evaluation of nonnatural L-iminosugar C,C-glycosides, a new class of C-branched iminosugars, as glycosidase inhibitors

Capitalizing on a previously developed Staudinger/azaWittig/Grignard (SAWG)-ring contraction sequence that furnished protected six-membered L-iminosugar C,C-glycosides bearing an allyl group and various substituents at the pseudoanomeric position, the synthesis and glycosidase inhibition of a small library of six- and seven-membered L-iminosugar C,C-glycosides is reported. Their hydrogenolysis or cyclization by RCM followed by deprotection afforded eleven L-iminosugars including spirocyclic derivatives. All compounds adopt a 1C4 conformation in solution according to NMR data. Compared to previously reported branched L-iminosugars, the L-iminosugar C,C-glycosides reported herein were less potent glycosidase inhibitors. However, some of these compounds showed micromolar inhibition of human lysosome β-glucocerebrosidase suggesting that such iminosugars could be useful to access potent CGase inhibitors by adjusting the structure/length of the pseudoanomeric substituents.

Inside Back Cover

This cover picture shows a ligand‐controlled, palladium‐catalyzed migration reaction of [60]fullerene with allyloxy‐tethered aryl iodides. Using 1,2‐bis(diphenylphosphino)benzene (DPPBz) as a ligand, the chemoselectivity is switched to synthesize [60]fullerene‐fused allylbenzofurans instead of previous spirocyclic derivatives through a sequential C—O bond cleavage/allyl‐migration/intermolecular cycloaddition cascade process. Such transformation provides a unique and efficient route to rare [60]fullerene‐fused benzofurans. More details are discussed in the article by Liu et al. on page 1733—1739.image

Synthesis of novel pyrimido[4,5-e]indolizine- and pyrimido[5,4-c]quinolizine-6-carboxylic acids

An effective method for the synthesis of previously undescribed 1,3,4,5,6a,7,8,9-octahydropyrimido[4,5-e]indolizine- and 1,3,4,5,7,8,9,10-octahydro-2H-pyrimido[5,4-c]quinolizine-6-carboxylic acids by hydrolysis and decarboxylation of new spiro-substituted derivatives was proposed. The corresponding spirocyclic derivatives were obtained by boiling of 6-dialkylamino-1,3-dimethyl-5-formyluracils with Meldrum's acid in acetonitrile. The reaction proceeds according to the tert-amino effect mechanism without the release of Knoevenagel condensation products

Exploration of Spirocyclic Derivatives of Ciprofloxacin as Antibacterial Agents.

The previously reported as well as newly synthesized derivatives of the 1-oxa-9-azaspiro[5.5]undecane were employed in the synthesis of thirty-six derivatives of ciprofloxacin using commercially available 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and the literature protocol involving the preparation of boron chelate complex to facilitate nucleophilic aromatic substitution. All new fluoroquinolone derivatives were tested against two gram-positive as well as three gram-negative strains of bacteria. With the activity spectrum of the new derivatives being substantially narrower than that of ciprofloxacin, compounds were distinctly active against two of the five strains: gram-negative Acinetobacter baumannii 987® and gram-positive Bacillus cereus 138®. Towards these two strains, a large group of compounds displayed equal or higher potency than ciprofloxacin.

Homochiral Chemistry Strategy To Trigger Dielectric Switching and Second-Harmonic Generation Response on Spirocyclic Derivatives.

Organic-inorganic hybrid materials with switchable properties have significant potential applications in intelligent devices. There are some conventional ways to obtain optical and/or electric multiple responses, such as asymmetric design, chirality, doping, and structural dimension in hybrid materials. Among them, the homochirality strategy is one of the best ways to regulate the molecular structure and symmetry, thereby ensuring second-harmonic generation (SHG) and dielectric dual response characteristics. Here, we report a homochiral design strategy to obtain noncentrosymmetric [R-(HASD)][Cd(SCN)3] (HASD = 7-hydroxy-5-azaspiro[4.5]decan) and [S-(HASD)][Cd(SCN)3]; [Rac-(HASD)][Cd(SCN)3] was also synthesized as a comparative experiment to illustrate the relationship between structural chirality and physical properties. With the help of homochiral regulation, the SHG response is excited and dielectric phase transition temperature (Tc) is also highly improved. In addition, both the optical SHG and dielectric phase change show an optical/electric switchable response. This work is of great significance for the further exploration of multifunctional molecular switching materials through homochiral chemistry.

Construction of Chiral Quaternary Carbon Stereocenters by Asymmetric Michael Addition of 4‐Amido‐5‐hydroxylpyrazoles to Ethylene Sulfonyl Fluoride

AbstractConstruction of chiral quaternary carbon sterocenters especially spirocycles in complex organic molecules is one of the great synthetic challenges. Using a quinine‐derived squaramide catalyst, the enantioselective Michael addition of 4‐amido‐5‐hydroxypyrazoles to ethylene sulfonyl fluoride (ESF) was developed. This method provides a facile strategy to access a series of structurally diverse pyrazolone derivatives with excellent yields and enantioselectivities. The introduction of quaternary carbon stereocenters and sulfonyl fluoride group leads to the valuable candidates for the drug discovery. Furthermore, the products could be transferred to the spirocyclic derivatives under mild reaction conditions without any loss of the enantioselectivities.

