Nitrogen Heterocycles Research Articles

Recent Advances in the Synthesis of Piperazines: Focus on C–H Functionalization

Piperazine ranks as the third most common nitrogen heterocycle in drug discovery, and it is the key component of several blockbuster drugs, such as Imatinib (also marketed as Gleevec) or Sildenafil, sold as Viagra. Despite its wide use in medicinal chemistry, the structural diversity of piperazines is limited, with about 80% of piperazine-containing drugs containing substituents only at the nitrogen positions. Recently, major advances have been made in the C–H functionalization of the carbon atoms of the piperazine ring. Herein, we present an overview of the recent synthetic methods to afford functionalized piperazines with a focus on C–H functionalization.

ABCpred: a webserver for the discovery of acetyl- and butyryl-cholinesterase inhibitors.

Alzheimer's disease (AD) is one of the most common forms of dementia and is associated with a decline in cognitive function and language ability. The deficiency of the cholinergic neurotransmitter known as acetylcholine (ACh) is associated with AD. Acetylcholinesterase (AChE) hydrolyses ACh and inhibits the cholinergic transmission. Furthermore, both AChE and butyrylcholinesterase (BChE) plays important roles in early and late stages of AD. Therefore, the inhibition of either or both cholinesterase enzymes represent a promising therapeutic route for treating AD. In this study, a large-scale classification structure-activity relationship model was developed to predict cholinesterase inhibitory activities as well as revealing important substructures governing their activities. Herein, a non-redundant dataset constituting 985 and 1056 compounds for AChE and BChE, respectively, was obtained from the ChEMBL database. These inhibitors were described by 12 sets of molecular fingerprints and predictive models were developed using the random forest algorithm. Evaluation of the model performance by means of Matthews correlation coefficient and consideration of the model's interpretability indicated that the SubstructureCount fingerprint was the most robust with five-fold cross-validated MCC of [0.76, 0.82] for AChE and BChE, respectively, and test MCC of [0.73, 0.97]. Feature interpretation revealed that the aromatic ring system, heterocyclic nitrogen containing compounds and amines are important for cholinesterase inhibition. Finally, the model was deployed as a publicly available webserver called the ABCpred at http://codes.bio/abcpred/ .

Effect of Methods and Catalysts on the One-pot Synthesis of Tetrahydropyridine Derivatives: A Mini-Review

As heterocyclic nitrogen molecules, tetrahydropyridines have been recognized as significant constituents of many natural and synthetic compounds, many of which have interesting biological and pharmacological properties. Tetrahydropyridines (THPs) play a pivotal role in synthesizing a range of remedial compounds. They have exhibited impressive curative efficacy for the treatment of numerous diseases. Due to this reason, they are attractive synthetic targets for organic chemists. Several techniques and schemes have been adopted for the synthesis of these molecules. Among these, multicomponent reactions (MCRs) are proved to be one of the best tools for achieving compounds containing complex diversity in a single step and production of their vast libraries. Along with this, the employment of various catalysts makes this technique more vibrant. This review article discussed different catalysts adopted in the synthesis of tetrahydropyridine derivatives via multicomponent reactions to provide information for the development of new-fangled processes aiming at less reaction time, better yield, and minimum side effects. DOI: http://dx.doi.org/10.17807/orbital.v13i4.1585

Discovery of interstellar 3-cyano propargyl radical, CH2CCCN

We report the first detection in interstellar space of the 3-cyano propargyl radical (CH2C3N). This species was observed in the cold dark cloud TMC-1 using the Yebes 40m telescope. A total of seven rotational transitions for both ortho- and para-CH2C3N species were observed in the 31.0–50.4 GHz range. We derive a total column density of (1.6 ± 0.4) × 1011 cm−2 and an ortho/para ratio of 2.4 ± 1.2, which implies an abundance ratio CH2C3N/CH3C3N ∼ 0.1, in sharp contrast with the smaller analogues, in which case CH2CN/CH3CN ∼ 3. This indicates that the chemistry of the cyanides CH2C3N and CH3C3N behaves differently to that of the smaller analogues CH2CN and CH3CN. According to our chemical model calculations, the radical CH2C3N is mostly formed through the neutral-neutral reactions C + CH2CHCN, C2 + CH3CN, and CN + CH2CCH together with the dissociative recombination of the CH3C3NH+ ion with electrons. The neutral-neutral reaction N + C4H3 could also lead to CH2C3N, although its role is highly uncertain. The identified radical CH2C3N could play a role in the synthesis of large organic N-bearing molecules, such as benzonitrile (c–C6H5CN) or nitrogen heterocycles.

