Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis.

The utility of sterically hindered phenols (SHPs) in drug design is based on their chameleonic ability to switch from an antioxidant that can protect healthy tissues to highly cytotoxic species that can target tumor cells. This work explores the biological activity of a family of 45 new hybrid molecules that combine SHPs equipped with an activating phosphonate moiety at the benzylic position with additional urea/thiourea fragments. The target compounds were synthesized by reaction of iso(thio)cyanates with C-arylphosphorylated phenols containing pendant 2,6-diaminopyridine and 1,3-diaminobenzene moieties. The SHP/urea hybrids display cytotoxic activity against a number of tumor lines. Mechanistic studies confirm the paradoxical nature of these substances which combine pronounced antioxidant properties in radical trapping assays with increased reactive oxygen species generation in tumor cells. Moreover, the most cytotoxic compounds inhibited the process of glycolysis in SH-SY5Y cells and caused pronounced dissipation of the mitochondrial membrane of isolated rat liver mitochondria. Molecular docking of the most active compounds identified the activator allosteric center of pyruvate kinase M2 as one of the possible targets. For the most promising compounds, 11b and 17b, this combination of properties results in the ability to induce apoptosis in HuTu 80 cells along the intrinsic mitochondrial pathway. Cyclic voltammetry studies reveal complex redox behavior which can be simplified by addition of a large excess of acid that can protect some of the oxidizable groups by protonations. Interestingly, the re-reduction behavior of the oxidized species shows considerable variations, indicating different degrees of reversibility. Such reversibility (or quasi-reversibility) suggests that the shift of the phenol-quinone equilibrium toward the original phenol at the lower pH may be associated with lower cytotoxicity.

One-Step Synthesis of Functionalized Pyrazolo[3,4-b]pyridines via Ring Opening of the Pyrrolinium Ion.

Herein, we report a highly regioselective one-pot synthesis of pyrazolo[3,4-b]pyridines via the reaction of 3-arylidene-1-pyrrolines with aminopyrazoles. The reaction proceeds through the sequential nucleophilic addition/electrophilic substitution/C-N bond cleavage and provides easy access to pyrazolo[3,4-b]pyridine derivatives featuring a primary amino group. Moreover, the reaction can be terminated at the electrophilic substitution stage, thus providing convenient entry to the hardly accessible pyrazolopyrrolopyridine scaffold.

Copper(II) Chelates of Schiff Bases Enriched with Aliphatic Fragments: Synthesis, Crystal Structure, In Silico Studies of ADMET Properties and a Potency against a Series of SARS-CoV-2 Proteins.

We report two complexes [Cu(LI)2] (1) and [Cu(LII)2] (2) (HLI = N-cyclohexyl-3-methoxysalicylideneimine, HLII = N-cyclohexyl-3-ethoxysalicylideneimine). The ligands in both complexes are trans-1,5-N,O-coordinated, yielding a square planar CuN2O2 coordination core. The molecule of 1 is planar with two cyclohexyl groups oriented to the opposite sites of the planar part of a molecule, while the molecule of 2 is significantly bent with two cyclohexyl groups oriented to the same convex site of a molecule. It was established that both complexes in MeOH absorb in the UV region due to intraligand transitions and LMCT. Furthermore, the UV-vis spectra of both complexes revealed two low intense shoulders in the visible region at about 460 and 520 nm, which were attributed to d-d transitions. Both complexes were predicted to belong to a fourth class of toxicity with the negative BBB property and positive gastrointestinal absorption property. According to the molecular docking analysis results, both complexes are active against all the applied SARS-CoV-2 proteins with the best binding affinity with Nsp 14 (N7-MTase), PLpro and Mpro. The obtained docking scores of complexes are either comparable to or even higher than those of the initial ligands. Complex 1 was found to be more efficient upon interaction with the applied proteins in comparison to complex 2. Ligand efficiency scores for the initial ligands, 1 and 2 were also revealed.

A Novel Ambroxol-Derived Tetrahydroquinazoline with a Potency against SARS-CoV-2 Proteins.

