An Insight into Fluorinated Imines and Hydrazones as Antibacterial Agents.

Fluorinated imines (Schiff bases) and fluorinated hydrazones are of particular interest in medicinal chemistry due to their potential usefulness in treating opportunistic strains of bacteria that are resistant to commonly used antibacterial agents. The present review paper is focused on these fluorinated molecules revealing strong, moderate or weak in vitro antibacterial activities, which have been reported in the scientific papers during the last fifteen years. Fluorinated building blocks and reaction conditions used for the synthesis of imines and hydrazones are mentioned. The structural modifications, which have an influence on the antibacterial activity in all the reported classes of fluorinated small molecules, are highlighted, focusing mainly on the importance of specific substitutions. Advanced research techniques and innovations for the synthesis, design and development of fluorinated imines and hydrazones are also summarized.

Nitrile Imines as Peptide and Oligonucleotide Photo-Cross-Linkers in Gas-Phase Ions.

Nitrile imines produced by photodissociation of 2,5-diaryltetrazoles undergo cross-linking reactions with amide groups in peptide-tetrazole (tet-peptide) conjugates and a tet-peptide-dinucleotide complex. Tetrazole photodissociation in gas-phase ions is efficient, achieving ca. 50% conversion with 2 laser pulses at 250 nm. The formation of cross-links was detected by CID-MS3 that showed structure-significant dissociations by loss of side-chain groups and internal peptide segments. The structure and composition of cross-linking products were established by a combination of UV-vis action spectroscopy and cyclic ion mobility mass spectrometry (c-IMS). The experimental absorption bands were found to match the bands calculated for vibronic absorption spectra of nitrile imines and cross-linked hydrazone isomers. The calculated collision cross sections (CCSth) for these ions were related to the matching experimental CCSexp from multipass c-IMS measurements. Loss of N2 from tet-peptide conjugates was calculated to be a mildly endothermic reaction with ΔH0 = 80 kJ mol-1 in the gas phase. The excess energy in the photolytically formed nitrile imine is thought to drive endothermic proton transfer, followed by exothermic cyclization to a sterically accessible peptide amide group. The exothermic nitrile imine reaction with peptide amides is promoted by proton transfer and may involve an initial [3 + 2] cycloaddition followed by cleavage of the oxadiazole intermediate. Nucleophilic groups, such as cysteine thiol, did not compete with the amide cyclization. Nitrile imine cross-linking to 2'-deoxycytidylguanosine was found to be >80% efficient and highly specific in targeting guanine. The further potential for exploring nitrile-imine cross-linking for biomolecular structure analysis is discussed.

An imine reductase that captures reactive intermediates in the biosynthesis of the indolocarbazole reductasporine.

Imine reductases (IREDs) and reductive aminases have been used in the synthesis of chiral amine products for drug manufacturing; however, little is known about their biological contexts. Here we employ structural studies and site-directed mutagenesis to interrogate the mechanism of the IRED RedE from the biosynthetic pathway to the indolocarbazole natural product reductasporine. Cocrystal structures with the substrate-mimic arcyriaflavin A reveal an extended active site cleft capable of binding two indolocarbazole molecules. Site-directed mutagenesis of a conserved aspartate in the primary binding site reveals a new role for this residue in anchoring the substrate above the NADPH cofactor. Variants targeting the secondary binding site greatly reduce catalytic efficiency, while accumulating oxidized side-products. As indolocarbazole biosynthetic intermediates are susceptible to spontaneous oxidation, we propose the secondary site acts to protect against autooxidation, and the primary site drives catalysis through precise substrate orientation and desolvation effects. The structure of RedE with its extended active site can be the starting point as a new scaffold for engineering IREDs and reductive aminases to intercept large substrates relevant to industrial applications.

In-silico molecular modelling studies of some camphor imine based compounds as anti-influenza A (H1N1) pdm09 virus agents.