Construction of NH-Unprotected Spiropyrrolidines and Spiroisoindolines by [4+1] Cyclizations of γ-Azidoboronic Acids with Cyclic N-Sulfonylhydrazones.

The reactions of N‐sulfonylhydrazones derived from cyclic ketones with γ‐azidopropylboronic acid and 2‐(azidomethyl)phenylboronic acid give rise to spirocyclic pyrrolidines and spiroisoindolines, respectively. The reactions proceed without the need of any transition‐metal catalyst through a domino process that comprises the formation of a Csp3‐C and a Csp3‐N bond of the former hydrazonic carbon. The scope of the reaction has been explored by the preparation of over 50 examples of NH‐unprotected spirocyclic derivatives. Importantly, this methodology could be applied for the preparation of alkaloid steroids from steroid N‐tosylhydrazones.

Construction of NH‐Unprotected Spiropyrrolidines and Spiroisoindolines by [4+1] Cyclizations of γ‐Azidoboronic Acids with Cyclic N‐Sulfonylhydrazones

AbstractThe reactions of N‐sulfonylhydrazones derived from cyclic ketones with γ‐azidopropylboronic acid and 2‐(azidomethyl)phenylboronic acid give rise to spirocyclic pyrrolidines and spiroisoindolines, respectively. The reactions proceed without the need of any transition‐metal catalyst through a domino process that comprises the formation of a Csp3‐C and a Csp3‐N bond of the former hydrazonic carbon. The scope of the reaction has been explored by the preparation of over 50 examples of NH‐unprotected spirocyclic derivatives. Importantly, this methodology could be applied for the preparation of alkaloid steroids from steroid N‐tosylhydrazones.

Synthesis of Purines and Related Molecules by Cyclization ­Reactions of Heterocyclic Enamines

AbstractA great variety of pharmacologically relevant fluorinated purine analogues are available by cyclization reactions of heterocyclic enamines with 1,3-dielectrophiles. The reactions usually proceed with excellent regioselectivities. As electrophiles, 1,3-diketones, enaminones or 3-chloro-2-en-1-ones were used. Other synthetic strategies are based on inverse-electron-demand Diels–Alder reactions of heterocyclic enamines with triazines. Purine analogues were further functionalized by transition-metal-catalyzed CH-coupling reactions or oxidative cyclizations, giving rise to more complex polycyclic products. Amidino-C-glycosides in their reactions with 1,3-dielectrophiles afforded pyrimidine-C-glycosides. Multicomponent reactions of heterocyclic enamines afforded complex products, including spirocyclic derivatives.1 Introduction2 1,3-Diketones3 Enaminones4 3-Chloro-2-en-1-ones5 Triazines6 Transition-Metal-Catalyzed Functionalizations7 Pyrimidine-C-Nucleosides8 Multicomponent Reactions9 Conclusions

Synthesis of α-substituted 2-(1H-1,2,4-triazol-3-yl)acetates and 5-amino-2,4-dihydro-3H-pyrazol-3-ones via the Pinner strategy

A series of 2-(1H-1,2,4-triazol-3-yl)acetates, as well as 4-mono- and 4,4-disubstituted 5-amino-2,4-dihydro-3H-pyrazol-3-ones (including spirocyclic derivatives) have been synthesized using the Pinner reaction strategy. α-Mono- and α,α-disubstituted ethyl cyanoacetates were converted into the corresponding carboxyimidate salts that served as the key intermediates. Their further reaction with formylhydrazide or hydrazine hydrate provided triazolylacetates or aminopyrazolones (including spirocyclic derivatives), depending on the structure of the starting Pinner salt and the nature of the nucleophile. The scope and limitations of the developed synthetic method have been established.

Spirocyclic derivatives as antioxidants: a review.

In recent years, spiro compounds have attracted significant interest in medicinal chemistry due to their numerous biological activities attributed primarily to their versatility and structural similarity to important pharmacophore centers. Currently, the development of drugs with potential antioxidant activities is of great importance since numerous investigations have shown that oxidative stress is involved in the development and progression of numerous diseases such as cancer, senile cataracts, kidney failure, diabetes, high blood pressure, cirrhosis, and neurodegenerative diseases, among others. This article provides an overview of the synthesis and various antioxidant activities found in naturally occurring and synthetic spiro compounds. Among the antioxidant activities reviewed are DPPH, ABTS, FRAP, anti-LPO, superoxide, xanthine oxidase, peroxide, hydroxyl, and nitric oxide tests, among others. Molecules that presented best results for these tests were spiro compounds G14, C12, D41, C18, C15, D5, D11, E1, and C14. In general, most active compounds are characterized for having at least one oxygen atom; an important number of them (around 35%) are phenolic compounds, and in molecules where this functional group was absent, aryl ethers and nitrogen-containing functional groups such as amine and amides could be found. Recent advances in the antioxidant activity profiles of spiro compounds have shown that they have a significant position in discovering drugs with potential antioxidant activities.

