Heterocyclic Backbone Research Articles

Synthesis, Photophysical, Antimicrobial Activity and In‐silico Study of Homoleptic Dithiocarbamate Complexes [MII{k2S^S‐S2CN(R)CH2C6H4OH}2] (R=2‐picolyl, 3‐picolyl; M=NiII, CuII, ZnII)

AbstractAn array of mononuclear dithiocarbamate complexes [MII{k2S^S‐S2CN(R)CH2C6H4OH}2] (R=2‐picolyl, M=NiII 1, CuII 2, ZnII 3, R=3‐picolyl, M=NiII 4, CuII 5, ZnII 6); incorporating heterocyclic backbone were synthesised from (2‐hydroxybenzyl)(2‐picolyl)amine (HL1) and (2‐hydroxybenzyl)(3‐picolyl)amine (HL2) precursors. The formulation of these complexes was examined using various spectroscopic and analytical techniques (1H NMR, 13C NMR, FTIR, UV‐visible, Fluorescence, TGA/DTA) and further corroborated by DFT level calculation. Notably, precursors HL1 and HL2 exhibits maximum emission in the visible nm region (ca 502 and 408 nm) upon excitation of ultraviolet radiation at ~280 nm with concomitant Stokes shift ca 220 and 128 nm, respectively. The emission properties of these evidently suppressed after complexation with metal ions. Stability of 1–6 were determined by thermogravimetric analysis. The magnetic moment along with UV‐visible of 1–6 suggests square‐planar environment around NiII and CuII and tetrahedral environment around ZnII in 1–6 which is in accord with their optimized geometries. Compounds were screened for in‐ vitro antimicrobial activity against E. coli, P. aeruginosa, S. aureus, S. pyogenes, C. albicans, A. niger, A. clavatus by broth dilution method. Molecular docking study was performed to rationalize the results.

Palladium-Catalyzed, Site-Selective C(sp2)8-H Halogenation and Nitration of 4-Quinolone Derivatives.

Selective installation of halo and nitro groups in heterocyclic backbone through a transition-metal-catalyzed C-H bond activation strategy is immensely alluring to access high-value scaffolds. Here in, we disclosed N-pyrimidyl-directed assisted palladium(II)-catalyzed C(sp2)8-H halogenation and nitration of substituted 4-quinolone derivatives in the presence of N-halosuccinimide and tert-butyl nitrite, respectively, offering structurally diversified 8-halo/nitro-embedded 4-quinolone frameworks in high yields. Mechanistic studies indicated that the reaction follows an organometallic pathway with a reversible C-H metalation step. This operationally simple protocol is scalable with a broad substrate scope and excellent functional group compatibility. Moreover, the postdiversifications of the synthesized derivatives are also showcased to ensure the synthetic versatility of the methodology.

Plant-Derived Coumarins: A Narrative Review of Their Structural and Biomedical Diversity.

Plant-derived coumarin (PDC) is a naturally occurring heterocyclic backbone that belongs to the benzopyrone family. PDC and its based products are characterized by low toxicity and high distribution in a variety of herbal treatments that have numerous therapeutic potentials. These include anticoagulants, antibacterials, anti-inflammatory agents, anticancer agents, antioxidants, and others. So, it may be appropriate to investigate the qualities and potential bioactivities of PDCs. This article provides an overview of the biomedical potentials, availability, and clinical use possibilities of PDCs, with a focus on their important modes of action, using information on various pharmacological qualities discovered. The data used in this study came from published research between 2015 and 2023. We reviewed a selection of databases, including PubMed, Scopus, Web of Science, and Google Scholar, during that period. In conclusion, because of their abundance in medicinal plants, the clinical biochemistry attributes of PDCs are currently of interest. In a variety of medical specialties, PDCs serve a useful role as therapeutic agents.