The advent of influenza A (H1N1) drug-resistant strains led to the search quest for more potent inhibitors of the influenza A virus, especially in this devastating COVID-19 pandemic era. Hence, the present research utilized some molecular modelling strategies to unveil new camphor imine-based compounds as anti-influenza A (H1N1) pdm09 agents. The 2D-QSAR results revealed GFA-MLR (R2train = 0.9158, Q2=0.8475) and GFA-ANN (R2train = 0.9264, Q2=0.9238) models for the anti-influenza A (H1N1) pdm09 activity prediction which have passed the QSAR model acceptability thresholds. The results from the 3D-QSAR studies also revealed CoMFA (R2train =0.977, Q2=0.509) and CoMSIA_S (R2train =0.976, Q2=0.527) models for activity predictions. Based on the notable information derived from the 2D-QSAR, 3D-QSAR, and docking analysis, ten (10) new camphor imine-based compounds (22a-22j) were designed using the most active compound 22 as the template. Furthermore, the high predicted activity and binding scores of compound 22j were further justified by the high reactive sites shown in the electrostatic potential maps and other quantum chemical calculations. The MD simulation of 22j in the active site of the influenza hemagglutinin (HA) receptor confirmed the dynamic stability of the complex. Moreover, the appraisals of drug-likeness and ADMET properties of the proposed compounds showed zero violation of Lipinski's criteria with good pharmacokinetic profiles. Hence, the outcomes in this work recommend further in-depth in vivo and in-vitro investigations to validate these theoretical findings.Communicated by Ramaswamy H. Sarma.

ortho-Boronic Acid Carbonyl Compounds and Their Applications in Chemical Biology.

Iminoboronates and diazaborines are related classes of compounds that feature an imine ortho to an arylboronic acid (iminoboronate) or a hydrazone that cyclizes with an ortho arylboronic acid (diazaborine). Rather than acting as independent chemical motifs, the arylboronic acid impacts the rate of imine/hydrazone formation, hydrolysis, and exchange with competing nucleophiles. Increasing evidence has shown that the imine/hydrazone functionality also impacts arylboronic acid reactivity toward diols and reactive oxygen and nitrogen species (ROS/RNS). Untangling the communication between C=N linked functionalities and arylboronic acids has revealed a powerful and tunable motif for bioconjugation chemistries and other applications in chemical biology. Here, we survey the applications of iminoboronates and diazaborines in these fields with an eye toward understanding their utility as a function of neighboring group effects.

Asymmetric Reduction of Cyclic Imines by Imine Reductase Enzymes in Non-Conventional Solvents.

The first enantioselective reduction of 2-substituted cyclic imines to the corresponding amines (pyrrolidines, piperidines, and azepines) by imine reductases (IREDs) in non-conventional solvents is reported. The best results were obtained in a glycerol/phosphate buffer 1 : 1 mixture, in which heterocyclic amines were produced with full conversions (>99 %), moderate to good yields (22-84 %) and excellent S-enantioselectivities (up to >99 % ee). Remarkably, the process can be performed at a 100 mM substrate loading, which, for the model compound, means a concentration of 14.5 g L-1 . A fed-batch protocol was also developed for a convenient scale-up transformation, and one millimole of substrate 1 a was readily converted into 120 mg of enantiopure amine (S)-2 a with a remarkable 80 % overall yield. This aspect strongly contributes to making the process potentially attractive for large-scale applications in terms of economic and environmental sustainability for a good number of substrates used to produce enantiopure cyclic amines of high pharmaceutical interest.

Protein fibers with self-recoverable mechanical properties via dynamic imine chemistry.

