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The click reaction of propargylisatins with some azido-sugars was used to synthesize new isatin derivatives, in which the carbohydrate residue is linked to the 2,3-dioxindole scaffold via the 1,2,3-triazole ring. A number of water-soluble acylhydrazones with various structure of cationic fragment were obtained on their basis. It was shown that the newly obtained compounds do not exhibit hemotoxic action and have a significant antiaggregatory and anticoagulant activity at the level of reference drugs such as acetylsalicylic acid and pentoxifylline.

The dependence of the level of antimicrobial activity of some ammonium isatin-3-acylhydrazones on the sterical hindrance and electronic nature of substituents in the benzyl moiety was elucidated using simple molecular descriptors and quantum chemical calculations. The structure and electronic nature of substituents in position 1 and the lipophilicity of compounds of this series were shown to be the key factors determining the activity.

The reaction of 1-acylisatins with Girard’s reagent T proceeds with elimination of the acyl substituent and the formation of isatin-3-hydrazone with a quaternary nitrogen atom in the side chain. Depending on the structure of the substituent in position 1, 1-(aminomethyl)isatins reacted with the Girard’s reagent T to form hydrazones either with the elimination of the aminomethyl substituent or with its retention. Isatin derivatives containing no substituents in the aromatic fragment exhibit moderate activity against gram-positive bacteria S. aureus 209p and B. cereus 8035. Low hemotoxicity of the obtained compounds was revealed.

The synthesis of new isatin derivatives containing the 1,2,3-thiadiazole ring in the hydrazone fragment was carried out. It was shown that the obtained compounds do not possess a hemolytic effect and do not exhibit cytotoxicity with respect to normal Chang liver human cell lines.

Water-soluble 1-(3,5-di-tert-butyl-4-hydroxybenzyl)isatin 3-acylhydrazones containing an acyclic, bicyclic, or pyridinium quaternary ammonium center in the acyl moiety showed antibacterial activity against some gram-positive bacteria. Derivatives with a 2,3-dimethylpyridine or diazabicyclooctane fragment exhibited the highest activity against S. aureus and B. cereus as expressed by the minimum bactericidal concentration and were 4 times more active than chloramphenicol.

Water-soluble trialkylammonium isatin-3-hydrazone derivatives bearing phenolic substituent were easily synthesized with high yields. XRD studies confirmed the presence of these compounds as trans-(Z)-isomers in a crystal. It was shown that an increase in the lipophilicity of the cationic center leads to an increase in activity against Gram-positive bacteria Staphylococcus aureus and Bacillus cereus, including methicillin-resistant Staphylococcus aureus (MRSA) strains. The MIC values of all compounds turned out to be 2-100 times higher than the MIC of norfloxacin against the MRSA strains in the absence of hemo- and cytotoxicity. Antiaggregation and anticoagulation properties were in vitro better than for acetylsalicylic acid and sodium heparin drugs. It has been shown by UV spectroscopy and fluorescence microscopy that the mechanism of antimicrobial action of new acylhydrazones is associated with their ability to destroy the bacterial cell membrane.

The introduction of enzyme nanoreactors in medicine is relatively new. However, this technology has already been experimentally successful in cancer treatments, struggle against toxicity of reactive oxygen species in inflammatory processes, detoxification of drugs and xenobiotics, and correction of metabolic and genetic defects by using encapsulated enzymes, acting in single or cascade reactions. Biomolecules, e.g. enzymes, antibodies, reactive proteins capable of inactivating toxicants in the body are called bioscavengers. In this review, we focus on enzyme-containing nanoreactors for in vivo detoxification of organophosphorous compounds (OP) to be used for prophylaxis and post-exposure treatment of OP poisoning. A particular attention is devoted to bioscavenger-containing injectable nanoreactors operating in the bloodstream. The nanoreactor concept implements single or multiple enzymes and cofactors co-encapsulated in polymeric semi-permeable nanocontainers. Thus, the detoxification processes take place in a confined space containing highly concentrated bioscavengers. The article deals with historical and theoretical backgrounds about enzymatic detoxification of OPs in nanoreactors, nanoreactor polymeric enveloppes, realizations and advantages over other approaches using bioscavengers.

The increase in the resistance of pathogens, in particular Staphylococcus aureus, to the action of antibiotics necessitates the search for new readily available and non-toxic drugs. In solving this problem, phenolic acylhydrazones have high potential. In this communication, the synthesis of quaternary ammonium compounds containing a differently substituted phenolic moiety has been performed. An initial study of antimicrobial activity showed that these compounds are highly selective against S. aureus and B. cereus. The highest activity (MIC 2.0 μm) was shown by hydrazones containing a catechol fragment. These compounds are more than 3-fold more active against S. aureus and 3-10-fold more active against B. cereus than norfloxacin. Low hemolytic and high antioxidant activities of all new compounds were also established.

