Heterocyclic Core Research Articles

Synthesis and Reactivity of a Zinc Diazoalkyl Complex: [3+2] Cycloaddition Reaction with Carbon Monoxide

AbstractThis work reports the synthesis, characterization, and reactivity of the first example of a well‐defined zinc α‐diazoalkyl complex. Treatment of zinc(I)‐zinc(I) bonded compound L2Zn2 [L=CH3C(2,6‐iPr2C6H3N)CHC(CH3)(NCH2CH2PPh2)] or zinc(II) hydride LZnH with trimethylsilyldiazomethane affords zinc diazoalkyl complex LZnC(N2)SiMe3. This complex liberates N2 in the presence of a nickel catalyst to form an α‐zincated phosphorus ylide by reacting with the pendant phosphine. It selectively undergoes formal [3+2] cycloaddition with CO2 or CO to form the corresponding product with a five‐membered heterocyclic core. Notably, the use of CO in such a [3+2] cycloaddition reaction is unprecedented, reflecting a novel CO reaction mode.

Trifluoromethyl-substituted 2,8-diaryl-imidazo[1,2-a][1,8]naphthyridines: Synthesis, remarkable optical emission, and redox and thermal properties

A novel series of thirteen examples of 2,8-diaryl-4-(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridines (6) was synthesized at 21–96% yields, in which 2,8-diaryl = C6H5, 4-BrC6H4, 4-OMeC6H4, 4-CF3C6H4, and 2-naphtyl by intermolecular and regioselective [3+2] cyclocondensation reaction of a series of selected 7-aryl-2-amino-5-(trifluoromethyl)-[1,8]naphthyridines (3) with 1-aryl-2-bromo-ethanones (5). Aromatic amines 3 and bromo ethanones 5 were obtained by previously reported methods, which reacted 2,6-diamino-pyridine (2) with 4-aryl-4-methoxy-1,1,1-trifluorobut-3-en-2-ones (1) to obtain 3 and some acetophenones 4 with elemental bromo to synthesize 5. All new compounds 6 were fully characterized by 1H-, 13C, 19F NMR and IR spectroscopy, SC-XRD, and HRMS methods. The optical and electrochemical properties of the derivatives were determined by UV–Vis, steady-state and time-resolved fluorescence emission (solution and solid state), TD-DFT calculations, and redox potential and discussed, indicating a dependence of the substitution position in the heterocyclic core. In addition, the TGA experiments showed that compounds 6 presented good thermal stability at the 150–300 °C range.

Synthesis and Reactivity of a Zinc Diazoalkyl Complex: [3+2] Cycloaddition Reaction with Carbon Monoxide.

This work reports the synthesis, characterization, and reactivity of the first example of a well-defined zinc α-diazoalkyl complex. Treatment of zinc(I)-zinc(I) bonded compound L2 Zn2 [L=CH3 C(2,6-i Pr2 C6 H3 N)CHC(CH3 )(NCH2 CH2 PPh2 )] or zinc(II) hydride LZnH with trimethylsilyldiazomethane affords zinc diazoalkyl complex LZnC(N2 )SiMe3 . This complex liberates N2 in the presence of a nickel catalyst to form an α-zincated phosphorus ylide by reacting with the pendant phosphine. It selectively undergoes formal [3+2] cycloaddition with CO2 or CO to form the corresponding product with a five-membered heterocyclic core. Notably, the use of CO in such a [3+2] cycloaddition reaction is unprecedented, reflecting a novel CO reaction mode.

Motifs in Natural Products as Useful Scaffolds to Obtain Novel Benzo[d]imidazole-Based Cannabinoid Type 2 (CB2) Receptor Agonists.