The manipulation of internal interactions at the molecular level within biological fibers is of particular importance but challenging, severely limiting their tunability in macroscopic performances and applications. It thus becomes imperative to explore new approaches to enhance biological fibers' stability and environmental tolerance and to impart them with diverse functionalities, such as mechanical recoverability and stimulus-triggered responses. Herein, we develop a dynamic imine fiber chemistry (DIFC) approach to engineer molecular interactions to fabricate strong and tough protein fibers with recoverability and actuating behaviors. The resulting DIF fibers exhibit extraordinary mechanical performances, outperforming many recombinant silks and synthetic polymer fibers. Remarkably, impaired DIF fibers caused by fatigue or strong acid treatment are quickly recovered in water directed by the DIFC strategy. Reproducible mechanical performance is thus observed. The DIF fibers also exhibit exotic mechanical stability at extreme temperatures (e.g., -196 °C and 150 °C). When triggered by humidity, the DIFC endows the protein fibers with diverse actuation behaviors, such as self-folding, self-stretching, and self-contracting. Therefore, the established DIFC represents an alternative strategy to strengthen biological fibers and may pave the way for their high-tech applications.

Synthesis of portimines reveals the basis of their anti-cancer activity.

Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chemical structure and notable anti-cancer therapeutic potential1-4. However, access to large quantities of these toxins is currently not feasible, and the molecular mechanism underlying their potent activity remains unknown until now. To address this, a scalable and concise synthesis of portimines is presented, which benefits from the logic used in the two-phase terpenoid synthesis5,6 along with other tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through self-protection. Notably, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency and is efficacious in vivo in tumour-clearance models. Finally, practical access to the portimines and their analogues simplified the development of photoaffinity analogues, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.

Mild and Functional Group-Tolerant Aerobic N-Dealkylation of Tertiary Amines Promoted by Photoredox Catalysis.

This article describes the development of a mild method for the N-dealkylation of tertiary amines via photoredox catalysis and its application in late-stage functionalization. Using the developed method, more than 30 diverse aliphatic, aniline-type, and complex substrates are shown to undergo N-dealkylation, providing a method with broader functional group tolerance compared to methods found in the literature. The scope also includes tertiary and secondary amine molecules with complex substructures and drug substrates. Interestingly, α-oxidation to imines was observed in several cyclic substructures instead of N-dealkylation, suggesting that imines are relevant reaction intermediates.

Computational modeling of imines based anti-oxidant and anti-esterases compounds: Synthesis, single crystal and In-vitro assessment.

Molecular modeling strategy was adopted to check the biological potential of the imine based molecules against free radical, acetylcholine esterase and butyrylcholine esterase. Three Schiff based compounds as (E)-2-(((4-bromophenyl)imino)methyl)-4-methylphenol (1), (E)-2-(((3-fluorophenyl)imino)methyl)-4-methylphenol (2) and (2E,2E)-2-(2-(2-hydroxy-5-methylbenzylidene)hydrazono)-1,2-diphenylethanone (3) were synthesized with high yield. The synthesized compounds were characterized with the help of modern techniques such as UV, FTIR and NMR while exact structure was depicted with Single Crystal X-Ray diffraction technique which disclosed that compound 1 is orthorhombic, while 2 and 3 are monoclinic. A hybrid functional (B3LYP) method with general basis set of 6-31 G(d,p) were applied to optimize synthesized Schiff bases. The contribution of in-between molecular contacts within a crystalline assembly of compounds were studied using Hirshfeld surface analysis (HS). In order to check the ability of the synthesized compounds toward free radical and enzyme inhibition, in vitro models were used to assess the radical scavenging and enzyme inhibition potential which depicted that compound 3 showed highest potential (57.43 ± 1.0%; DPPH, 75.09 ± 1.0%; AChE and 64.47 ± 1.0%; BChE). The ADMET assessments suggested the drug like properties of the synthesized compounds. It was concluded from results (in vitro and in silico) that synthesized compound have ability to cure the disorder related to free radical and enzyme inhibition. Compound 3 was shown to be the most active compared to other compounds.

Sulfenate Anion Catalyzed Diastereoselective Synthesis of Aziridines.