Pharmacological Studies on Novel Triazino Quinolines

Pharmacological importance of the nitrogen heterocycles is countless. The triazines are found to possess exceptional biological antitumor, anti-HIV, antiviral, antimalarial, antimicrobial, cytotoxic activities. The current investigation attempts to evaluate invitro antibacterial, antifungal, antioxidant potential, and cytotoxicity of newly synthesized substituted 4'-methyl-3-thioxo-1,2,4-triazinoquinolin-5-one. The antimicrobial activity was done by Agar Well Diffusion Method and the MIC of the compound was found using the Broth dilution assay method. The compounds showed excellent antibacterial activity against selected bacterial strains, including Gram-positive S. aureus, S. pyogens, and Gram-negative bacteria P. aeroginosa, E. coli, K. peumoniae, Pseudomonas Sp with the zones of inhibition 9 to 19nm. The standard drug Ampicillin showed a maximum inhibitory zone 18 nm. Among all the screened compounds, sample exhibited good activity. Similarly, the compounds were screened for antifungal properties, which showed an excellent reduction in the growth of selected fungal strain for Candida albicans. The compounds were also screened for 1,1-diphenyl-2-picrylhydrazyl (DPPH) activity. Cytotoxicity was done in Dalton's Lymphoma Ascites (DLA) cells which were obtained from Amala Cancer Research Center. The tested compounds exhibited significant antioxidant activity in a concentration-dependent manner.

Conditions for increasing the hydrodesulfurization of dibenzothiophene when co-feeding naphthalene, quinoline, and indole

In this work, we report a statistically significant increase in the rates of direct C–S bond scission of dibenzothiophene when co-reactants such as naphthalene, quinoline, and indole are present during its hydrodesulfurization over a Ni–MoS2/γ-Al2O3 catalyst. The competitive adsorption of these compounds on the same active sites has usually been associated with inhibitory effects of sulfur elimination. However, we carried out statistically designed experiments at temperatures between 260 and 300 °C, concentrations of dibenzothiophene between 1.0 and 3.7 wt%, and concentrations of the co-reactants between 0.13 and 0.52 wt%, and observed that the kinetic constant of the direct desulfurization pathway can increase up to 200% when either naphthalene, indole, or quinoline is co-fed to the reaction system at 260 °C and 3.7 wt% of dibenzothiophene. Therefore, the classical paradigm that aromatics and nitrogen heterocycles always inhibit hydrodesulfurization needs reexamination.

Electrocyclizations of Conjugated Azapolyenes Produced in Reactions of Azaheterocycles with Metal Carbenes

Conjugated azapolyenes (azabuta-1,3-dienes, aza-/diaza-/oxaza-/oxadiazahexa-1,3,5-trienes) are highly reactive in electrocyclization reactions, which makes them convenient precursors for the synthesis of a wide range of four-, five-, and six-membered nitrogen heterocycles that are of relevance for medicinal chemistry. Ring opening reactions of 2H-azirines and azoles containing an N–N or N–O bond, initiated by a transition metal carbene, have become increasingly important in recent years, since they easily allow the generation of azapolyenes with different numbers of double bonds and heteroatoms in various positions. This review summarizes the literature, published mainly in the last decade, on the synthetic and mechanistic aspects of electrocyclizations of azapolyenes generated by the carbene method.

Marine Pyrrole Alkaloids.

Nitrogen heterocycles are essential parts of the chemical machinery of life and often reveal intriguing structures. They are not only widespread in terrestrial habitats but can also frequently be found as natural products in the marine environment. This review highlights the important class of marine pyrrole alkaloids, well-known for their diverse biological activities. A broad overview of the marine pyrrole alkaloids with a focus on their isolation, biological activities, chemical synthesis, and derivatization covering the decade from 2010 to 2020 is provided. With relevant structural subclasses categorized, this review shall provide a clear and timely synopsis of this area.