We report synthesis of a novel 1,2,3,4-tetrahydroquinazoline derivative, named 2-(6,8-dibromo-3-(4-hydroxycyclohexyl)-1,2,3,4-tetrahydroquinazolin-2-yl)phenol (1), which was obtained from the hydrochloride of 4-((2-amino-3,5-dibromobenzyl)amino)cyclohexan-1-ol (ambroxol hydrochloride) and salicylaldehyde in EtOH. The resulting compound was produced in the form of colorless crystals of the composition 1∙0.5EtOH. The formation of the single product was confirmed by the IR and 1H spectroscopy, single-crystal and powder X-ray diffraction, and elemental analysis. The molecule of 1 contains a chiral tertiary carbon of the 1,2,3,4-tetrahydropyrimidine fragment and the crystal structure of 1∙0.5EtOH is a racemate. Optical properties of 1∙0.5EtOH were revealed by UV-vis spectroscopy in MeOH and it was established that the compound absorbs exclusively in the UV region up to about 350 nm. 1∙0.5EtOH in MeOH exhibits dual emission and the emission spectra contains bands at about 340 and 446 nm upon excitation at 300 and 360 nm, respectively. The DFT calculations were performed to verify the structure as well as electronic and optical properties of 1. ADMET properties of the R-isomer of 1 were evaluated using the SwissADME, BOILED-Egg, and ProTox-II tools. As evidenced from the blue dot position in the BOILED-Egg plot, both human blood-brain barrier penetration and gastrointestinal absorption properties are positive with the positive PGP effect on the molecule. Molecular docking was applied to examine the influence of the structures of both R-isomer and S-isomer of 1 on a series of the SARS-CoV-2 proteins. According to the docking analysis results, both isomers of 1 were found to be active against all the applied SARS-CoV-2 proteins with the best binding affinities with Papain-like protease (PLpro) and nonstructural protein 3 (Nsp3_range 207-379-AMP). Ligand efficiency scores for both isomers of 1 inside the binding sites of the applied proteins were also revealed and compared with the initial ligands. Molecular dynamics simulations were also applied to evaluate the stability of complexes of both isomers with Papain-like protease (PLpro) and nonstructural protein 3 (Nsp3_range 207-379-AMP). The complex of the S-isomer with Papain-like protease (PLpro) was found to be highly unstable, while the other complexes are stable.

Heteroligand α-Diimine-Zn(II) Complexes with O,N,O'- and O,N,S-Donor Redox-Active Schiff Bases: Synthesis, Structure and Electrochemical Properties.

A number of novel heteroligand Zn(II) complexes (1-8) of the general type (Ln)Zn(NN) containing O,N,O'-, O,N,S-donor redox-active Schiff bases and neutral N,N'-chelating ligands (NN) were synthesized. The target Schiff bases LnH2 were obtained as a result of the condensation of 3,5-di-tert-butyl-2-hydroxybenzaldehyde with substituted o-aminophenols or o-aminothiophenol. These ligands with combination with 2,2'-bipyridine, 1,10-phenanthroline, and neocuproine are able to form stable complexes upon coordination with zinc(II) ion. The molecular structures of complexes 4∙H2O, 6, and 8 in crystal state were determined by means of single-crystal X-ray analysis. In the prepared complexes, the redox-active Schiff bases are in the form of doubly deprotonated dianions and act as chelating tridentate ligands. Complexes 6 and 8 possess a strongly distorted pentacoordinate geometry while 4∙H2O is hexacoordinate and contains water molecule coordinated to the central zinc atom. The electrochemical properties of zinc(II) complexes were studied by the cyclic voltammetry. For the studied complexes, O,N,O'- or O,N,S-donor Schiff base ligands are predominantly involved in electrochemical transformations in the anodic region, while the N,N'-coordinated neutral nitrogen donor ligands demonstrate the electrochemical activity in the cathode potential range. A feature of complexes 5 and 8 with sterically hindered tert-butyl groups is the possibility of the formation of relatively stable monocation and monoanion forms under electrochemical conditions. The values of the energy gap between the boundary redox orbitals were determined by electrochemical and spectral methods. The parameters obtained in the first case vary from 1.97 to 2.42 eV, while the optical bang gap reaches 2.87 eV.

Diastereoselective Synthesis of Novel Spiro-Phosphacoumarins and Evaluation of Their Anti-Cancer Activity.