Aziridines are highly valued synthetic targets in organic and medicinal chemistry. The organocatalytic synthesis of such structures with broad substrate scope and good diastereoselectivity, however, is rare. Herein, we report a broadly applicable and diastereoselective synthetic method for the synthesis of trans-aziridines from imines and benzylic or alkyl halides utilizing sulfenate anions (PhSO- ) as the catalyst. Substrates bearing heterocyclic aromatic groups, alkyl, and electron-rich and electron-poor aryl groups were shown to be compatible with this method (33 examples), giving good yields and high diastereoselectivities (trans : cis >20 : 1). Further functionalization of aziridines containing cyclopropyl or cyclobutyl groups was achieved through ring-opening reactions, with a cyclobutyl-substituted norephedrine derivative obtained through a four-step synthesis. We offer a mechanistic proposal involving reversible addition of the deprotonated benzyl sulfoxide to the imine to explain the high trans-diastereoselectivity.

Schiff Bases and Stereocontrolled Formation of Fused 1,3-Oxazolidines from 1-Amino-2-Indanol: A Systematic Study on Structure and Mechanism.

This paper thoroughly explores the formation of Schiff bases derived from salicylaldehydes and a conformationally restricted amino alcohol (1-amino-2-indanol), as well as the generation of 1,3-oxazolidines, a key heterocyclic core present in numerous bioactive compounds. We provide enough evidences, both experimental-including crystallographic analyses and DFT-based calculations on imine/enamine tautomerism in the solid state and solution. In the course of imine formation, a pentacyclic oxazolidine-oxazine structure could be isolated with complete stereocontrol, whose configuration has been determined by merging theory and experiment. Mechanistic studies reveal that, although oxazolidines can be obtained under kinetic conditions, the prevalence of imines obeys to thermodynamic control as they are the most stable structures. The stereochemical outcome of imine cyclization under acylating conditions leads to formation of 2,4-trans-oxazolidines.

Stereoselective synthesis of the spirocyclic core of 13-desmethyl spirolide C using an aza-Claisen rearrangement and an exo-selective Diels-Alder cycloaddition.

13-Desmethyl spirolide C is a marine natural product of the cyclic imine class that demonstrates remarkable bioactivity against several biomarkers of Alzheimer's Disease, which renders its [7,6]-spirocyclic imine pharmacophore of significant synthetic interest. This work describes a facile and efficient synthesis of the [7,6]-spirocyclic core of 13-desmethyl spirolide C from inexpensive starting materials, featuring an aza-Claisen rearrangement to simultaneously set both stereocentres of the dimethyl moiety with complete atom economy, and a highly exo-selective Diels-Alder cycloaddition to construct the challenging contiguous tertiary and quaternary stereocentres of the spirocyclic core of 13-desmethyl spirolide C. A comprehensive study of the key Diels-Alder reaction was also performed to evaluate the stereoselectivity and reactivity of various functionalised dienes and protected lactam dienophiles, wherein the first successful exo-selective Diels-Alder cycloaddition to construct spirocyclic structures using a bromodiene and α-exo-methylene dienophiles is reported. This strategy not only establishes a more efficient stereoselective access to the spirocyclic core that can be used for the total synthesis of 13-desmethyl spirolide C, but also serves as a sound platform for convenient preparations of a range of spirocyclic analogues required for a comprehensive biological evaluation of this desirable pharmacophore.

Regioselective Cycloaddition of Nitrile Imines to 5-Methylidene-3-phenyl-hydantoin: Synthesis and DFT Calculations.

Nitrile imine cycloaddition to hydantoins containing an exocyclic C=C double bond has been previously described in a very limited number of examples. In this work, regioselective synthesis of spiro-pyrazoline-imidazolidine-2,4-diones based on a 1,3-dipolar cycloaddition reaction of nitrile imines to 5-methylidene-3-phenyl-hydantoin have been proposed. It was found that, regardless of the nature of the aryl substituents at the terminal C and N atoms of the C-N-N fragment of nitrile imine (electron donor or electron acceptor), cycloaddition to the 5-methylidenhydantoin exocyclic C=C bond proceeds regioselectively, and the terminal nitrogen atom of the nitrile imine connects to the more sterically hindered carbon atom of the double bond, which leads to the formation of a 5-disubstituted pyrazoline ring. The observed cycloaddition regioselectivity was rationalized using DFT calculations of frontier molecular orbital interactions, global CDFT reactivity indices, and minimum energy paths.