Energy and reactivity profile and proton affinity analysis of rimegepant with special reference to its potential activity against SARS-CoV-2 virus proteins using molecular dynamics

Rimegepant is a new medicine developed for the management of chronic headache due to migraine. This manuscript is an attempt to study the various structural, physical, and chemical properties of the molecules. The molecule was optimized using B3LYP functional with 6-311G + (2d,p) basis set. Excited state properties of the compound were studied using CAM-B3LYP functional with same basis sets using IEFPCM model in methanol for the implicit solvent atmosphere. The various electronic descriptors helped to identify the reactivity behavior and stability. The compound is found to possess good nonlinear optical properties in the gas phase. The various intramolecular electronic delocalizations and non-covalent interactions were analyzed and explained. As the compound contain several heterocyclic nitrogen atoms, they have potential proton abstraction features, which was analyzed energetically. The most important result from this study is from the molecular docking analysis which indicates that rimegepant binds irreversibly with three established SARS-CoV-2 proteins with ID 6LU7, 6M03, and 6W63 with docking scores − 9.2988, − 8.3629, and − 9.5421 kcal/mol respectively. Further assessment of docked complexes with molecular dynamics simulations revealed that hydrophobic interactions, water bridges, and π–π interactions play a significant role in stabilizing the ligand within the binding region of respective proteins. MMGBSA-free energies further demonstrated that rimegepant is more stable when complexed with 6LU7 among the selected PDB models. As the pharmacology and pharmacokinetics of this molecule are already established, rimegepant can be considered as an ideal candidate with potential for use in the treatment of COVID patients after clinical studies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00894-021-04885-z.

From the sensitive primary explosive ICM-103 to insensitive heat-resistant energetic materials through a local azide-to-amino structural modification strategy

With the increasing demand for deep mineral resources and rapid development of space exploration, the search for advanced heat-resistant energetic compounds have attracted increasing attention in the field of energetic materials. In this study, we designed and prepared two new fused aromatic nitrogen heterocyclic compounds of 4-amino-5-nitro-7H-pyrazolo[3,4-d][1,2,3]triazine-2-oxide (PTO) and 4-amino-7-methyl-5-nitro-7H-pyrazolo[3,4-d][1,2,3]triazine-2-oxide (MPTO) by a local structural modification on a highly sensitive initiating explosive (ICM-103). This minor structural adjustment endows PTO and MPTO with totally different properties in contrast to the starting material (ICM-103). The decomposition temperatures of PTO and MPTO reached 365.0 °C and 347.7 °C, respectively, around 200 °C higher than that (160.3 °C) of ICM-103. Moreover, PTO and MPTO also exhibit good detonation velocity (8528 m s−1 and 8102 m s−1, respectively) and low impact sensitivity (20 J and 18 J, respectively). The comprehensive performances of PTO and MPTO are superior to the widely used heat-resistant energetic materials HNS (Td: 318 °C, Dv: 7612 m s−1, IS: 5 J) and PYX (Td: 360 °C, Dv: 7757 m s−1, IS: 10 J), demonstrating their important applied potentiality as novel heat-resistant energetic materials.

Modulating Triplet Excited-State Energy in Phosphorescent Carbon Dots for Information Encryption and Anti-Counterfeiting.

Room-temperature phosphorescent carbon dots (RTP-CDs) may be used in anti-counterfeiting, information encryption, and optoelectronic devices, but modulating their triplet-state energy is still challenging. Here, a type of RTP-CDs was developed via hydrothermal polymerization-carbonization of azamacrocycle and poly(acrylic acid). The introduction of nitrogen heterocycle promotes the intersystem crossing from the singlet state to the triplet state, and the functional groups of CDs can form interdot hydrogen bonds to protect the triplet state. In addition, the uncarbonized heterocycle groups in the CDs provide coordination sites for metal ions. In this case, the excited triplet-state energy of CDs is quenched by paramagnetic ions (Co2+ and Cu2+) or transfers to luminescent ions (Tb3+ and Eu3+). Furthermore, the modulation of the triplet state by metal ion binding was demonstrated in information encryption and anti-counterfeiting applications.

From Glycals to Nitrogen Heterocycles and Carbocycles via "Cleavage-Intramolecular Recombination Strategy".