The endocannabinoid system (ECS) constitutes a broad-spectrum modulator of homeostasis in mammals, providing therapeutic opportunities for several pathologies. Its two main receptors, cannabinoid type 1 (CB1) and type 2 (CB2) receptors, mediate anti-inflammatory responses; however, their differing patterns of expression make the development of CB2-selective ligands therapeutically more attractive. The benzo[d]imidazole ring is considered to be a privileged scaffold in drug discovery and has demonstrated its versatility in the development of molecules with varied pharmacologic properties. On the other hand, the main psychoactive component of Cannabis sativa, delta-9-tetrahydrocannabinol (THC), can be structurally described as an aliphatic terpenoid motif fused to an aromatic polyphenolic (resorcinol) structure. Inspired by the structure of this phytocannabinoid, we combined different natural product motifs with a benzo[d]imidazole scaffold to obtain a new library of compounds targeting the CB2 receptor. Here, we synthesized 26 new compounds, out of which 15 presented CB2 binding and 3 showed potent agonist activity. SAR analysis indicated that the presence of bulky aliphatic or aromatic natural product motifs at position 2 of the benzo[d]imidazoles ring linked by an electronegative atom is essential for receptor recognition, while substituents with moderate bulkiness at position 1 of the heterocyclic core also participate in receptor recognition. Compounds 5, 6, and 16 were further characterized through in vitro cAMP functional assay, showing potent EC50 values between 20 and 3 nM, and compound 6 presented a significant difference between the EC50 of pharmacologic activity (3.36 nM) and IC50 of toxicity (30-38 µM).

Total Synthesis of Racemic Thieno[3,2-f]thiochromene Tricarboxylate, a Luciferin from Marine Polychaeta Odontosyllis undecimdonta.

We report the first total synthesis of racemic Odontosyllis undecimdonta luciferin, a thieno[3,2-f]thiochromene tricarboxylate comprising a 6-6-5-fused tricyclic skeleton with three sulfur atoms in different electronic states. The key transformation is based on tandem condensation of bifunctional thiol-phosphonate, obtained from dimethyl acetylene dicarboxylate, with benzothiophene-6,7-quinone. The presented convergent approach provides the synthesis of the target compound with a previously unreported fused heterocyclic core in 11 steps, thus allowing for unambiguous confirmation of the chemical structure of Odontosyllis luciferin by 2D-NMR spectroscopy.

Exploring the chemical space of functionalized [1,2,4]triazolo[4,3-a]quinoxaline-based compounds targeting the bromodomain of BRD9

Here we report a detailed structure–activity relationship (SAR) study related to [1,2,4]triazolo[4,3-a]quinoxaline-based compounds targeting the reader module of bromodomain containing-protein 9 (BRD9). 3D structure-based pharmacophore models, previously introduced by us, were here employed to evaluate a second generation of compounds, exploring different substitution patterns on the heterocyclic core. Starting from the promising data obtained from our previously identified [1,2,4]triazolo[4,3-a]quinoxaline-based compounds 1–4, the combination of in silico studies, chemical synthesis, biophysical and in vitro assays led to the identification of a new set of derivatives, selected for thoroughly exploring the chemical space of the bromodomain binding site. In more details, the investigation of different linkers at C-4 position highlighted the amine spacer as mandatory for the binding with the protein counterpart and the crucial role of the alkyl substituents at C-1 for increasing the selectivity toward BRD9. Additionally, the importance of a hydrogen bond donor group, critical to anchor the ZA region and required for the interaction with Ile53 residue, was inferred from the analysis of our collected results. Herein we also propose an optimization and an update of our previously reported “pharm-druglike2” 3D structure-based pharmacophore model, introducing it as “pharm-druglike2.1”. Compounds 24-26, 32, 34 and 36 were identified as new valuable BRD9 binders featuring IC50 values in the low micromolar range. Among them, 24 and 36 displayed an excellent selectivity towards BRD9 and a good antiproliferative effect on a panel of leukemia models, especially toward CCRF-CEM cell line, with no cytotoxicity on healthy cells. Notably, the interaction of 24 and 36 with the bromodomain and PHD finger-containing protein 1 (BRPF1) also emerged, disclosing them as new and unexplored dual inhibitors for these two proteins highly involved in leukemia. These findings highlight the potential for the identification of new attractive dual epidrugs as well as a promising starting point for the development of chemical degraders endowed with anticancer activities.

Exploring Pyrrolo-Fused Heterocycles as Promising Anticancer Agents: An Integrated Synthetic, Biological, and Computational Approach.