Concerted Enantioselective [2+2] Cycloaddition Reaction of Imines Mediated by a Magnesium Catalyst.

Enantioselective [2 + 2] cyclization between an imine and a carbon-carbon double bond is a versatile strategy to build chiral azetidines. However, α-branched allenoates have never been successfully applied in [2 + 2] cyclization reactions with imines, as they always undergo Kwon's [4 + 2] annulation in previous catalytic methods. Herein, a simple in situ generated magnesium catalyst was employed to successfully achieve the enantioselective [2 + 2] cyclization reaction of DPP-imines and α-branched allenoates for the first time. Insightful experiments including KIE experiments, controlled experiments, Hammett plot analysis, and 31P NMR studies of initial intermediates indicate that the current [2 + 2] cyclization of imine most likely involves an asynchronous concerted transition state. Further mechanistic investigations by combining kinetic studies, ESI experiments, 31P NMR studies of coordination complexes, and controlled experiments on reaction rates under different catalyst loading amounts provided the coordination details for this [2 + 2] cyclization reaction between DPP-imines and α-branched allenoates. This new approach was applied to the synthesis of various chiral aza-heterocycles, including the enantioselective synthesis of the key intermediate of a lipid-lowering agent Ezetimibe.

Use of (E,E)-Dienoic Acids as Switchable (E,E)- and (Z,E)-Dienyl Anion Surrogates via Ligand-Controlled Palladium Catalysis.

Carboxylic acids are not readily applied as carbon-based nucleophiles due to their intrinsic acidic group. Here, we demonstrate that free (E,E)-2,4-dienoic acids form electron-neutral and highest occupied molecular orbital-raised η2-complexes with Pd(0) and undergo Friedel-Crafts-type additions to imines with exclusive α-regioselectivity, giving formal dienylated products after decarboxylation. Unusual and switchable (E,E)- and (Z,E)-selectivity, along with excellent enantioselectivity, is achieved via ligand-controlled outer-sphere or inner-sphere reaction modes, respectively, which are well supported by comprehensive density functional theory calculation studies. An unprecedented formal reductive Mannich reaction between (E,E)-dienoic acids and imines is also developed to furnish enantioenriched ß-amino acid derivatives.

A Mechanistic Study of Asymmetric Transfer Hydrogenation of Imines on a Chiral Phosphoric Acid Derived Indium Metal-Organic Framework.

A density functional theory (DFT) study is reported to examine the asymmetric transfer hydrogenation (ATH) of imines catalyzed by an indium metal-organic framework (In-MOF) derived from a chiral phosphoric acid (CPA). It is revealed that the imine and reducing agent (i.e., thiazoline) are simultaneously adsorbed on the CPA through H-bonding to form an intermediate, subsequently, a proton is transferred from thiazoline to imine. The transition state TS-R and TS-S are stabilized on the CPA via H-bonding. Compared to the TS-S, the TS-R has shorter H-bonding distances and longer C-H···π distances, it is more stable and experiences less steric hindrance. Consequently, the TS-R exhibits a lower activation barrier affording to the (R)-enantiomer within 68.1% ee in toluene. Imines with substituted groups such as -NO2, -F, and -OCH3 are used to investigate the substitution effects on the ATH. In the presence of an electron-withdrawing group like -NO2, the electrophilicity of imine is enhanced and the activation barrier is decreased. The non-covalent interactions and activation-strain model (ASM) analysis reveal that the structural distortions and the differential noncovalent interactions of TSs in a rigid In-MOF provide the inherent driving force for enantioselectivity. For -OCH3 substituted imine, the TS-S has the strongest steric hindrance, leading to the highest enantioselectivity. When the solvent is changed from toluene to dichloromethane, acetonitrile, and dimethylsulfoxide with increasing polarity, the activation energies of transition state increase whereas their difference decreases. This implies the reaction is slowed down and the enantioselectivity becomes lower in a solvent of smaller polarity. Among the four solvents, toluene turns out to be the best for the ATH. The calculated results in this study are in fairly good agreement with experimental observations. This study provides a mechanistic understanding of the reaction mechanism, as well as substitution and solvent effects on the activity and enantioselectivity of the ATH. The microscopic insights are useful for the development of new chiral MOFs toward important asymmetric reactions.