Functionalization of fused imidazole-oxadiazole, triazole-oxadiazole and tetrazole-oxadiazole skeletons: Search for stable and potential energetic materials

In this study, 21 energetic molecules were designed based on imidazo[2,1-b][1,3,4]oxadiazole, [1,2,4]triazolo[3,4-b][1,3,4]oxadiazole, and [1,3,4]oxadiazolo[3,2-d]tetrazole fused heterocyclic backbones by inserting NH2, N3, NO2, NHNO2, ONO2, CH(NO2)2, and C(NO2)3 functional groups. These compounds have high densities and excellent detonation performance. Among them, compounds with NO2, NHNO2, ONO2, CH(NO2)2, and C(NO2)3 substituents showed satisfactory detonation velocities (D > 8.70 km/s) and pressures (P > 35.2 GPa), which are equivalent to the performance of RDX and HMX. The analysis of energy gap (ΔE) in frontier molecular orbitals, free volume (ΔV) in a crystalline unit cell, maximum heat of detonation (Q), and percentage positive electrostatic potential reveal their moderate sensitivity. Combined with high nitrogen content, good density, energy content, and stability, imidazole-oxadiazole, triazole-oxadiazole, and tetrazole-oxadiazole [5 + 5] fused heterocyclic backbones will facilitate the preparation and development of new energetic materials.

Divergent Diazo Approach toward Alkyl 5/4-Hydroxy-3H-benzo[e]indole-4/5-carboxylates.

A divergent diazo approach toward alkyl 5/4-hydroxy-3H-benzo[e]indole-4/5-carboxylates has been developed. The reaction of 1,3-diketones with alkyl 2-diazo-3-oxo-3-(2H-azirin-2-yl)propanoates catalyzed by Co(acac)3 or Ni(acac)2 gives various alkyl 3-(1H-pyrrol-2-yl)-2-diazo-3-oxopropanoate in good yields. The latter undergo Wolff rearrangement followed by the 6π-cyclization of transient ketene to form alkyl 5-hydroxy-3H-benzo[e]indole-4-carboxylates bearing various substituents in positions 1, 2, 7, and 8, as well as derivatives of methyl 4-hydroxy-6H-thieno[2,3-e]indole-5-carboxylates and methyl 5-hydroxy-7H-benzo[c]carbazole-6-carboxylate under thermolysis or Rh2(OAc)4 catalysis. Isomeric benzoindoles, alkyl 4-hydroxy-3H-benzo[e]indole-5-carboxylates, have been prepared by Boc-protection of the pyrrole nitrogen of alkyl 3-(1H-pyrrol-2-yl)-2-diazo-3-oxopropanoates followed by an intramolecular formal carbene insertion into the aromatic C-H bond catalyzed by Cu(OTf)2. The hydroxyl group of alkyl 5/4-hydroxy-3H-benzo[e]indole-4/5-carboxylates, through the formation of the corresponding triflates, allows the introduction of various substituents into the 5/4 position of benzo[e]indoles using the cross-coupling reaction and even form a new heterocyclic backbone, benzo[k]pyrrolo[2,3-i]phenanthridine, via a tandem Suzuki reaction/nucleophilic acyl substitution.

Synthesis, characterization, testing, and detonation performance studies of fused pyrazole-based fluorescent energetic materials

Experts in the field of high energy materials strive to maintain a fine balance between energy and stability using nitrogen-rich materials and to apply sustainable development principles. Among the heterocyclic backbones, fused moieties are considered a significant backbone in energetic materials owing to their high energy content, dense nature, and stability. We have synthesized pyrazole-based fused compounds with high thermal stability, insensitivity, and moderate detonation performance to contribute to this development. All the compounds were isolated without column chromatography in one or two steps using commercially available affordable starting materials with excellent yields. Their molecular structure, crystallization, physicochemical properties, thermal stability and sensitivity behaviour were evaluated and compared with 2,4,6-trinitrotoluene (TNT), hexanitrostilbene (HNS), and 3,5-dinitro-N,N′-bis(2,4,6-trinitrophenyl) (PYX). All the compounds show acceptable detonation velocities (VOD: 7344–8068 m s−1), pressures (DP: 19–24.5 GPa), and insensitive to impact (25 - > 40 J) and friction (360 N). Among all the compounds, ammonium salt of 4-oxo-3,4-dihydropyrazolo[3,4-d] [1,2,3]triazin-6-ide (6) shows good density (1.77 g cm−3), detonation velocity (8068 m s−1) as well as 4-amino-pyrimidine 5-oxide (13) shows good physicochemical properties (d: 1.85 g cm−3, VOD: 7924 m s−1) Along with excellent insensitivity to impact and friction (35 - > 40 J and >360 N, respectively). These properties suggest that this can be a suitable replacement for benchmark explosives such as TNT, HNS, and PYX. Interestingly 4-amino-2H-pyrazolo[3,4-d]pyrimidine-5-oxide (3) exhibits fluorescence property, which can be used as a potential candidate in energetic filler or the formulations of energetic material for easy detection.