Isatin derivatives containing a 4-nitrophenyl group in the side chain or a nitro group in the aromatic fragment reacted with tris(diethylamino)phosphine to give the corresponding isoindigo derivatives with high yields and chemoselectivity.

A mild and effective method for the synthesis of new tetraarylphosphonium zwitterions and salts containing methoxy and hydroxy groups in aryl substituents at the phosphorus atom was developed. The structure of phosphorus-containing betaines and phosphonium salts was obtained by NMR spectroscopy.

Here we present the consecutive study of colloid systems formed by novel isatin derivative as compound with high pharmacological potential and series of carboxyresorcinarenes. The azo-modified isatin derivative bearing ammonium moiety (I-3) was synthesized and its antimicrobial activity was investigated. To increase its solubility the solubilization experiment using amphiphilic carboxyresorcinarenes, characterized by low hemolytic activity, was carried out. The I-3 – macrocycles systems were studied by NMR, UV–vis, DLS and TEM. The FT PGSE and 2D NOESY NMR methods demonstrated, that solubilization of I-3 is caused by the incorporation of its molecules in the hydrophobic part of the macrocycles associates. Herewith the loading efficiency of I-3 into the macrocycles associates was reached of 20–30% due to the change of the volume of hydrophobic part of associates by varying the length and structure of hydrophobic substituents of macrocyclic amphiphiles.

Isatin derivatives are widely used in organic synthesis, in medicinal chemistry and in the chemistry of materials. This report summarizes modern trends in the synthesis of substituted indolin-2,3-diones covering the literature from 2007 to 2017. Studies on the influence of the structure of substituents in the initial substrates on the formation of the heterocyclic isatin system and the yields of the target compounds are also discussed.1 Introduction2 Oxidation of Indole Derivatives3 Cyclization of o-Aminoacetophenones4 Cyclization of N-Acylanilines5 Miscellaneous6 Conclusion

Condensation reactions of isatin derivatives with 3,5-di(tert-butyl)-4-hydroxybenzyl acetate and the Girard’s reagent T has afforded a series of novel water-soluble isatin-3-acyl hydrazones containing a sterically hindered phenolic fragment in position 1 of the heterocycle; antimicrobial activity of the products has been estimated. It has been shown that the isatin derivatives with bromine or methoxy substituent in the benzo fragment as well as the acyl hydrazones containing 5-methyl or 5-ethyl group are the most active against Staphylococcus aureus and Bacillus cereus.

Mild opening of the five-membered ring in 1-acetylisatins by the action of an equimolar amount of 4,4-diethoxybutan-1-amine afforded 2-(2-acetamidophenyl)-N-(4,4-diethoxybutyl)-2-oxoacetamides in almost quantitative yield.

By acid-catalyzed reaction of substituted isatins with Girard’s reagent T, new water-soluble isatin-3-acylhydrazones were obtained with high yields. Their antimicrobial activity was evaluated. Selective activity against Gram-positive bacteria (S. aureus 209p and B. cereus 8035) and yeast-like fungus Candida albicans 855–653 along with low hematoxicity was established.

Over the last decade isoindigo derivatives have attracted much attention due to their high potential in pharmacy and in the chemistry of materials. In addition, isoindigo derivatives can be modified to form supramolecular structures with tunable morphologies for the use in drug delivery. Amphiphilic long-chain dialkylated isoindigos have the ability to form stable solid nanoparticles via a simple nanoprecipitation technique. Their self-assembly was investigated using tensiometry, dynamic light scattering, spectrophotometry, and fluorometry. The critical association concentrations and aggregate sizes were measured. The hydrophilic–lipophilic balance of alkylated isoindigo derivatives strongly influences aggregate morphology. In the case of short-chain dialkylated isoindigo derivatives, supramolecular polymers of 200 to 700 nm were formed. For long-chain dialkylated isoindigo derivatives, micellar aggregates of 100 to 200 nm were observed. Using micellar surfactant water-soluble forms of monosubstituted 1-hexadecylisoindigo as well as 1,1′-dimethylisoindigo were prepared for the first time. The formation of mixed micellar structures of different types in micellar anionic surfactant solutions (sodium dodecyl sulfate) was determined. These findings are of practical importance and are of potential interest for the design of drug delivery systems and new nanomaterials.

