Lactam Derivatives Research Articles

Directed Copper-Catalyzed Tandem Radical Cyclization Reaction of Alkyl Bromides and Unactivated Olefins.

The free radical cyclization reaction is a promising strategy for ring framework formation. Herein, we report a copper-catalyzed tandem radical cyclization strategy for preparing substituted lactam derivatives. This reaction proceeds through a radical coupling approach, which not only allows a wide range of alkenes but also is quite compatible with the primary, secondary, and tertiary radicals. In addition, density functional theory calculations were performed to gain insights into the reaction mechanism.

β-Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models.

Transient receptor potential melastatin subtype 8 (TRPM8) is a cation channel extensively expressed in sensory neurons and implicated in different painful states. However, the effectiveness of TRPM8 modulators for pain relief is still a matter of discussion, since structurally diverse modulators lead to different results, depending on the animal pain model. In this work, we described the antinociceptive activity of a β–lactam derivative, RGM8-51, showing good TRPM8 antagonist activity, and selectivity against related thermoTRP channels and other pain-mediating receptors. In primary cultures of rat dorsal root ganglion (DRG) neurons, RGM8-51 potently reduced menthol-evoked neuronal firing without affecting the major ion conductances responsible for action potential generation. This compound has in vivo antinociceptive activity in response to cold, in a mouse model of oxaliplatin-induced peripheral neuropathy. In addition, it reduces cold, mechanical and heat hypersensitivity in a rat model of neuropathic pain arising after chronic constriction of the sciatic nerve. Furthermore, RGM8-51 exhibits mechanical hypersensitivity-relieving activity, in a mouse model of NTG-induced hyperesthesia. Taken together, these preclinical results substantiate that this TRPM8 antagonist is a promising pharmacological tool to study TRPM8-related diseases.

Origin of High Diastereoselectivity in Reactions of Seven‐Membered‐Ring Enolates

AbstractUnlike many reactions of their six‐membered‐ring counterparts, the reactions of chiral seven‐membered‐ring enolates are highly diastereoselective. Diastereoselectivity was observed for a range of substrates, including lactam, lactone, and cyclic ketone derivatives. The stereoselectivity arises from torsional and steric interactions that develop when electrophiles approach the diastereotopic π‐faces of the enolates, which are distinguished by subtle differences in the orientation of nearby atoms of the ring.

Predicting Antifouling Activity and Acetylcholinesterase Inhibition of Marine-Derived Compounds Using a Computer-Aided Drug Design Approach.

Biofouling is the undesirable growth of micro- and macro-organisms on artificial water-immersed surfaces, which results in high costs for the prevention and maintenance of this process (billion €/year) for aquaculture, shipping and other industries that rely on coastal and off-shore infrastructure. To date, there are still no sustainable, economical and environmentally safe solutions to overcome this challenging phenomenon. A computer-aided drug design (CADD) approach comprising ligand- and structure-based methods was explored for predicting the antifouling activities of marine natural products (MNPs). In the CADD ligand-based method, 141 organic molecules extracted from the ChEMBL database and literature with antifouling screening data were used to build the quantitative structure–activity relationship (QSAR) classification model. An overall predictive accuracy score of up to 71% was achieved with the best QSAR model for external and internal validation using test and training sets. A virtual screening campaign of 14,492 MNPs from Encinar’s website and 14 MNPs that are currently in the clinical pipeline was also carried out using the best QSAR model developed. In the CADD structure-based approach, the 125 MNPs that were selected by the QSAR approach were used in molecular docking experiments against the acetylcholinesterase enzyme. Overall, 16 MNPs were proposed as the most promising marine drug-like leads as antifouling agents, e.g., macrocyclic lactam, macrocyclic alkaloids, indole and pyridine derivatives.