Antioxidant and Anticholinesterase Potentials of Novel 4,6-Dimethoxyindole based Unsymmetrical Azines: Synthesis, Molecular Modeling, In Silico ADME Prediction and Biological Evaluations

Chemically and biologically important -C = N-N = C- diimine linkage was used to build unsymmetrical azine systems with indole heterocyclic backbone and substituted aromatic carbaldehydes. Ten novel compounds 7a-j were synthesized by the Schiff base reaction of 4,6-dimethoxyindole-7-hydrazone 5 and a range of substituted carbaldehydes 6a-j with high yields and purities. The biological study was directed to identify the antioxidant potentials due to the expected electronic delocalization capability of designated linkage which is important for possible hydrogen or electron donation. The three different assays, namely DPPH free radical scavenging, ABTS cationic radical decolarization and CUPRAC (cupric reducing antioxidant capacity) were employed to detect the antioxidant properties. The antioxidant potentials were found to be moderate for ABTS and CUPRAC assays and the compound 7j was the most potent candidate for all the antioxidant assays. More importantly, the anticholinesterase properties were investigated by acetylcholinesterase (ACh) and butyrylcholinesterase (BCh) enzyme inhibition assays. The molecular docking studies were also carried out to determine the possible poses of ligands 7a-j in binding sites of enzymes and ligand-residue interactions. The synthesized compounds were found to be more effective for the anticholinesterase activity with three promising candidates 7d, 7h and 7j in the case of BChE inhibitions. The compound 7h was determined as the best candidate with the comparable IC50 values for AChE and better inhibition potency for BChE with 7j. A range of hydrophobic and hydrophilic interactions were detected for the designated compound 7h and 7j through different amino acid residues and the computational results were found to be compatible with the biological counterparts.

Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH3, CH2D, CD2H, CD3and13CH3Groups onto (Hetero)Arenes

Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH₃, CH₂D, CD₂H, CD₃and¹³CH₃Groups onto (Hetero)Arenes

Ru-Catalyzed One-Pot Synthesis of Heterocyclic Backbones

Ruthenium complexes are remarkable catalysts for the C–H activation approaches and organic transformations. Combining a Ru-catalyst with oxidants and other additives in a one-pot process is considered a sustainable approach due to the reduction in reaction steps and the minimal usage of solvents during synthesis, work-up, isolation of chemicals, and purification of the products. This review highlights the ruthenium-catalyzed organic transformations in a one-pot manner to achieve heterocyclic backbones, including indoles, benzofurans, indazoles, pyrans, pyrimidines, quinolines, and isoquinolines.

Redox-neutral C-H annulation strategies for the synthesis of heterocycles via high-valent Cp*Co(III) catalysis.