Five new series of pyrrolo-fused heterocycles were designed through a scaffold hybridization strategy as analogs of the well-known microtubule inhibitor phenstatin. Compounds were synthesized using the 1,3-dipolar cycloaddition of cycloimmonium N-ylides to ethyl propiolate as a key step. Selected compounds were then evaluated for anticancer activity and ability to inhibit tubulin polymerization in vitro. Notably, pyrrolo[1,2-a]quinoline 10a was active on most tested cell lines, performing better than control phenstatin in several cases, most notably on renal cancer cell line A498 (GI50 27 nM), while inhibiting tubulin polymerization in vitro. In addition, this compound was predicted to have a promising ADMET profile. The molecular details of the interaction between compound 10a and tubulin were investigated through in silico docking experiments, followed by molecular dynamics simulations and configurational entropy calculations. Of note, we found that some of the initially predicted interactions from docking experiments were not stable during molecular dynamics simulations, but that configurational entropy loss was similar in all three cases. Our results suggest that for compound 10a, docking experiments alone are not sufficient for the adequate description of interaction details in terms of target binding, which makes subsequent scaffold optimization more difficult and ultimately hinders drug design. Taken together, these results could help shape novel potent antiproliferative compounds with pyrrolo-fused heterocyclic cores, especially from an in silico methodological perspective.

DIPINODIAZAFLUORENES AS REAGENTS FOR SELECTIVE EXTRACTION OF PALLADIUM, GOLD AND RUTHENIUM

Dipinodiazafluorenes are hybrid nopinane-annelated heterocycles whose molecules include a heterocyclic core of 4,5-diazafluorene condensed with fragments of terpene hydrocarbon, capable of selectively extracting palladium (88−100%), gold (42−96%) and ruthenium (8−19%) by single extraction from acidic aqueous solutions (pH 1.2) containing complex mixtures of 3d-elements and precious metals.

Torsional Control of Frustrated Lewis Pair Behaviour Involving PNP‐type Phosphines

AbstractWe present convenient syntheses of a range of PNP‐type phosphines which feature a pair of ortho‐functionalized ArPPh2 moieties linked via a central NMe unit, but which differ in the nature of the additional backbone ‘tether’ linking the aryl groups. These comprise the acyclic system bis(2‐diphenylphosphinophenyl)methylamine, together with related systems centred around 5‐, 6‐ and 7‐membered heterocycles. Structurally, contraction of the backbone tether causes the phosphine centres to be projected further apart, and to be more constrained torsionally to the plane containing the NMe unit. In terms of potential frustrated Lewis pair (FLP) reactivity, the conformationally more flexible systems based on an acyclic linker or a cyclic core featuring a 7‐membered ring, are capable of achieving P−B bond formation and generating a classical Lewis adduct with B(C6F5)3. The less flexible carbazole‐derived compound (featuring a five membered heterocyclic core) gives rise to an FLP at room temperature, and an equilibrium mixture of frustrated and classical Lewis pairs at lower temperatures. Most interestingly, the PNP system based on a central six‐membered acridine ring ‐ which gives rise to the shortest contacts in the solid state between phosphorus and the N‐bound methyl group – undergoes C−H activation in the presence of B(C6F5)3, resulting in the formation of B−H and P−C bonds.

Push-pull chromophores with π-deficient benzoazine and π-excessive thiophene cores in conjugated bridge as sources of quadratic nonlinear optical activity of composite polymer materials and molecular glasses

Impact of π-deficient heterocyclic core (A′) in conjugated bridge of D-π-A′-π-A chromophores (D = N,N-dihexylaniline, A = tricyanofuran derivative) on optical and thermal properties has been investigated. Three new chromophores with vinyl-hetaryl-vinyl bridges containing π-deficient benzoazine moiety (quinoxaline, quinoxalinone and quinoline) have been synthesized along with new chromophores with vinyl-thiophene-vinyl bridge containing π-excessive heterocycle and short vinylene bridge, and their properties are compared to reveal the role of π-deficient hetaryl moiety. Their linear optical properties were systematically investigated by UV–Vis spectroscopy and molecular nonlinear optical (NLO) characteristics were predicted by DFT calculations. As the aromaticity of the heterocycle in the bridge increases, a hypochromicity and hypsochromic shift of the absorption maximum manifest themselves in the UV–Vis spectra, the origin of electron transitions was studied by TD-DFT with CAM-B3LYP and PBE0 density functionals. The calculated first hyperpolarizability, βtot, for A′ = quinoxaline, quinoline and thiophene, was shown to be almost independent on the type of the π-bridge core, being in a narrow interval 800–831⋅10−30 esu, while for A′ = quinoxalinone βtot is essentially higher (996⋅10−30 esu). All chromophores exhibit good thermal stability (Td > 192 °C). Thin films of composite polymer materials with PMMA matrix and studied chromophores as guests as well as of some molecular glasses were spin-cast and corona-poled, and their quadratic NLO activity was measured by two different techniques. For materials with guest chromophores containing quinoxalinone, quinoxaline and thiophene moieties in the bridges NLO coefficients d33 were found to be rather close and reached 76 pm/V, what is almost 3 times higher than that for polymer film with quinoline-based chromophore. Rather high values of NLO coefficients for molecular glasses based on chromophores with quinoline, thiophene and quinoxalinone cores were obtained: 52, 124 and 132 pm/V, respectively, which notably exceed the values for composite materials with these chromophores as guests.