New isatin derivatives bearing benzotriazole substituent at the endocyclic nitrogen atom were synthesized. The resulting compounds and trimethylammonium acylhydrazones on their basis show a pronounced antimicrobial activity.

This microreview compiles the methods of opening of 1-acylisatin ring in reactions with primary and secondary amines published over the past 8 years.

The first examples of phosphorus-containing analogues of natural alkaloids, convolutamydines, have been obtained by aldol condensation of 4-[dialkyl(diphenyl)phosphoryl]-4-methylpentan-2-one with isatin. An unusually facile reversible process of dehydration–hydration of these phosphorus-containing hydroxy indoles has been discovered.

Depending on the structure of the substituent at the endocyclic nitrogen atom, the reactions of aminomethylisatins with the Girard’s reagent T can proceed both with the elimination of the aminomethyl group and with its retention resulting in the formation of the corresponding positively charged isatin-3-acylhydrazones.

Reactions of 1-chloroacetyloxindole and 1-chloroacetylisatin with some secondary amines, Girard’s reagent T and thiourea were studied. All investigated reactions proceeded via cleavage of the acyl group to form 3-substituted isatin or oxindole derivatives.

A Mannich reaction of isatin with monosubstituted piperazines in the presence of aqueous formaldehyde was used to synthesize new, as well as two previously described derivatives of 1-piperazinomethylisatins, which were further converted to isoindigo derivatives. The antimicrobial activity of the obtained heterocycles was evaluated.

Reactions of tris(diethylamino)phosphine with indanetrione, 2-diazoindane-1,3-dione, 2-diazodimedone, and pyrimidine-2,4,5,6(1H,3H)-tetraone (alloxan) afforded crystalline adducts of bipolar type, whose structure was established by X-ray diffraction analysis.

Oxidation of alkyl- and alkenylisatins with m-chloroperbenzoic acid proceeds with high chemoselectivity leading to the formation of 1-substituted isatoic anhydrides (benzo[d][1,3]oxazine-2,4-diones) without epoxidation of the double bond of the alkenyl substituent. This result is in accordance with the data of DFT quantum chemical calculations using the B3LYP functional in conjunction with the basis set of atomic orbitals 6-31G(d,p). The structure of the synthesized heterocyclic compounds was proved by NMR and X-ray diffraction data.

Synthetic approaches towards isoindigo derivatives and their application in medicinal chemistry as well as in the chemistry of materials are reviewed. The literature data up to 2014 are covered.

A Pfitzinger reaction of isatin with 2-methyl-(4-oxopent-2-yl)dialkyl(diphenyl)phosphine oxides was used to synthesize new derivatives of 4-quinolinecarboxylic acids, containing a phosphine oxide fragment, and screening for antimicrobial activity was performed.

In this review we generalize and analyze information about reactions between isatin and three-, four-, and five-coordinate phosphorus compounds, published between 1966 and 2014.

A series of isatin derivatives were synthesized and studied by XRD. For the first time the peculiarities of the molecule structure and crystal packing effects were analyzed. Indoline heterocycles are planar in all the investigated structures. The molecules bearing the sterically hindered substituents at nitrogen atom of indoline heterocycle have the maximum deviations of two oxygen atoms from the indoline plane. The substituent nature at nitrogen atom does not effect on the bond lengths of indoline moiety. The value of endocyclic bond angle at nitrogen not so strongly depends on the substituent and is almost equal to the one in unsubstituted isatin. In contrast to the unsubstituted isatin, where the system of classical hydrogen N H⋯O-bonds is realized, in crystals of investigated compounds there is no opportunity to reveal ones, and the crystal structure is stabilized by C H⋯O- and π–π-interactions.

The features of the synthesis of long-chain isatin and isoindigo derivatives were demonstrated by the example of bromododecyl representatives. It was shown that the synthesis of bromododecylisatin was accompanied by the formation of the bis-isatin even at low temperatures. The deoxygenation of 1-(12-bromododecyl)isatin by tris(diethylamino)phosphine led to the formation of novel bis(bromoalkyl)isoindigo which easily reacted with nucleophilic reagents resulting in amino- or chloro-derivatives and phosphonium salts. The reaction of 1,1′-bis(bromododecyl)isoindigo with isatin sodium salt in slightly alkaline medium afforded mainly IZIN-12 and bis(2,3-dioxindolin-1-yl)isoindigo. In addition, several unexpected products were separated from this reaction. .

The reaction of diverse symmetrically-substituted isoindigo derivatives with 80% aqueous hydrazine hydrate is described. The influence of the structure of the substituent on either oxindole or isatin-3-hydrazone formation is discussed.