Synthesis of 4,4‐Disubstituted 1,2‐Thiazinane‐5‐one 1,1‐Dioxides via the CSIC[≠]Reaction Strategy

AbstractA series ofsp3‐enriched 2,2‐disubstituted 1,2‐thiazinane‐5‐one 1,1‐dioxides (including spirocyclic derivatives) has been synthesized through the CSIC [Carbanion mediated Sulfonate (Sulfonamido) Intramolecular Cyclization] reaction strategy. In particular, 2,2‐disubstituted alkyl 3‐aminopropanoates were subsequently sulfonylated with mesyl chloride followed by alkylation with methyl iodide to give the key precursor 2,2‐disubstituted methyl 3‐(methylsulfonamido)propanoates. The latter were treated with sodium hydride and underwent the intramolecular sulfa‐Dieckmann cyclization yielding the target 4,4‐disubstituted 1,2‐thiazinane‐5‐one 1,1‐dioxides (so‐called β‐keto‐δ‐sultams). The structure of the target compounds was confirmed by an X‐ray diffraction study.

Gold-Catalyzed Spirocyclization Reactions of N-Propargyl Tryptamines and Tryptophans in Aqueous Media.

N-Propargyl tryptamine and tryptophan derivatives that are readily available from both synthetic and biocatalytic approaches undergo gold-catalyzed dearomative cyclizations in aqueous media to the corresponding spirocyclic derivatives. In addition to the efficiency of the method, operating in aqueous media affords a selective entry to C2-unsubstituted spiroindolenines that have long remained unattainable by Au(I) catalysis. Moderate to excellent yields of the desired spirocyclic products bearing various substituents were obtained.

Spiro N-oxidized pyrrolidone-appended hemicyanine: Synthesis, lower pH-sensing and colormetric temperature sensing

Three novel spiro N-oxidized pyrrolidone-appended hemicyanine derivatives have been synthesized and characterized by 1H NMR, 13C NMR, UV–Vis and HRMS. The molecular structures of spirocyclic dye 2a and its opening-ring product 2aa have been determined by single-crystal X-ray diffraction analysis. The UV–vis spectra show significant solvatochromic behavior of three spirocyclic derivatives, especially in acidic and alkaline solvents. Spirocyclic dye 2a displays an excellent pH dependent behavior and responds linearly to extreme acidic conditions in the pH ranges of 1-4. The absorption spectra studies on opening-ring reaction reveal that acid and heat dual stimulation can induce opening-ring of 2a, which exhibits temperature-responsive linear in the range of 25–45 °C, behaving a colorimetric thermometer sensing. These properties provide the possibility for 2a-c to be used as stimulating response molecule switch.

Investigation of bisphenol-substituted spirocyclic phosphazenes as cotton textile–based flame retardants

Bisphenol-substituted spirocyclic phosphazene derivatives were synthesized in 85%–94% yields and analyzed for flame retardant application to cotton fabric using Limiting Oxygen Index, Fourier transform infrared thermogravimetric analysis, differential scanning calorimetry, microscale combustion calorimetry, thermogravimetric analysis, and scanning electron microscopy. The thermogravimetric analysis methods indicate a decomposition pathway consistent for phosphorus-nitrogen-containing compounds. Levoglucosan phosphorylation and carbonaceous char formation were observed. Limiting Oxygen Index testing of these compounds on cotton-based fabrics showed improved flame resistance compared to untreated fabrics.

Synthesis and Antimicrobial Evaluation of Novel Triazole, Tetrazole, and Spiropyrimidine-Thiadiazole Derivatives

The aim of the present work was the synthesis of some new heterocyclic compounds derived from 6-(2,4-dimethyl-3H-benzo[f][1,3,5]triazepin-3-yl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1) and 6-(2,4-dimethyl-3H-benzo[f][1,3,5]triazepin-3-yl)-2-hydrazinyl- pyrimidin-4(3H)-one (3). A series of novel triazole, tetrazole, and spirocyclic (pyrimidine and thiadiazole) derivatives were synthesized in moderate to excellent yields (61%–95%). The products were obtained under moderate reaction conditions. The structures of the new compounds were confirmed using different spectroscopic methods such as UV, IR, NMR, MS, and elemental analysis. The in vitro antimicrobial activity was evaluated for the synthesized compounds against Gram-positive bacteria (Rhodopseudomonas fp., Bacillus cereus, and Micrococcus luteus) and Gram-negative bacteria (Escherichia coli (HD 701) and Salmonella typhi) as well as fungi including Alternaria alternate, Aspergillus flavus (ATCC-24556), Candida albicans (ATCC 15056) and Curvularia lunata. Benzo[f][1,3,5]triazepine derivatives exhibited potent antimicrobial activity against Gram-positive, and Gram-negative bacteria and fungi (MIC 1–11 µmol L−1) and the results were comparable to the positive controls levofloxacin (MIC 2–5 µmol L−1) and nystatin (MIC 1–3 µmol L−1).