Triad pyrazole–thiazole–coumarin heterocyclic core effectively inhibit HSP and drive cancer cells to apoptosis

Intensive studies on hepatocellular carcinoma (HCC), which is spreading rapidly around the world and has a high mortality rate, is due to the lack of adequate preventive or curative treatment methods. Treating patients with HCC has become very challenging because of the heterogeneity in the patient population lead activation of different signaling pathways, and pathway crosstalk for patients. Therefore, understanding these molecular mechanisms and combining drugs with molecular therapies to overcome these drawbacks has become an area of utmost importance. In this study, the biological activities of the designed and characterized triad Pyrazole–Thiazol–Coumarin (PTC) compounds were determined by performing cell viability, qPCR array, apoptosis and cell cycle assays. One of the compounds (PTC10) implicitly suppresses multiple pathways (RAS/MAP kinase and PI3K-AKT) simultaneously. This action is provided by (i) arresting cancer cells at G2 phase, (ii) driving cancer cells to apoptosis and (iii) inhibiting HSP network. Remarkably, HSP is an apoptotic factor and help cancer cell to survive. HSP90 also coordinates with Cdk4/Cdc37, therefore inhibiting HSP both drives cells to arrest and apoptosis. ATP hydrolysis and aggregation assay further displayed specific HSP inhibition. Therefore, PTC provides a unique drug template for HCC treatment.

Synthesis and Properties of Diphenylbenzo[j]naphtho[2,1,8-def][2,7]phenanthrolines.

A series of hitherto unknown 5,14-diphenylbenzo[j]naphtho[2,1,8-def][2,7]phenanthrolines, containing a 5-azatetracene and a 2-azapyrene subunit, were prepared by combination of Pd-catalyzed cross-coupling reactions with a one-pot Povarov/cycloisomerization reaction. In the final key step four new bonds are formed in one step. The synthetic approach allows for a high degree of diversification of the heterocyclic core structure. The optical and electrochemical properties were studied experimentally and by DFT/TD-DFT and NICS calculations. Due to the presence of the 2-azapyrene subunit, the typical electronic nature and characteristics of the 5-azatetracene moiety are lost and the compounds are electronically and optically more related to 2-azapyrenes.

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.

Late-Stage C(sp3)-H Methylation of Drug Molecules.

Methyl groups are well understood to play a critical role in pharmaceutical molecules, especially those bearing saturated heterocyclic cores. Accordingly, methods that install methyl groups onto complex molecules are highly coveted. Late-stage C-H functionalization is a particularly attractive approach, allowing chemists to bypass lengthy syntheses and facilitating the expedited synthesis of drug analogues. Herein, we disclose the direct introduction of methyl groups via C(sp3)-H functionalization of a broad array of saturated heterocycles, enabled by the merger of decatungstate photocatalysis and a unique nickel-mediated SH2 bond formation. To further demonstrate its synthetic utility as a tool for late-stage functionalization, this method was applied to a range of drug molecules en route to an array of methylated drug analogues.

Multicomponent DNA-Compatible Synthesis of an Annelated Benzodiazepine Scaffold for Focused Chemical Libraries.

Annelated benzodiazepines are attractive drug-like scaffolds with a broad spectrum of biological activities. Incorporation of this heterocyclic core into DNA-encoded chemical libraries (DELs) via multicomponent assembly is highly demanded. Herein, we developed a DNA-compatible method to generate the tricyclic benzodiazepine scaffold via catalyst-free three-component condensation using a broad range of aldehyde, o-phenylenediamine, and diketone sources. With either aldehyde or o-phenylenediamine conjugated with DNA tags, functionalized 1,5-benzodiazepine scaffolds were efficiently forged, expanding the chemical space of the diazepine-centered drug-like DEL.

Diversity-Oriented Synthesis (DOS) of On-DNA Peptidomimetics from Acid-Derived Phosphonium Ylides.