Depending on the substituent on the phosphorus(III) atom, reactions of tris(dialkylamino)phosphines, 2-diethylamino-1,3,2-benzodioxaphosphole, and benzene-1,4-diylbis(N,N,N′,N′-tetraethylphosphonous diamide) with 1-alkylisatins lead to the formation of isoindigo derivatives, spirophosphoranes, or spirooxiranes whose structure was determined by NMR spectroscopy and X-ray analysis.

An easy, high-yield and atom-economic procedure of a C60 fullerene modification using a reaction of fullerene C60 with N-alkylisatins in the presence of tris(diethylamino)phosphine to form novel long-chain alkylindolinone-substituted methanofullerenes (AIMs) is described. Optical absorption, electrochemical properties and solubility of AIMs were studied. Poly(3-hexylthiophene-2,5-diyl) (P3HT)/AIMs solar cells were fabricated and the effect of the AIM alkyl chain length and the P3HT:AIM ratio on the solar cell performance was studied. The power conversion efficiencies of about 2% were measured in the P3HT/AIM devices with 1:0.4 P3HT:AIM weight ratio for the AIMs with hexadecyl and dodecyl substituents. From the optical and AFM data, we suggested that the AIMs, in contrast to [6,6]-phenyl-C61-butyric acid methyl ester (PCBM), do not disturb the P3HT crystalline domains. Moreover, the more soluble AIMs do not show a better miscibility with the P3HT crystalline phase.

A mild, catalyst-free and simple synthesis of 1,1′-di(n-alkyl)-isoindigo via the reaction of substituted isatins with tris(diethylamino)phosphine is reported. Their self-assembly in water–DMF (50% v/v) solution was investigated. Unexpectedly, no surface activity was observed for compound 2h. Spectrophotometry and fluorimetry allowed determining critical micelle concentration (0.1 mM and 0.8 mM respectively). Aggregation numbers of 8 and sizes of aggregates were determined.

A series of 1-fluorobenzylated isatins and water-soluble pyridinium isatin-3-acylhydrazones on their base were obtained. The biological evaluation of novel hydrazones showed a significant dependence of their antimicrobial activity on the position of fluorine atom in benzyl substituent. The best activity showed compounds containing a 2-fluoro-6-chlorobenzyl fragment with selective action against S. aureus. The absence of hemotoxicity of both fluorine-containing products and their some non-fluorinated analogues was shown.

This work deals with polyfunctional biocompatible amphiphilic isatin derivatives. Isatin-3-acylhydrazones containing a quaternary ammonium moiety (Is-Q-n) with varying hydrophobicity (R = CnH2n+1, where n = 10, 12, 14, 16, 18, 20) were synthesized. Tunable self-assembly behavior, morphology of nanostructures, and their biological activity were modulated by hydrophilic-lipophilic balance of π-amphiphiles and solvent polarity. Self-assembly of Is-Q-n was investigated by tensiometry, conductometry, IR and UV–Vis spectroscopy, fluorimetry and dynamic light scattering. The unexpected values of the physicochemical parameters at long alkyl chain length have been interpreted. The CAC of Is-Q-16 is lower than CMC of classical surfactant CTAB. Solvent-induced self-assembly for Is-Q-16 was observed. The hydrophobic dye Orange OT was solubilized in Is-Q-10 solutions twice better than in CTAB solutions. Is-Q-n self-assembled structures with size 50 nm and 100 nm in a concentration range from 0.01 mM (below CAC) to 10 mM were found. Is-Q-10 forms small associates with size 3 nm. Selective antimicrobial activity of low toxic ammonium salts against Gram-positive bacteria (S. aureus 209p and B. cereus 8035) and fungus Candida albiсans 855–653 was shown. Newly synthesized 1-dodecylisatin derivatives containing a quaternary ammonium moiety may be recommended as antimicrobial agents and for drug solubilization, in particular for drugs capable for π-π stacking interactions.

The Mannich reaction of isatin with different primary and secondary amines and effect of the substituent in aromatic amines on the reaction pathway is studied. The efficient high-yield synthesis of novel isoindigo derivatives by the mild deoxygenation reaction of the corresponding isatins with tris(diethylamino)phosphine is described.

Regioselective bromination of 4-phenyl-2,7-dichloro-2H-chryseno[6,5-e][1,2]phosphinine 2-oxide proceeded in the position 3 with the formation of 3-bromo-4-phenyl-2,7-dichloro-2H-chryseno[6,5-e][1,2] phosphinine 2-oxide; the structure of its 2-tert-butylamino derivative was established by XRD analysis and correlation spectroscopy.