Heteroaromatic Groups Research Articles

Accessing a Medicinal-Chemistry-Relevant Chemical Space with sp2–sp3 Hybrid Heterocyclic Fragments

AbstractTarget-first drug discovery relies heavily on protein structure information, which severely limits its application. In recent years, fragment-based drug Design (FBDD) has been identified as an alternative solution, where screening of smaller molecules for lower affinity allowed the use of focused libraries with a higher hit rate. It is shown that coupling an sp2-rich heteroaromatic group with a monofunctional sp3-rich core gives fragments (186 examples) with advantageous physical-chemical properties, covering a chemical space often neglected in traditional libraries.

BAY-9835: Discovery of the First Orally Bioavailable ADAMTS7 Inhibitor.

The matrix metalloprotease ADAMTS7 has been identified by multiple genome-wide association studies as being involved in the development of coronary artery disease. Subsequent research revealed the proteolytic function of the enzyme to be relevant for atherogenesis and restenosis after vessel injury. Based on a publicly known dual ADAMTS4/ADAMTS5 inhibitor, we have in silico designed an ADAMTS7 inhibitor of the catalytic domain, which served as a starting point for an optimization campaign. Initially our inhibitors suffered from low selectivity vs MMP12. An X-ray cocrystal structure inspired us to exploit amino acid differences in the binding site of MMP12 and ADAMTS7 to improve selectivity. Further optimization composed of employing 5-membered heteroaromatic groups as hydantoin substituents to become more potent on ADAMTS7. Finally, fine-tuning of DMPK properties yielded BAY-9835, the first orally bioavailable ADAMTS7 inhibitor. Further optimization to improve selectivity vs ADAMTS12 seems possible, and a respective starting point could be identified.

Discovery of an enantiopure N-[2-hydroxy-3-phenyl piperazine propyl]-aromatic carboxamide derivative as highly selective α1D/1A-adrenoceptor antagonist and homology modelling

α1-Adrenergic receptor (AR) blockers can be effective for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS), their usage is limited by cardiovascular-related side effects that are caused by the subtype nonselective nature or low selectivity of many current drugs. We previously reported that phenylpiperazine analogues with amide and propane linker were moderate α1D/1A adrenoceptor antagonists and exhibited better anti-BPH effect than lead compound naftopidil (NAF) in vivo, however, with modest α1D/1A-subtype selectivity. Herein, we replaced propane moiety with 2-hydroxypropanol linker and synthesized twenty-seven racemic derivatives with modified aromatic and hetero aromatic groups. Of these new compounds, quinoline surrogate 17 exhibited extremely weak antagonistic affinity on α1B in both cell-based calcium assay and tissue-based functional assay, so that elicited significant α1A/1B and α1D/1B selectivity. Intriguingly, the R enantiomer of 17 preferentially displayed superior anti-BPH effect in rat model compared with S-17, supporting ligand regulates the receptor in a highly stereospecific manner. Finally, the computer-aided modelling research was also performed in order to deeply understand the unique binding mode of R-17 in complex with α1A and the subtype receptor selectivity for R-17 was also rationalized in this study. Taken together, our work enriched the diversity of phenylpiperazines for the treatment of BPH/LUTS, and provided a basis for discovery of α1D/1A-selective ligands.

Cross-over from pyrene to acene optical and electronic properties: a theoretical investigation of a series of pyrene derivatives fused with N-, S, and O-containing heterocycles.

Pyrene and acene derivatives are an important source of materials for optoelectronic device applications both as emitters and organic semiconductors. The mobility of major charge carriers is correlated with the coupling constants of the respective major charge carrier as well as the relaxation energies. Herein, we have applied range-separated density functionals for the estimation of said values. A series of five alkylated derivatives of pyrene laterally extended by heteroaromatic or phenyl groups were explored and contrasted to nascent pyrene, alkylated pyrene and tetracene. The ground state geometries along with absorption properties and relaxation energies are presented as well as a discussion of the suitability of the material toward hole and electron transport materials.

Radiofluorination of an Anionic, Azide-Functionalized Teroligomer by Copper-Catalyzed Azide-Alkyne Cycloaddition.

This study describes the synthesis, radiofluorination and purification of an anionic amphiphilic teroligomer developed as a stabilizer for siRNA-loaded calcium phosphate nanoparticles (CaP-NPs). As the stabilizing amphiphile accumulates on nanoparticle surfaces, the fluorine-18-labeled polymer should enable to track the distribution of the CaP-NPs in brain tumors by positron emission tomography after application by convection-enhanced delivery. At first, an unmodified teroligomer was synthesized with a number average molecular weight of 4550 ± 20 Da by free radical polymerization of a defined composition of methoxy-PEG-monomethacrylate, tetradecyl acrylate and maleic anhydride. Subsequent derivatization of anhydrides with azido-TEG-amine provided an azido-functionalized polymer precursor (o14PEGMA-N3) for radiofluorination. The 18F-labeling was accomplished through the copper-catalyzed cycloaddition of o14PEGMA-N3 with diethylene glycol-alkyne-substituted heteroaromatic prosthetic group [18F]2, which was synthesized with a radiochemical yield (RCY) of about 38% within 60 min using a radiosynthesis module. The 18F-labeled polymer [18F]fluoro-o14PEGMA was obtained after a short reaction time of 2-3 min by using CuSO4/sodium ascorbate at 90 °C. Purification was performed by solid-phase extraction on an anion-exchange cartridge followed by size-exclusion chromatography to obtain [18F]fluoro-o14PEGMA with a high radiochemical purity and an RCY of about 15%.