The DNA-encoded library (DEL) technology represents a revolutionary drug-discovery tool with unprecedented screening power originating from the association of combinatorial chemistry and DNA barcoding. The chemical diversity of DELs and its chemical space will be further expanded as new DNA-compatible reactions are introduced. This work introduces the use of DOS in the context of on-DNA peptidomimetics. Wittig olefination of aspartic acid-derived on-DNA Wittig ylide, combined with a broad substrate scope of aldehydes, led to formation of on-DNA , -unsaturated ketones. The synthesis of on-DNA multi-peptidyl-ylides was performed by incorporating sequential amino acids onto a monomeric ylide. Di-, tri- and tetrameric peptidyl-ylides were validated for Wittig olefination and led to on-DNA , -unsaturated-based peptidomimetics, an important class of intermediates. One on-DNA aryl Wittig ylide was also developed and applied to Wittig olefination for synthesis of on-DNA chalcone-based molecules. Furthermore, DOS was used successfully with electron-deficient peptidomimetics and led to the development of different heterocyclic cores containing on-DNA peptidomimetics.

Diversity Oriented Approach to New Tetrahedral Building Blocks by Ring‐Closing Metathesis

AbstractWe disclose an approach to a library of novel multidimensional O‐heterocycles based on a rigid, tetrahedral core. New derivatives of tetraphenylmethane (TPM) have been synthesized by employing Claisen rearrangement (CR) and ring‐closing metathesis (RCM) as key steps. Mono‐, di‐, tri‐, and tetra‐substituted benzofurans, 2H‐chromenes, and benzoxepine derivatives are reported. Various heterocyclic cores present in these compounds are key structural elements present in several natural products and pharmaceuticals as well as valuable precursors for the construction of complex molecules with the tetrahedral framework. To the best of our knowledge, this is the first report involving the synthesis of five‐, six‐, and seven‐membered O‐heterocycles in TPM core and the basecatalyzed inexpensive synthesis of several isomerized intermediates that are useful to prepare oxacycles such as benzofuran and 2H‐chromenes. The symmetrical and unsymmetrical one, two, three, and four‐armed architecture of TPM makes it a valuable starting point for building complex molecular and supramolecular architectures. To expand the unmet chemical space of the TPM core, we have prepared twenty new derivatives by a unified approach. Additionally, we report a simple, catalyst‐free, and inexpensive recipe for double bond isomerization based on KOtBu to assemble various oxacycles derived from different trityl chloride derivatives.

Chlorination effects of a non-fullerene acceptor based on a selenium heterocyclic core for high-efficiency organic solar cells

The photovoltaic performance of three chlorinated NFAs based on a selenium heterocyclic core (namely BTSeIC-2Cl-γ, BTSeIC-2Cl-mix and BTSeIC-4Cl) were researched by precisely regulating the number and position of end-group chlorine atoms.

NH-1,2,3-triazoles as versatile building blocks in denitrogenative transformations.

The utilization of NH-1,2,3-triazoles as easily accessible building blocks in denitrogenative ring cleavage transformations with electrophiles to provide multifunctionalized nitrogen heterocycles and N-alkenyl compounds is reviewed. Leveraging the ready availability of NH-1,2,3-triazoles, these processes provide a convenient route to a range of pharmaceutically relevant heterocyclic cores and N-alkenyl compounds. The synthetic usefulness of in situ acylated NH-1,2,3-triazoles as viable alternatives to widely explored N-sulfonyl-1,2,3-triazoles in ring cleavage processes is highlighted.

In-vitro ANTI-INFLAMMATORY AND ANTIOXIDANT ACTIVITY OF NOVEL 1-SUBSTITUTED-3-SUBSTITUTED PROPANE-1,3-DIONES (β-DIKETONES) DERIVED FROM VANILLIN

In synthetic chemistry,propane-1,3-diones or β-diketones act as significant intermediates for the synthesis of core heterocycles due to their specific chemoselectivity properties as well as provide convenient building blocks to biologically active substituents. In the present work, a new series of β-diketones namely 1-(5’-Formyl-2’-hydroxy3’-methoxyphenyl)-3-(substitutedphenyl) propane-1,3-diones 4(a-e) have been synthesized from versatile 4- hydroxy-3-methoxybenzaldehyde viz. vanillin and studied their invitro anti-inflammatory and antioxidant potential by performing inhibition of protein denaturation assay and reducing power assay method respectively. All the newly synthesized compounds exhibit notable and satisfactory anti-inflammatory potential as well as potent antioxidant activity due to the presence of vanillin moiety in their molecular structure