Herein we present the regio- and diastereoselective synthesis of novel pyrrolidine-fused spiro-dihydrophosphacoumarins via intermolecular [3 + 2] cycloaddition reaction. The presented approach is complementary to existing ones and provides an easy entry to the otherwise inaccessible derivatives. Additionally, the unprecedented pathway of the reaction of 4-hydroxycoumarin with azomethine ylides is described. The anti-cancer activity of the obtained compounds was tested in vitro, the most potent compound being 2.6-fold more active against the HuTu 80 cell line than the reference 5-fluorouracil, with a selectivity index > 32.

Enamine-mediated Mannich reaction of cyclic N,O-acetals and amido acetals: the multigram synthesis of pyrrolidine alkaloid precursors.

The cooperative L-proline/Brønsted acid/base promoted reaction of 2-ethoxypyrrolidines or N-substituted 4,4-diethoxybutan-1-amines with methyl(alkyl/aryl)ketones for the synthesis of 2-(acylmethylene)pyrrolidine derivatives is reported. The key features of the developed protocol are gram-scale synthesis of the target compounds, easily available starting materials, operational simplicity and usage of non-expensive reagents.

One-Pot Synthesis of Novel Functionalized Fused Pyridine Derivatives via Consecutive Pyrrolidine Ring-Closure/Ring-Opening/Formal Aza-Diels-Alder Reactions.

In this article, we report a highly regioselective method for the synthesis of new fused pyridine derivatives─2,3-disubstituted quinolines and 1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one derivatives. The method is based on the reaction of 1,1-diethoxybutane derivatives with aromatic and heterocyclic nucleophiles. The isolated compounds are similar to the products formed as a result of the Debner-Miller reaction. However, we have shown that the interaction of 1,1-diethoxybutane derivatives with (hetero)aromatic amines proceeds according to a mechanism different from that of the Doebner-Miller reaction. The proposed method is distinguished by the possibility of obtaining a wide range of substituted quinolines and 1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one derivatives in one step, the absence of the need to use expensive metal-containing catalysts, and a high product yield.

Change in the Electronic Structure of the Cobalt(II) Ion in a One-Dimensional Polymer with Flexible Linkers Induced by a Structural Phase Transition.

A new 1D-coordination polymer [Co(Piv)2(NH2(CH2)6NH2)]n (1, Piv is Me3CCO2- anion) was obtained, the mononuclear fragments {Co(O2CR)2} within which are linked by µ-bridged molecules of hexamethylenediamine (NH2(CH2)6NH2). For this compound, two different monoclinic C2/c (α-1) and P2/n (ß-1) phases were found at room temperature by single-crystal X-ray diffraction analysis, with a similar structure of chains and their packages in unit cells. The low-temperature phase (γ-1) of crystal 1 at 150 K corresponds to the triclinic space group P-1. As the temperature decreases, the structural phase transition (SPT) in the α-1 and ß-1 crystals is accompanied by an increase in the crystal packing density caused by the rearrangements of both H-bonds and the nearest ligand environment of the cobalt atom ("octahedral CoN2O4 around the metal center at room temperature" → "pseudo-tetrahedral CoN2O2 at 150 K"). The SPT was confirmed by DSC in the temperature range 210-150 K; when heated above 220 K, anomalies in the behavior of the heat flow are observed, which may be associated with the reversibility of SPT; endo effects are observed up to 300 K. The SPT starts below 200 K. At 100 K, a mixture of phases was found in sample 1: 27% α-1 phase, 61% γ-1 phase. In addition, at 100 K, 12% of the new δ-1 phase was detected, which was identified from the diffraction pattern at 260 K upon subsequent heating: the a,b,c-parameters and unit cell volume are close to the structure parameters of γ-1, and the values of the α,ß,γ-angles are significantly different. Further heating leads to a phase transition from δ-1 to α-1, which both coexist at room temperature. According to the DC magnetometry data, during cooling and heating, the χMT(T) curves for 1 form a hysteresis loop with ~110 K, in which the difference in the χMT values reaches 9%. Ab initio calculations of the electronic structure of cobalt(II) in α-1 and γ-1 have been performed. Based on the EPR data at 10 K and the ab initio calculations, the behavior of the χMT(T) curve for 1 was simulated in the temperature range of 2-150 K. It was found that 1 exhibits slow magnetic relaxation in a field of 1000 Oe.