Nonselective Intercalation of G-Quadruplex-Targeting Ligands into Double-Stranded DNA Quantified by Single-Molecule Stretching.

Most G-quadruplex (G4)-targeting ligands reported so far contain planar heteroaromatic groups and can intercalate into adjacent base pairs of double-stranded DNA (dsDNA). However, quantitative data on the binding number γ (ligands/bp) of G4 ligands that intercalate into long dsDNA remain lacking, which are essential for understanding the selectivity of G4 ligands. Here, using a single-molecule stretching assay based on the lengthening of dsDNA, we analyzed the dissociation constants and the binding number of eight most commonly used G4 ligands that intercalate into dsDNA. We showed that five ligands (CX-5461, BRACO-19, RHPS4, TrisQ, and Phen-DC3) intercalate into dsDNA avidly (Kd = 0.5-2.1 μM, saturated γ > 0.2 ligands/bp), which was similar to the typical dsDNA intercalator EB. Two bisquinolines, PDS and 360A, showed moderate intercalation ability (Kd = 22.5 and 48.7 μM) and γ < 0.01 ligands/bp in the presence of 1 μM ligands. Porphyrin NMM showed no intercalative binding even at 200 μM. Molecular docking and molecular dynamics simulations were carried out to further evaluate the intercalative binding of these G4 ligands with dsDNA by calculating the binding energies and π-π stacking probability.

Imine‐Linked Porous Organic Polymer Gel and Immobilization of Copper(II): Easy Synthesis and Excellent Catalyst for Huisgen [3+2] Cycloaddition Reactions

AbstractPorous organic polymeric gels (POP gels) were made by condensation of a newly synthesized C3‐symmetrical azobenzene‐based tri‐salicylaldehyde building block, 1,3,5‐tris(4‐((3‐formyl‐4‐hydroxyphenyl)diazenyl)phenyl)benzene (TAzo) with suitable aromatic tri‐ and di‐amines in N,N‐dimethylformamide (DMF) at ambient conditions. Here, we have furnished the pathway of an efficient, gentle, and simple one‐pot synthesis of imine‐linked porous organic polymers at room temperature without any acid catalysts. Detail rheological properties of the POP‐gels were studied and were also found to be stable for at least a year at room temperature. Nitrogen isotherm revealed the mesoporous nature of the gel‐powders with moderate surface area. Iminophenol moieties are known to provide binding sites to metallic species via the strong coordination interaction with hydroxy (−OH) and imine (−HC=N−) groups. We have successfully synthesized a copper‐metallated POP by immobilizing copper ions in one of the POP‐gels. The mesoporous POP material having 3 wt % copper loading was utilized for the solvent‐free Huisgen [3+2] cycloaddition reactions of various aryl, benzyl, and alkyl azides with terminal alkynes containing aromatic, heteroaromatic, and alkyl groups with excellent yield. The heterogeneous catalyst with low catalyst loading (1 mol %) was highly regioselective towards 1,4‐disubstituted 1,2,3‐triazoles, recyclable, and did not require the addition of a reducing agent.

Modified distance optimization method for the asymmetric bioreduction conditions of phenyl(thiophen-2-yl)methanone by Weissella paramesenteroides N7

Chirality plays a significant part in life since it is closely linked to carrying out the many metabolic processes that make up a living being. Chiral secondary alcohols such as diaryl-, aryl heteroaryl-, and diheteroaryl are employed in pharmaceuticals as drug intermediates. Although biocatalytic asymmetric reduction of prochiral ketones containing aromatic and heteroaromatic groups is widely known, biocatalytic reduction of heteroaromatic prochiral ketones containing sulfur heteroatoms is rarely known. Very few studies exist in the literature, including the biocatalytic reduction of phenyl(thiophen-2-yl)methanone (1). Moreover, the biocatalytic reduction of 1 with a mathematical modelling and optimization technique is unknown until now. In this study, Weissella paramesenteroides N7 biocatalyst for the asymmetric bioreduction of 1 using a novel modified distance optimization method. Optimization conditions were found as pH = 6.46, temperature = 26 °C, incubation period = 71 h, agitation speed = 200 rpm by the modified distance optimization method, and it was determined that the conversion and enantiomeric excess (ee) under these conditions could be 98.7% and 98%, respectively. Under these proposed optimization conditions, (S)-phenyl(thiophen-2-yl)methanol ((S)-2) was obtained with >99% ee, >99% conversion, and 97% yield. In addition, 11.29 g of 1 was completely converted into (S)-2 (11.07 g, 97% isolated yield) under optimized conditions. This is the first report about the fabrication of enantiopure (S)-2 in high gram scale using a biocatalyst and a novel modified distance optimization technique. In this study, the successful applicability of the new modified distance optimization method in biocatalytic asymmetric reduction reactions has been successfully demonstrated.