Comparison of enhanced fluidity liquid chromatography with liquid chromatography for enantioseparation of selected [formula omitted]-lactam derivatives

The present paper describes the study of eight racemic γ-lactam derivatives with the goal of comparing three modes of liquid chromatography which are the reversed-phase mode, the normal-phase mode and the polar organic solvent chromatography mode with super/subcritical fluid chromatography and enhanced fluidity liquid chromatography in extreme conditions i.e. when the CO2 percentage is practically zero. For this study two CPSs were chosen. Chiralcel OD-H was used in HPLC conditions and Chiralcel OD-H and Lux Cellulose-2 were used in SFC conditions. It is reported in this work that the introduction of chlorine substituent on polysaccharide-based selectors contributes to an improved enantioselectivity in supercritical fluid chromatography (SFC) compared to the electron-donating substituted phenyl carbamate column, allowing the complete separation of seven analytes out of the eight.The effect of enhanced fluidity liquid chromatography conditions, described as an intermediate mode between HPLC and SFC is also explored. In this case, the composition of the mobile phase starting at 80% CO2 was replaced with almost 100% ethanol at the end, this assay achieving further extension of the polarity range of the mobile phase in a single run and successfully enabling the simultaneous analysis and separation of the racemates. Under a mobile phase constituted of 99% ethanol, the resolution values of the γ-lactam derivatives on Lux Cellulose-2 CSP, were comprised between 1.91 and 3.44. High values of flowrates, ranging from 4 mL/min to 10 mL/min were also evaluated for some analytes on the highly retentive Lux Cellulose-2 CSP, leading to resolution equal to 6.24 for compound 6 and 4.64 for compound 8.

High Value-Added Application of Natural Products in Crop Protection: Semisynthesis and Acaricidal Activity of Limonoid-Type Derivatives and Investigation of Their Biocompatible O/W Nanoemulsions as Agronanopesticide Candidates.

The increasingly serious resistance of Tetranychus cinnabarinus Boisduval to a wide range of insecticides/acaricides poses a major challenge to their control. The citrus processing industry generates a huge quantity of various wastes that contain many limonoids. To effectively utilize these byproducts and discover more potent green acaricidal molecules as sustainable alternatives for traditional resistant pesticides, various limonoid-type derivatives (halogenated/seven-membered lactam derivatives of obacunone and halogenated/oxime esters/oxime ethers/seven-membered lactam derivatives of limonin) were synthesized based on a diversity-oriented synthetic strategy. The key steric configurations of 10 derivatives were further confirmed by X-ray crystallography. Compound 9m, which displayed greater than 9.7-fold potent acaricidal activity of limonin, was of preeminence. In addition, some interesting structure-activity relationships were observed. Moreover, a biocompatible O/W nanoemulsion delivery system was used to prepare the limonin-based agronanoacaricide, which exhibited pronounced control efficiency against T. cinnabarinus Boisduval in the greenhouse. This systematic investigation will provide valuable information and guidance for future value-added applications of novel eco-friendly natural product-based nanopesticides.

Use of a Removable Backbone Modification Strategy to Prevent Aspartimide Formation in the Synthesis of Asp Lactam Cyclic Peptides†

Main observation and conclusionThe synthesis of an Asp lactam derivative of A‐183, a selective inhibitor of Factor 7a with good anticoagulant and antithrombotic activity, is described. Our synthesis depends on the use of a removable backbone modification (RBM) strategy to prevent aspartimide formation, which thwarted all attempts to synthesize this target using direct solid‐phase peptide synthesis. Validation of the RBM strategy in the synthesis of a second Asp lactam derivative was also accomplished. The RBM strategy is therefore proposed as a general method for the synthesis of Asp lactam cyclic peptides.

Amide-Type Substrates in the Synthesis of N-Protected 1-Aminomethylphosphonium Salts

Herein we describe the development and optimization of a two-step procedure for the synthesis of N-protected 1-aminomethylphosphonium salts from imides, amides, carbamates, or lactams. Our “step-by-step” methodology involves the transformation of amide-type substrates to the corresponding hydroxymethyl derivatives, followed by the substitution of the hydroxyl group with a phosphonium moiety. The first step of the described synthesis was conducted based on well-known protocols for hydroxymethylation with formaldehyde or paraformaldehyde. In turn, the second (substitution) stage required optimization studies. In general, reactions of amide, carbamate, and lactam derivatives occurred at a temperature of 70 °C in a relatively short time (1 h). On the other hand, N-hydroxymethylimides reacted with triarylphosphonium salts at a much higher temperature (135 °C) and over longer reaction times (as much as 30 h). However, the proposed strategy is very efficient, especially when NaBr is used as a catalyst. Moreover, a simple work-up procedure involving only crystallization afforded good to excellent yields (up to 99%).

Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity.

Transient receptor potential cation channel subfamily M member 8 (TRPM8) is a Ca2+ non-selective ion channel implicated in a variety of pathological conditions, including cancer, inflammatory and neuropathic pain. In previous works we identified a family of chiral, highly hydrophobic β–lactam derivatives, and began to intuit a possible effect of the stereogenic centers on the antagonist activity. To investigate the influence of configuration on the TRPM8 antagonist properties, here we prepare and characterize four possible diastereoisomeric derivatives of 4-benzyl-1-[(3′-phenyl-2′-dibenzylamino)prop-1′-yl]-4-benzyloxycarbonyl-3-methyl-2-oxoazetidine. In microfluorography assays, all isomers were able to reduce the menthol-induced cell Ca2+ entry to larger or lesser extent. Potency follows the order 3R,4R,2′R > 3S,4S,2′R ≅ 3R,4R,2′S > 3S,4S,2′S, with the most potent diastereoisomer showing a half inhibitory concentration (IC50) in the low nanomolar range, confirmed by Patch-Clamp electrophysiology experiments. All four compounds display high receptor selectivity against other members of the TRP family. Furthermore, in primary cultures of rat dorsal root ganglion (DRG) neurons, the most potent diastereoisomers do not produce any alteration in neuronal excitability, indicating their high specificity for TRPM8 channels. Docking studies positioned these β-lactams at different subsites by the pore zone, suggesting a different mechanism than the known N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist.

Monosaccharides as Useful Platform in the Synthesis of Bio-Molecules to Fight the Pathologies

The development of new drugs from heterocyclic biomolecules is a challenge for scientific research. In this regard, the case of Hydantoins, tetrazoles, lactams and lactones, the most prominent of the heterocyclics offer conditions for this purpose, given their potential to confer a great diversity of bioactivities. Therefore, the development of new methods for their preparation constitutes an interesting challenge for organic chemists in general and in the area of carbohydrates in particular. In this work we report the synthesis of hydantoin, tetrazole, lactone and lactam derivatives, known as antibiotics, insecticides, analgesics, antitumor, antibacterials, antifungals and others, prepared using Schmidt, Bucherer-bergs, A.P. Rauter and Farkas reactions to monosaccharide derivatives such as keto sugars and epoxy sugars. Although they are usually reactions used for normal organic molecules, these reactions were also feasible in the monosaccharide derivatives and made it possible to obtain two tetrazole derivatives 5 and 10 with 82.9% and 48% yield, a Hydantoin derivative 3 with 62.5% yield, a lactam derivative 4 with 84.4% yield and four lactone derivatives 7a, 7b, 8a and 8b with 51%, 80%, 88.23% and 91% yield respectively. The yields were considered good in general and the methods efficient in the field of monosaccharides. The structures of these compounds were elucidated by chemical and physical tests and its IR spectra’s.

Discovery of γ-Lactam Alkaloid Derivatives as Potential Fungicidal Agents Targeting Steroid Biosynthesis.

Biological control of plant pathogens is considered as one of the green and effective technologies using beneficial microorganisms or microbial secondary metabolites against plant diseases, and so microbial natural products have played important roles in the research and development of new and green agrochemicals. To explore the potential applications for natural γ-lactam alkaloids and their derivatives, 26 γ-lactams that have flexible substituent patterns were synthesized and characterized, and their in vitro antifungal activities against eight kinds of plant pathogens belonging to oomycetes, basidiomycetes, and deuteromycetes were fully evaluated. In addition, the high potential compounds were further tested using an in vivo assay against Phytophthora blight of pepper to verify a practical application for controlling oomycete diseases. The potential modes of action for compound D1 against Phytophthora capsici were also investigated using microscopic technology (optical microscopy, scanning electron microscopy, and transmission electron microscopy) and label-free quantitative proteomics analysis. The results demonstrated that compound D1 may be a potential novel fungicidal agent against oomycete diseases (EC50 = 4.9748 μg·mL-1 for P. capsici and EC50 = 5.1602 μg·mL-1 for Pythium aphanidermatum) that can act on steroid biosynthesis, which can provide a certain theoretical basis for the development of natural lactam derivatives as potential antifungal agents.