Isatin-3-acylhydrazones with Enhanced Lipophilicity: Synthesis, Antimicrobial Activity Evaluation and the Influence on Hemostasis System.

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 Highly Regioselective Synthesis of Novel Imidazolidin-2-Ones via the Intramolecular Cyclization/Electrophilic Substitution of Urea Derivatives and the Evaluation of Their Anticancer Activity.

A series of novel 4-(het)arylimidazoldin-2-ones were obtained by the acid-catalyzed reaction of (2,2-diethoxyethyl)ureas with aromatic and heterocyclic C-nucleophiles. The proposed approach to substituted imidazolidinones benefits from excellent regioselectivity, readily available starting materials and a simple procedure. The regioselectivity of the reaction was rationalized by quantum chemistry calculations and control experiments. The anti-cancer activity of the obtained compounds was tested in vitro.

Molecular and Polymer Ln2M2 (Ln = Eu, Gd, Tb, Dy; M = Zn, Cd) Complexes with Pentafluorobenzoate Anions: The Role of Temperature and Stacking Effects in the Structure; Magnetic and Luminescent Properties.

Varying the temperature of the reaction of [{Cd(pfb)(H2O)4}+n·n(pfb)-], [Ln2(pfb)6(H2O)8]·H2O (Hpfb = pentafluorobenzoic acid), and 1,10-phenanthroline (phen) in MeCN followed by crystallization resulted in the isolation of two type of products: 1D-polymers [LnCd(pfb)5(phen)]n·1.5nMeCN (Ln = Eu (I), Gd (II), Tb (III), Dy (IV)) which were isolated at 25 °C, and molecular compounds [Tb2Cd2(pfb)10(phen)2] (V) formed at 75 °C. The transition from a molecular to a polymer structure becomes possible because of intra- and intermolecular interactions between the aromatic cycles of phen and pfb from neighboring tetranuclear Ln2Cd2 fragments. Replacement of cadmium with zinc in the reaction resulted in molecular compounds Ln2Zn2 [Ln2Zn2(pfb)10(phen)2]·4MeCN (Ln = Eu (VI), Tb (VIII), Dy (IX)) and [Gd2Zn2(pfb)10(H2O)2(phen)2]·4MeCN (VII). A new molecular EuCd complex [Eu2Cd2(pfb)10(phen)4]·4MeCN (X)] was isolated from a mixture of cadmium, zinc, and europium pentafluorobenzoates (Cd:Zn:Ln = 1:1:2). Complexes II-IV, VII and IX exhibit magnetic relaxation at liquid helium temperatures in nonzero magnetic fields. Luminescent studies revealed a bright luminescence of complexes with europium(III) and terbium(III) ions.

B7-H3 as a Prognostic Biomarker and Therapeutic Target in Pediatric central nervous system Tumors.

B7-H3 (CD276), a member of the B7 superfamily, is an important factor in downregulating immune responses against tumors. It is also aberrantly expressed in many human malignancies. Beyond immune regulatory roles, its overexpression has been linked to invasive metastatic potential and poor prognosis in patients with cancer. Antibody-dependent cell-mediated cytotoxicity strategies targeting B7-H3 are currently in development, and early-phase clinical trials have shown encouraging preliminary results. To understand the role of B7-H3 in pediatric central nervous system (CNS) malignancies, a comprehensive panel of primary CNS tumors of childhood was examined by immunohistochemistry for levels and extent of B7-H3 expression. In addition, B7-H3 m-RNA expression status and association with overall survival in various pediatric CNS tumor types was accessed by curating publicly available patient gene expression data sets derived from bioinformatics analysis and visualization platforms (GlioVis). We demonstrate that B7-H3 is broadly expressed in pediatric glial and nonglial CNS tumors, and its aberrant expression, as determined by immunohistochemical staining intensity, correlates with tumor grade. Moreover, high B7-H3 m-RNA expression is significantly associated with worse survival and could potentially improve prognostication in various brain tumor types of childhood. B7-H3 can be used as a therapeutic target, given its tumor selectivity and the availability of targeted therapeutic agents to this antigen.