A variety of biologically active molecules, pharmaceuticals, and natural products consist of a nitrogen-containing heterocyclic backbone. The majority of them are isoquinolones, indoles, isoquinolines, etc.; thereby the synthesis and derivatization of such heterocycles are synthetically very relevant. Also, certain naphthol derivatives have high synthetic utility as agrochemicals and in dye industries. Previous approaches have utilized ruthenium, rhodium, or iridium which may not be desirable due to the high toxicity, low abundance, and high cost of such 4d and 5d metals. Moreover, the need for an external oxidant during the reaction also adds by-products to the system. A high-valent cobalt-catalyzed redox-neutral C-H functionalization strategy has emerged to be a far better alternative in this regard. The use of the non-noble metal cobalt allows for selectivity and specificity in product formation. Also, the redox-neutral concept avoids the use of an external oxidant either due to the presence of a metal in a non-variable oxidation state throughout the catalytic cycle or due to the presence of an oxidizing directing group or an oxidizing coupling partner. Such an oxidizing directing group not only directs the catalyst to a specific reaction site by chelation but also regenerates the catalyst at the end of the cycle. Certain bonds such as N-O, N-N, N-Cl, N-S, and C-S are the main game-players behind the oxidizing property of such directing groups. In the other case, the directing group only chelates the catalyst to a reaction center, whereas the oxidation is carried out by the upcoming group/coupling partner. Overall, merging the redox-neutral concept with the high-valent cobalt catalysis is paving the way forward toward a sustainable and environmentally friendly approach. This review critically describes the mechanistic understanding, scope, limitations, and synthesis of various biologically relevant heterocycles via the redox-neutral concept in the high-valent Cp*Co(III)-catalyzed C-H functionalization chemistry domain.

Recent Advances in Catalytic Asymmetric Syntheses of Functionalized Heterocycles via Halogenation/Chalcogenation of Carbon‐Carbon Unsaturated Bonds

AbstractHalogen (fluorine, chlorine, bromine, iodine) or chalcogen (sulfur, selenium)‐containing heterocycles are widely recognized as key building blocks in many natural products and bioactive targets. Catalytic asymmetric halogenation/chalcogenation of carbon‐carbon unsaturated bonds via onium ion transformations are efficient methods to obtain diverse chiral heterocyclic backbones. In the past few years, catalytic enantioselective versions of halo/thio/seleno‐functionalizations with various halogen and chalcogen electrophiles have experienced constant development. This review highlights those advances in preparing functionalized heterocycles promoted by chiral organocatalysts or metal‐based catalysts.magnified image

New Membrane Active Antibacterial and Antiviral Amphiphiles Derived from Heterocyclic Backbone of Pyridinium-4-Aldoxime

Quaternary ammonium salts (QAS) are irreplaceable membrane-active antimicrobial agents that have been widely used for nearly a century. Cetylpyridinium chloride (CPC) is one of the most potent QAS. However, recent data from the literature indicate that CPC activity against resistant bacterial strains is decreasing. The major QAS resistance pathway involves the QacR dimer, which regulates efflux pump expression. A plausible approach to address this issue is to structurally modify the CPC structure by adding other biologically active functional groups. Here, a series of QAS based on pyridine-4-aldoxime were synthesized, characterized, and tested for antimicrobial activity in vitro. Although we obtained several potent antiviral candidates, these candidates had lower antibacterial activity than CPC and were not toxic to human cell lines. We found that the addition of an oxime group to the pyridine backbone resulted in derivatives with large topological polar surfaces and with unfavorable cLog P values. Investigation of the antibacterial mode of action, involving the cell membrane, revealed altered cell morphologies in terms of corrugated and/or disrupted surface, while 87% of the cells studied exhibited a permeabilized membrane after 3 h of treatment at 4 × minimum inhibitory concentration (MIC). Molecular dynamic (MD) simulations of the interaction of QacR with a representative candidate showed rapid dimer disruption, whereas this was not observed for QacR and QacR bound to the structural analog CPC. This might explain the lower bioactivity of our compounds, as they are likely to cause premature expression of efflux pumps and thus activation of resistance.