Glycals (carbohydrate enol-ethers) have enjoyed profound applications in organic synthesis for more than a century. They not only serve as versatile glycosyl donors or as substrates for Ferrier rearrangement, but also find extensive synthetic applications especially as a "chiral pool" for accomplishing the synthesis of a variety of natural and biologically important compounds. As cyclic enol ethers, they demonstrate high reactivity and are among the most and variously transformable monosaccharide derivatives. The uniqueness of the reactivity of glycals is that they can be synthetically tuned to get a library of derivatives through stereo- and regioselective introduction of a variety of functional groups at C1, C2, C3 as well as C4 carbons of the sugar. We have developed a practical approach for stereoselective mono- and diamination of glycals and over the years utilized these scaffolds for the synthesis of a variety of biologically important nitrogen heterocycles and carbocycles through a "Diversity Oriented Approach". Our synthetic strategy in this direction mainly relied on the cleavage of ring O-C bond of the sugar followed by an "intramolecular recombination" reaction. Utilizing this strategy, we have accomplished the synthesis of several biologically important natural products, their analogues and related unnatural derivatives. Examples of such compounds reported from our group include polyhydroxypyrrolidines, DMDP, anisomycin, steviamine, pochonicine, conduramines, bulgecinine, aminocyclitols, azepanes, 4-hydroxy-D-proline, azanucleosides and their analogues. A personal account highlighting these syntheses is presented here.

Effect of heterocyclic nitrogen ionic liquid additives on the rate of backreaction in DSSCS: An electrochemical characterization

The backreaction in dye-sensitized solar cells (DSSCs) was long ago recognized as one of the main causes of decreasing energy conversion efficiency. Hence, many different approaches have been attempted to reduce the backreaction. In the present work, we use nitrogen additives in the electrolyte to reduce the backreaction with TiO 2 and I 3 − . Intensity-modulated photocurrent/photovoltage (IMPS/IMVS) and charge extraction (CE) techniques are used to obtain information on the dynamics of charge carriers in DSSCs assembled with and without nitrogen additives. The passivation process occurring on the nanoparticles, which is promoted by the additives, prevents recombination but does not change the electron transport time. Therefore, the description of transport and electron recombination kinetics in DSSCs is well established in this work with the emerging IMPS, IMVS, and CE techniques. • Conversion efficiency of DSSC had improved. • The methods IMPS/VS and CE evaluated electrolyte/electrode interface. • Ionic liquids formed a block layer on TiO 2 surface. • The backreaction was decreased. • Ionic liquids have no role in TiO 2 electron transport smoothing.

Diarylborinic Acid-Catalyzed Regioselective Ring Openings of Epoxy Alcohols with Pyrazoles, Imidazoles, Triazoles, and Other Nitrogen Heterocycles.

A method for regioselective ring openings of 3,4- and 2,3-epoxy alcohols with ambident nitrogen heterocycles is described. Using a diarylborinic acid catalyst, a single regioisomer is favored in couplings of nucleophile and electrophile partners that display low regioselectivity under conventional conditions. The method provides access to aromatic heterocycles bearing stereochemically defined, functionalized alkyl substituents, a product class similar in structure to medicinally relevant compounds such as the acyclic nucleoside analogues.

A Comparative Test on the Sensitivity of Freshwater and Marine Microalgae to Benzo-Sulfonamides, -Thiazoles and -Triazoles

The evaluation of the ecotoxicological effects of water pollutants is performed by using different aquatic organisms. The effects of seven compounds belonging to a class of widespread contaminants, the benzo-fused nitrogen heterocycles, on a group of simple organisms employed in reference ISO tests on water quality (unicellular algae and luminescent bacteria) have been assessed to ascertain their suitability in revealing different contamination levels in the water, wastewater, and sediments samples. Representative compounds of benzotriazoles, benzothiazoles, and benzenesulfonamides, were tested at a concentration ranging from 0.01 to 100 mg L−1. In particular, our work was focused on the long-term effects, for which little information is up to now available. Species-specific sensitivity for any whole family of pollutants was not observed. On average, the strongest growth rate inhibition values were expressed by the freshwater Raphidocelis subcapitata and the marine Phaeodactylum tricornutum algae. R. subcapitata was the only organism for which growth was affected by most of the compounds at the lowest concentrations. The tests on the bioluminescent bacterium Vibrio fisheri gave completely different results, further underlining the need for an appropriate selection of the best biosensors to be employed in biotoxicological studies.