Mold inhalation causes innate immune activation, neural, cognitive and emotional dysfunction.

Individuals living or working in moldy buildings complain of a variety of health problems including pain, fatigue, increased anxiety, depression, and cognitive deficits. The ability of mold to cause such symptoms is controversial since no published research has examined the effects of controlled mold exposure on brain function or proposed a plausible mechanism of action. Patient symptoms following mold exposure are indistinguishable from those caused by innate immune activation following bacterial or viral exposure. We tested the hypothesis that repeated, quantified doses of both toxic and nontoxic mold stimuli would cause innate immune activation with concomitant neural effects and cognitive, emotional, and behavioral symptoms. We intranasally administered either 1) intact, toxic Stachybotrys spores; 2) extracted, nontoxic Stachybotrys spores; or 3) saline vehicle to mice. As predicted, intact spores increased interleukin-1ß immunoreactivity in the hippocampus. Both spore types decreased neurogenesis and caused striking contextual memory deficits in young mice, while decreasing pain thresholds and enhancing auditory-cued memory in older mice. Nontoxic spores also increased anxiety-like behavior. Levels of hippocampal immune activation correlated with decreased neurogenesis, contextual memory deficits, and/or enhanced auditory-cued fear memory. Innate-immune activation may explain how both toxic mold and nontoxic mold skeletal elements caused cognitive and emotional dysfunction.

Synthesis of Novel 2-(Het)arylpyrrolidine Derivatives and Evaluation of Their Anticancer and Anti-Biofilm Activity.

A library of novel 2-(het)arylpyrrolidine-1-carboxamides were obtained via a modular approach based on the intramolecular cyclization/Mannich-type reaction of N-(4,4-diethoxybutyl)ureas. Their anti-cancer activities both in vitro and in vivo were tested. The in vitro activity of some compounds towards M-Hela tumor cell lines was twice that of the reference drug tamoxifen, whereas cytotoxicity towards normal Chang liver cell did not exceed the tamoxifen toxicity. In vivo studies showed that the number of surviving animals on day 60 of observation was up to 83% and increased life span (ILS) was up to 447%. Additionally, some pyrrolidine-1-carboxamides possessing a benzofuroxan moiety obtained were found to effectively suppress bacterial biofilm growth. Thus, these compounds are promising candidates for further development both as anti-cancer and anti-bacterial agents.

An [18F]-Positron Emitting Fluorophore Allows Safe Evaluation of Small Molecule Distribution in the CSF, CSF Fistulas, and CNS Device Placement.

The small molecule fluorescein is commonly used to guide the repair of cerebral spinal fluid leaks (CSFLs) in the clinic. We modified fluorescein so that it is also visible by positron emission tomography (PET). This probe was used to quantitatively track the fast distribution of small molecules in the CSF of rats. We tested this probe in models relevant to the clinical diagnosis and treatment of central nervous system (CNS) diseases that affect CSF flow. In this study, fluorescein was radiolabeled with fluorine-18 to produce Fc-AMBF3. [18/19F]-Fc-AMBF3 was introduced at trace quantities (13.2 nmols, 100 µCi) intrathecally (between L5 and L6) in rats to observe the dynamic distribution and clearance of small molecules in the CSF by both [18F]-PET and fluorescence (FL) imaging. Murine models were used to demonstrate the following utilities of Fc-AMBF3: (1) utility in monitoring the spontaneous CSFL repair of a compression fracture of the cribriform plate and (2) utility in quantifying CSF flow velocity during neurosurgical lumboperitoneal shunt placement. Fc-AMBF3 clearly delineated CSF-containing volumes based on noninvasive PET imaging and in ex vivo FL histology. In vivo morbidity (n = 16 rats, <2.7 mg/kg, 77 times the PET dose) was not observed. The clearance of the contrast agent from the CNS was rapid and quantitative (t1/2 = 33.8 ± 0.6 min by FL and t1/2 = 26.0 ± 0.5 min by PET). Fc-AMBF3 was cleared from the CSF through the vasculature and/or lymphatic system that supplies the cribriform plate and the temporal bone. Fc-AMBF3 can be used to diagnose CSFLs, image CSFL repair, and determine the CSF flow velocity in the CNS or through lumboperitoneal shunts by PET/FL imaging. In conclusion, Fc-AMBF3 PET imaging has been demonstrated to safely and dynamically quantitate CSF flow, diagnose fistulas associated with the CSF space, and approximate the clearance of small molecules in the CSF.