Induction of New Lactam Derivatives From the Endophytic Fungus Aplosporella javeedii Through an OSMAC Approach.

Fermentation of the endophytic fungus Aplosporella javeedii on solid rice medium in presence of either 3.5% NaNO3 or 3.5% monosodium glutamate caused a significant change of the fungal metabolite pattern compared to fungal controls grown only on rice. Chemical investigation of the former fungal extracts yielded 11 new lactam derivatives, aplosporellins A–K (2–12), in addition to the known compound, pramanicin A (1). All of these compounds were not detected when the fungus was grown on rice medium without these activators thereby indicating the power of this OSMAC approach. The structures of the new compounds were elucidated by one- and two- dimensional NMR spectroscopy, DFT-NMR calculations and by mass spectrometry as well as by comparison with the literature whereas the absolute configuration of the lactam core was determined by TDDFT-ECD and OR calculations. Pramanicin A (1) showed strong cytotoxicity against human lymphoma (Ramos) and leukemia (Jurkat J16) cells with IC50 values of 4.7 and 4.4 μM, respectively. Mechanistic studies indicated that 1 activates caspase-3 and induces apoptotic cell death.

Electrochemical Ring Expansion to Synthesize Medium-Sized Lactams Through C–C Bond Cleavage

Medium-sized nitrogen heterocycles are prevalent motifs in many kinds of bioactive molecules and natural products. Owing to the unfavorable enthalpic and entropic barriers during the transition sta...

Hydrophobicity and self‐association (micellization) of bile salts with a lactone or lactam group in a steroid skeleton

AbstractBile acid salts are amphiphiles that have planar polarity: the convex surface (the β side) of their steroid skeleton is hydrophobic, whereas the concave surface (the α side) is hydrophilic. Lactone and lactam derivatives of bile acid salts have reduced hydrophobicity on the convex surface (β side) of the steroid skeleton, but they are still able to build micelles. In the vicinity of their critical micellar concentration (CMC), they probably form Small's primary micelles. In this work, it is shown that retention capacities (reverse‐phase high‐performance liquid chromatography) are linearly dependent on temperature, for each tested bile acid. The parameters of this linear dependence (intercept and slope) can be used to describe the hydrophobicity of the analyzed bile acid salts. The first and the second principal components, derived from the covariance matrix of temperature dependence of retention capacity, can also be used as hydrophobicity parameters of the analyzed bile acid salts. There is a strong correlation between the CMC values and the values of the hydrophobicity parameters of the convex surface (the β side) of the steroid skeleton: the CMC values decrease as the hydrophobicity of the β side of the steroid skeleton decreases.

Metabolism of synthetic cathinones through the zebrafish water tank model: a promising tool for forensic toxicology laboratories

PurposeThe aim of this study was to identify in vivo phase I metabolites of five psychoactive substances: N-ethylpentylone, ethylone, methylone, α-PVP and 4-CDC, using the in house developed experimental set-up zebrafish (Danio rerio) water tank (ZWT). High-resolution mass spectrometry allowed for metabolite identification. A pilot study of reference standard collection of N-ethylpentylone from the water tank was conducted.MethodsZWT consisted in 8 fish placed in a 200 mL recipient-containing water for a single cathinone. Experiments were performed in triplicate. Water tank samples were collected after 8 h and pretreated through solid-phase extraction. Separation and accurate-mass spectra of metabolites were obtained using liquid chromatography–high resolution tandem mass spectrometry.ResultsPhase I metabolites of α-PVP were identified, which were formed involving ketone reduction, hydroxylation, and 2″-oxo-pyrrolidine formation. The lactam derivative was the major metabolite observed for α-PVP in ZWT. N-Ethylpentylone and ethylone were transformed into phase I metabolites involving reduction, hydroxylation, and dealkylation. 4-CDC was transformed into phase I metabolites, reported for the first time, involving N-dealkylation, N,N-bis-dealkylation and reduction of the ketone group, the last one being the most intense after 8 h of the experiment.ConclusionsZWT model indicated to be very useful to study the metabolism of the synthetic cathinones, such as N-ethylpentylone, ethylone, α-PVP and 4-CDC. Methylone seems to be a potent CYP450 inhibitor in zebrafish. More experiments are needed to better evaluate this issue. Finally, this approach was quite simple, straightforward, extremely low cost, and fast for “human-like” metabolic studies of synthetic cathinones.