N-Atom Deletion in Nitrogen Heterocycles.

Excising the nitrogen in secondary amines, and coupling the two residual fragments is a skeletal editing strategy that can be used to construct molecules with new skeletons, but which has been largely unexplored. Here we report a versatile method of N-atom excision from N-heterocycles. The process uses readily available N-heterocycles as substrates, and proceeds by N-sulfonylazidonation followed by the rearrangement of sulfamoyl azide intermediates, providing various cyclic products. Examples are provided of deletion of nitrogen from natural products, synthesis of chiral O-heterocycles from commercially available chiral β-amino alcohols, formal inert C-H functionalization through a sequence of N-directed C-H functionalization and N-atom deletion reactions in which the N-atom can serve as a traceless directing group.

4 + 1] Cyclization of benzohydrazide and ClCF2COONa towards 1,3,4-oxadiazoles and 1,3,4-oxadiazoles-d5

A facile synthesis of 1,3,4-oxadiazoles and 1,3,4-oxadiazoles-d5via [4 + 1] cyclization of ClCF2COONa with non-amine compounds containing amino groups is developed. Of note, this is the first time that halofluorinated compounds are used as C1 synthon to construct deuterated nitrogen-heterocyclic compounds. The current protocol features simple operation, readily accessible raw materials, wide substrate scope and valuable products

Asymmetric Alkylation of Ketones Catalyzed by Engineered TrpB

AbstractThe β‐subunit of tryptophan synthase (TrpB) catalyzes a PLP‐mediated β‐substitution reaction between indole and serine to form L‐Trp. A succession of TrpB protein engineering campaigns to expand the enzyme's nucleophile substrate range has enabled the biocatalytic production of diverse non‐canonical amino acids (ncAAs). Here, we show that ketone‐derived enolates can serve as nucleophiles in the TrpB reaction to achieve the asymmetric alkylation of ketones, an outstanding challenge in synthetic chemistry. We engineered TrpB by directed evolution to catalyze the asymmetric alkylation of propiophenone and 2‐fluoroacetophenone with a high degree of selectivity. In reactions with propiophenone, preference for the opposite product diastereomer emerges over the course of evolution, demonstrating that full control over the stereochemistry at the new chiral center can be achieved. The addition of this new reaction to the TrpB platform is a crucial first step toward the development of efficient methods to synthesize non‐canonical prolines and other chirally dense nitrogen heterocycles.

Asymmetric Alkylation of Ketones Catalyzed by Engineered TrpB.

The β-subunit of tryptophan synthase (TrpB) catalyzes a PLP-mediated β-substitution reaction between indole and serine to form L-Trp. A succession of TrpB protein engineering campaigns to expand the enzyme's nucleophile substrate range has enabled the biocatalytic production of diverse non-canonical amino acids (ncAAs). Here, we show that ketone-derived enolates can serve as nucleophiles in the TrpB reaction to achieve the asymmetric alkylation of ketones, an outstanding challenge in synthetic chemistry. We engineered TrpB by directed evolution to catalyze the asymmetric alkylation of propiophenone and 2-fluoroacetophenone with a high degree of selectivity. In reactions with propiophenone, preference for the opposite product diastereomer emerges over the course of evolution, demonstrating that full control over the stereochemistry at the new chiral center can be achieved. The addition of this new reaction to the TrpB platform is a crucial first step toward the development of efficient methods to synthesize non-canonical prolines and other chirally dense nitrogen heterocycles.

N‐Atom Deletion in Nitrogen Heterocycles

AbstractExcising the nitrogen in secondary amines, and coupling the two residual fragments is a skeletal editing strategy that can be used to construct molecules with new skeletons, but which has been largely unexplored. Here we report a versatile method of N‐atom excision from N‐heterocycles. The process uses readily available N‐heterocycles as substrates, and proceeds by N‐sulfonylazidonation followed by the rearrangement of sulfamoyl azide intermediates, providing various cyclic products. Examples are provided of deletion of nitrogen from natural products, synthesis of chiral O‐heterocycles from commercially available chiral β‐amino alcohols, formal inert C−H functionalization through a sequence of N‐directed C−H functionalization and N‐atom deletion reactions in which the N‐atom can serve as a traceless directing group.