The Use of Aryl-Substituted Homophthalic Anhydrides in the Castagnoli-Cushman Reaction Provides Access to Novel Tetrahydroisoquinolone Carboxylic Acid Bearing an All-Carbon Quaternary Stereogenic Center.

Novel aryl-substituted homophthalic acids were cyclodehydrated to the respective homophthalic anhydrides for use in the Castagnoli-Cushman reaction. With a range of imines, this reaction proceeded smoothly and delivered hitherto undescribed 4-aryl-substituted tetrahydroisoquinolonic acids with remarkable diastereoselectivity, good yields and no need for chromatographic purification. These findings significantly extend the range of cyclic anhydrides employable in the Castagnoli-Cushman reaction and signify access to a novel substitution pattern around the medicinally relevant tetrahydroisoquinolonic acid scaffold.

Synthesis of Stereoenriched Piperidines via Chemo-Enzymatic Dearomatization of Activated Pyridines.

The development of efficient and sustainable methods for the synthesis of nitrogen heterocycles is an important goal for the chemical industry. In particular, substituted chiral piperidines are prominent targets due to their prevalence in medicinally relevant compounds and their precursors. A potential biocatalytic approach to the synthesis of this privileged scaffold would be the asymmetric dearomatization of readily assembled activated pyridines. However, nature is yet to yield a suitable biocatalyst specifically for this reaction. Here, by combining chemical synthesis and biocatalysis, we present a general chemo-enzymatic approach for the asymmetric dearomatization of activated pyridines for the preparation of substituted piperidines with precise stereochemistry. The key step involves a stereoselective one-pot amine oxidase/ene imine reductase cascade to convert N-substituted tetrahydropyridines to stereo-defined 3- and 3,4-substituted piperidines. This chemo-enzymatic approach has proved useful for key transformations in the syntheses of antipsychotic drugs Preclamol and OSU-6162, as well as for the preparation of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib.

Increasing Anticancer Activity with Phosphine Ligation in Zwitterionic Half-Sandwich Iridium(III), Rhodium(III), and Ruthenium(II) Complexes.

The synthesis and biological assessment of neutral or cationic platinum group metal-based anticancer complexes have been extremely studied, whereas there are few reports on the corresponding zwitterionic complexes. Herein, the synthesis, characterization, and bioactivity of zwitterionic half-sandwich phosphine-imine iridium(III), rhodium(III), and ruthenium(II) complexes were presented. The sulfonated phosphine-imine ligand and a group of zwitterionic half-sandwich P,N-chelating organometallic complexes were fully characterized by nuclear magnetic resonance (NMR), mass spectrum (electrospray ionization, ESI), elemental analysis, and X-ray crystallography. The solution stability of these complexes and their spectral properties were also determined. Notably, almost all of these complexes showed enhanced anticancer activity against model HeLa and A549 cancer cells than the corresponding zwitterionic pyridyl-imine N,N-chelating iridium(III) and ruthenium(II) complexes, which have exhibited inactive or low active in our previous work. The increase in the lipophilic property and intracellular uptake levels of these zwitterionic P,N-chelating complexes appeared to be associated with their superior cytotoxicity. In addition, these complexes showed biomolecular interactions with bovine serum albumin (BSA). The flow cytometry studies indicated that the representative complex Ir1 could induce early-stage apoptosis in A549 cells. Further, confocal microscopy imaging analysis displayed that Ir1 entered A549 cells through the energy-dependent pathway, targeted lysosome, and could cause lysosomal damage. In particular, these complexes could impede cell migration in A549 cells.