Redirecting RiPP Biosynthetic Enzymes to Proteins and Backbone-Modified Substrates.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are peptide-derived natural products with potent antibiotic, antiviral, and anticancer properties. RiPP enzymes known as cyclodehydratases and dehydrogenases work together to catalyze intramolecular, inter-residue condensation and dehydrogenation reactions that install oxazoline/oxazole and thiazoline/thiazole heterocycles within ribosomally produced polypeptide chains. Here, we show that the previously reported enzymes MicD-F and ArtGox accept backbone-modified monomers—including aminobenzoic acid derivatives and beta-amino acids—within leader-free polypeptides, even at positions immediately preceding or following the site of cyclization/dehydrogenation. The products are sequence-defined chemical polymers with multiple, diverse non-α-amino acid subunits. We show further that MicD-F and ArtGox can install heterocyclic backbones within protein loops and linkers without disrupting the native tertiary fold. Calculations reveal the extent to which these heterocycles restrict conformational space; they also eliminate a peptide bond—both features could improve the stability or add function to linker sequences now commonplace in emerging biotherapeutics. This work represents a general strategy to expand the chemical diversity of the proteome beyond and in synergy with what can now be accomplished by expanding the genetic code.

Molecular docking studies of Amidoxime-containing heterocyclic compounds from Zinc database against homology modelled PfADSL

Malaria remains one of the most infectious life-threatening diseases in the world. The lingering effect of drug resistance by malarial parasites, especially Plasmodium falciparum, has made it essential for the continuous search for novel antimalarial drugs that can act on new protein targets and through new modes of action. Amidoxime functional groups have, in recent years, shown to be good incorporations in heterocyclic backbones due to their vast biological activities. Hence, the antimalarial activities of some amidoxime-containing heterocyclic compounds have been predicted using molecular docking studies to determine the binding affinities and the inhibition constants of the compounds. The amidoxime-containing compounds were downloaded from the ZINC database and docked, using Auto Dock vina, against the active sites of homology modelled Plasmodium falciparumadenylosuccinate lyase (PfADSL) as obtained from the SWISS-MoDeL. The grid box was constructed using 80, 80, and 80, pointing in x, y, and z directions, respectively, with a grid point spacing of 0.375 A. The post-docking analysis, which entails determining the hydrogen bond formed and the bond length between the compounds and the protein target, was carried out using AutoDockTools, LigPlot and PyMOLmolecular viewer. The docking studies showed that the compounds possess binding affinities ranging from -8.6 to- 5.7 kcal/mol, with ZINC2268942 having the lowest binding affinity. The presence of the amidoxime-functional group on the best hit contributed significantly to the hydrogen bonds formed between the compound and the binding sites of PfADSL,which were observed atThr 124D, Ser 125D, Thr 172C, His 173C, Gln 250D, and Ser 299A. The results obtained from the molecular docking studies will be helpful in the development of a potential antimalarial drug that can target PfADSL after careful experimental validation of the target, then in vitro and in vivo screening.

Discovery of a series of 5-phenyl-2-furan derivatives containing 1,3-thiazole moiety as potent Escherichia coli β-glucuronidase inhibitors

Gut microbial β-glucuronidases have drawn much attention due to their role as a potential therapeutic target to alleviate some drugs or their metabolites-induced gastrointestinal toxicity. In this study, fifteen 5-phenyl-2-furan derivatives containing 1,3-thiazole moiety (1–15) were synthesized and evaluated for their inhibitory effects against Escherichia coli β-glucuronidase (EcGUS). Twelve of them showed satisfactory inhibition against EcGUS with IC50 values ranging from 0.25 μM to 2.13 μM with compound 12 exhibited the best inhibition. Inhibition kinetics studies indicated that compound 12 (Ki = 0.14 ± 0.01 μM) was an uncompetitive inhibitor for EcGUS and molecular docking simulation further predicted the binding model and capability of compound 12 with EcGUS. A preliminary structure-inhibitory activity relationship study revealed that the heterocyclic backbone and bromine substitution of benzene may be essential for inhibition against EcGUS. The compounds have the potential to be applied in drug-induced gastrointestinal toxicity and the findings would help researchers to design and develop more effective 5-phenyl-2-furan type EcGUS inhibitors.