Combined targeting of PI3K and MEK effector pathways via CED for DIPG therapy.

BACKGROUND: Midline gliomas like diffuse intrinsic pontine glioma (DIPG) carry poor prognosis and lack effective treatment options. Studies have implicated amplifications in the phosphatidylinositol 3-kinase (PI3K) signaling pathway in tumorigenesis; compensatory activation of parallel pathways (eg, mitogen-activated protein kinase [MEK]) may underlie the resistance to PI3K inhibition observed in the clinic. METHODS: Three patient-derived cell lines (SU-DIPG-IV, SU-DIPG-XIII, and SF8628) and a mouse-derived brainstem glioma cell line were treated with PI3K (ZSTK474) and MEK (trametinib) inhibitors, alone or in combination. Synergy was analyzed using Chou-Talalay combination index (CI). These agents were also used alone or in combination in a subcutaneous SU-DIPG-XIII tumor model and in an intracranial genetic mouse model of DIPG, given via convection-enhanced delivery (CED). RESULTS: We found that these agents abrogate cell proliferation in a dose-dependent manner. Combination treatments were found to be synergistic (CI < 1) across cell lines tested. They also showed significant tumor suppression when given systemically against a subcutaneous DIPG model (alone or in combination) or when given via direct intracranial injection (CED) in a intracranial DIPG mouse model (combination only, median survival 47 vs 35 days post-induction, P = .038). No significant short- or long-term neurotoxicity of ZSTK474 and trametinib delivered via CED was observed. CONCLUSIONS: Our data indicate that ZSTK474 and trametinib combinatorial treatment inhibits malignant growth of DIPG cells in vitro and in vivo, prolonging survival. These results suggest a promising new combinatorial approach using CED for DIPG therapy, which warrants further investigation.

Synthesis and Evaluation of Water-Soluble 2-Aryl-1-Sulfonylpyrrolidine Derivatives as Bacterial Biofilm Formation Inhibitors.

The approach to the novel 1-[(2-aminoethyl)sulfonyl]-2-arylpyrrolidines via unique intramolecular cyclization/aza-Michael reactions of N-(4,4-diethoxybutyl)ethenesulfonamide have been developed, which benefits from high yields of target compounds, mild reaction conditions, usage of inexpensive and low-toxic reagents, and allows for wide variability in both amine and aryl moieties. Biotesting with whole-cell luminescent bacterial biosensors responding to DNA damage showed that all tested compounds are not genotoxic. Tested compounds differently affect the formation of biofilms by Vibrio aquamarinus DSM 26054. Some of the tested compounds were found to suppress the bacterial biofilms growth and thus are promising candidates for further studies.

Golden Face of Phosphine: Cascade Reaction to Bridgehead Methanophosphocines by Intramolecular Double Hydroarylation.

Reported herein is the first example of a gold-catalyzed cyclization of bis(arylmethyl)ethynylphosphine oxides. This represents an original approach to bridgehead methanophosphocines 1, eight-membered heterocycles. Gold catalyst in combination with triflic acid activates alkyne and induces a double hydroarylation. Mechanistic studies suggest that the reaction proceeds stepwise, forming first the 1 H-isophosphinoline 2-oxide 5. Reduction and protection of the corresponding phosphine oxides 1 described herein also highlight the effectiveness of our approach to this new class of electron-rich ligands.

Synthesis and Antimicrobial Study of Novel 1-Benzylated Water-Soluble Isatin-3-hydrazones.

A high-yield synthesis of some novel isatin-3-acylhydrazones on the base of 5-ethylisatin derivatives and Girard's reagent T is described. Antimicrobial activity preliminary SAR study of both 1-benzylated isatins and water-soluble hydrazones was established. The most active against Staphylococcus aureus and Bacillus cereus are ammonium salts bearing 3,4-dichloro- or 4-CF3 substituents in benzyl fragment.