Synthesis and Cytotoxicity of 28-Oxo-Allobetulone Derivatives

28-Oxo-allobetulone derivatives that were newly synthesized or prepared earlier by modification of ring A (3- and 4-pyridylidene, furfurylidene, azepane, lactam, quinolone, spiroindole, pyrazole, isoxazole, and tetraoxane derivatives) and 3β,19β,28-oleantriol were tested in vitro for cytotoxicity against 60 cell lines of 9 human tumor types. Melanoma SK-MEL-5 and CNS SNB-75 cancer cells died in the presence of 3- or 4-pyridylidene derivatives of 28-oxo-allobetulone. 3β,19β,28-Oleantriol possessed selective cytotoxicity against CNS cancer cell line SNB-75.

Transamidation for the Synthesis of Primary Amides at Room Temperature.

Various primary amides have been synthesized using the transamidation of various tertiary amides under metal-free and mild reaction conditions. When (NH4)2CO3 reacts with a tertiary amide bearing an N-electron-withdrawing substituent, such as sulfonyl and diacyl, in DMSO at 25 °C, the desired primary amide product is formed in good yield with good funcctional group tolerance. In addition, N-tosylated lactam derivatives afforded their corresponding N-tosylamido alkyl amide products via a ring opening reaction.

Study the Biological Activity for Shiff Base and Β–Lactam Compounds that Synthesis and Identification from Pyrimidine Derivatives

In This study We are synthesis and characterization of some Schiff base and β- lactam derivatives) by three steps. The First react 2-amino-4-Chloro-6-methyl pyrimidine with 4-amino acetophenone in an acid medium to get shiff base derivative(E)-4-(1-((4-Chloro-6-methyl pyridine-2-yl)imino)ethyl)aniline (1), the second step (1) react with (3,4-dimethoxybenzal dehyde,4-methyl benzaldehyde,4-dimethylamino benzaldehyde,4-bromo benzaldehyde,4–hydroxy benzaldehyde, 4-Nitro benzaldehyde) to get Schiff base derivatives (2-7), the last step (2-7) derivatives react with Chloro acetyl chloride to get –β-lactam derivatives.(8-13) All these compounds are characterization by Fourier Transform Infrared Spectroscopy (FTIR), (1 H-NMR),(13C- NMR). After that study, the biological activity for all these derivatives to word two kinds of bacteria study the Enzymatic and Cancer Cell.

Total Synthesis of (−)-Lepadiformine A via Radical Translocation–Cyclization Reaction

Total synthesis of (-)-lepadiformine A featuring construction of the 1-azaspiro[4.5]decane skeleton by a highly diastereoselective radical translocation-cyclization reaction of a γ-lactam derivative bearing a chiral butenolide moiety is described. The enantioselective construction of butenolide is conducted via Krische's catalytic asymmetric allylation protocol. After the radical translocation-cyclization reaction, a hydroxymethyl group at the C-13 position was stereoselectively introduced by a one-pot partial reduction-allylation protocol of the unprotected lactam derivative. Finally, the total synthesis is completed by formation of a C ring.

Nickel-Catalyzed Annulation of Aliphatic Amides with Alkynyl­silanes: An Expeditious Approach to Five-Membered Lactams

An expeditious approach for the synthesis of diverse five-membered lactams through nickel-catalyzed annulation of the C(sp3)–H bonds of aliphatic amides with alkynylsilanes assisted by an 8-aminoquinolinyl directing group is reported, delivering the corresponding lactam derivatives in moderate to high yields. It is worth noting that alkynylsilanes are employed for the first time as coupling partners in the transition-metal-catalyzed functionalization of C(sp3)–H bonds of aliphatic amides. Equimolar amounts of alkynylsilanes and aliphatic amides are utilized, which greatly increases the efficiency of this protocol.