Tetranitro-diazinodiazines as high energy materials: computational investigation of structural aspects of fused heterocyclic backbone and isomerism

Thirteen tetranitro-diazinodiazines have been designed and investigated to find the importance of diazinodiazine fused-heterocyclic backbone for energetic materials. The positional influence of four nitrogen atoms in the diazinodiazine backbone on the heat of formation, performance, and stability has been investigated by density functional theory. It is observed that diazinodiazine is an efficient backbone to improve energy content in the designed derivatives. The energy contribution from the diazinodiazine backbone varies from 352–558 kJ/mol. Introducing four –NO2 groups into the diazinodiazine backbone resulted in new energetic molecules with acceptable detonation performance and stability. Their densities, detonation velocities, and detonation pressures were 1.87–1.89 g/cm3, 8.36–8.68 km/s, and 31.72–34.42 GPa, respectively. The bond dissociation energies for the longer C–NO2 bonds fall in the range of 207–233 kJ/mol, reveals the stable nature of tetranitro-diazinodiazines. Thus, diazinodiazine isomers may be regarded as promising aromatic heterocyclic backbone, and tetranitro-diazinodiazines appear to be potential candidates for energetic materials.

Synthesis of Spiro-β-lactam-pyrroloquinolines as Fused Heterocyclic Scaffolds through Post-transformation Reactions.

A sequential post-transformation of Ugi four-component reaction/nucleophilic substitution was developed for the synthesis of spiro-β-lactam-pyrroloquinolines. This method involves the Ugi-4CR of 2-chloro-3-formyl quinolines 1a-h, amines 2a-d, 2-chloroacetic acid 3, and isocyanides 4a, 4b for the synthesis of versatile precursors 5a-v. The Ugi adducts were intramolecularly cyclized under basic conditions through the sequential nucleophilic aromatic substitution (SNAr)/second-order nucleophilic substitution (SN2) reaction to give spiro-β-lactam-pyrroloquinoline scaffolds 6a-t. This approach is an efficient method for the synthesis of fused bioactive heterocyclic backbones containing quinoline, pyrrolidone, and β-lactam with high bond-forming efficiency.

Recent advances in the diversification of chromones and flavones by direct C[sbnd]H bond activation or functionalization

Chromone and flavone are both central backbones of natural products and clinical medicines. Synthesis of diversely functionalized chromones and flavones constitutes significant research contents of the modern synthetic science because abundant molecular libraries of such types are crucial in providing candidate compounds for the discovery of new pharmaceuticals and functional materials. The direct CH bond activation or functionalization on these heterocyclic backbones provides highly powerful tools for the rapid accesses to densely functionalized chromone and flavone derivatives. Considering the importance of the functionalized chromone and flavone compounds as well as the notable advances in the synthesis of such products by direct CH activation or functionalization, we review herein the research advances in the CH bond activation and functionalization reactions of chromone and flavones, in hope of showing the current states and promise of the research domain.

Diverse N-Substituted Azole-Containing Amino Acids as Building Blocks for Cyclopeptides.

The preparation of 16 oxazole- or thiazole-containing amino esters bearing a wide array of N-substitution is reported. These were accessed in 40–92% yield via an AgClO4-promoted substitution reaction between a primary amine and a chloromethyl-functionalized thiazole or oxazole. These new synthetic building blocks will be useful for the preparation of new cyclopeptide analogues bearing heterocyclic backbone modifications. Four macrocyclic N-substituted oligoamides that include thiazole or oxazole heterocycles were obtained, following cyclooligomerization reactions of azole-modified N-substituted amino acids.

N-Heterocyclic Olefin-Ligated Palladium(II) Complexes as Pre-Catalysts for Buchwald-Hartwig Aminations.

New N-heterocyclic olefins (NHOs) are described with functionalization on the ligand heterocyclic backbone and terminal alkylidene positions. Various PdII -NHO complexes have been formed and their use as pre-catalysts in Buchwald-Hartwig aminations was explored. The most active system for catalytic C-N bond formation between hindered arylamine and arylhalide substrates was accessed by combining a backbone methylated NHO with [Pd(cinnamyl)Cl]2 in the presence of NaOtBu as a base. In these active systems evidence suggests that catalysis is mediated by colloidal palladium metal, highlighting a different coordination ability of NHOs in comparison with commonly used N-heterocyclic carbene co-ligands.