Trading Symmetry for Stereoinduction in Tetradentate, non-C2 -Symmetric Fe(II)-Complexes for Asymmetric Catalysis.

A series of stereogenic-at-metal iron complexes comprising a non-C2 -symmetric chiral topology is introduced and applied to asymmetric 3d-transition metal catalysis. The chiral iron(II) complexes are built from chiral tetradentate N4-ligands containing a proline-derived amino pyrrolidinyl backbone which controls the relative (cis-α coordination) and absolute metal-centered configuration (Λ vs. Δ). Two chloride ligands complement the octahedral coordination sphere. The modular composition of the tetradentate ligands facilitates the straightforward incorporation of different terminal coordinating heteroaromatic groups into the scaffold. The influence of various combinations was evaluated in an asymmetric ring contraction of isoxazoles to 2H-azirines revealing that a decrease of symmetry is beneficial for the stereoinduction to obtain chiral products in up to 99 % yield and with up to 92 % ee. Conveniently, iron catalysis is feasible under open flask conditions with the bench-stable dichloro complexes exhibiting high robustness towards oxidative or hydrolytic decomposition. The versatility of non-racemic 2H-azirines was subsequently showcased with the conversion into a variety of quaternary α-amino acid derivatives.

An expeditious on-water regioselective synthesis of novel arylidene-hydrazinyl-thiazoles as DNA targeting agents

A series of twenty novel (E)-arylidene-hydrazinyl-thiazole derivatives has been synthesized employing α-bromo-β-diketones, thiosemicarbazide, and aromatic/heteroaromatic aldehydes with a simple and facile one-pot multicomponent reaction passageway. This organic transformation proceeds efficiently in aqueous media and demonstrated a large functional group tolerance. The structures and stereochemistry of the regioisomeric product were rigorously characterized using heteronuclear 2D NMR experiments. The binding potential of the synthesized analogs with B-DNA dodecamer d(CGCGAATTCGCG)2 was primarily screened using molecular modeling tools and further, mechanistic investigations (either groove or intercalation) were performed using various spectroscopic techniques such as UV–Visible, Fluorescence, and Circular dichroism. The absorption spectra showed a hyperchromic shift in the absorption maxima of ctDNA with successive addition of thiazole derivatives, implying groove binding mode of interactions, further supported by displacement assay and circular dichroism analysis. Furthermore, steady-state fluorescence analysis revealed the static mode of quenching and moderate bindings between the ligand and DNA biomolecule. The competitive studies showed that the derivatives having a pyridinyl (heteroaromatic) group in their structure, bind with the nucleic acid of calf-thymus (ctDNA) more effectively in the minor groove region as compared with the aromatic substitutions.

Transition-metal-free silylboronate-mediated cross-couplings of organic fluorides with amines

C–N bond cross-couplings are fundamental in the field of organic chemistry. Herein, silylboronate-mediated selective defluorinative cross-coupling of organic fluorides with secondary amines via a transition-metal-free strategy is disclosed. The cooperation of silylboronate and potassium tert-butoxide enables the room-temperature cross-coupling of C–F and N–H bonds, effectively avoiding the high barriers associated with thermally induced SN2 or SN1 amination. The significant advantage of this transformation is the selective activation of the C–F bond of the organic fluoride by silylboronate without affecting potentially cleavable C–O, C–Cl, heteroaryl C–H, or C–N bonds and CF3 groups. Tertiary amines with aromatic, heteroaromatic, and/or aliphatic groups were efficiently synthesized in a single step using electronically and sterically varying organic fluorides and N-alkylanilines or secondary amines. The protocol is extended to the late-stage syntheses of drug candidates, including their deuterium-labeled analogs.

Facilitating Rh-Catalyzed C-H Alkylation of (Hetero)arenes and 6-Arylpurine Nucleosides (Nucleotides) with Electrochemistry.

An electrochemical approach to promote the ortho-C-H alkylation of (hetero)arenes via rhodium catalysis under mild conditions is described. This approach features mild conditions with high levels of regio- and monoselectivity that tolerate a variety of aromatic and heteroaromatic groups and offers a widely applicable method for late-stage diversification of complex molecular architectures including tryptophan, estrone, diazepam, nucleosides, and nucleotides. Alkyl boronic acids and esters and alkyl trifluoroborates are demonstrated as suitable coupling partners. The isolation of key rhodium intermediates and mechanistic studies provided strong support for a rhodium(III/IV or V) regime.

Stereodivergent Desymmetrization of Simple Dicarboxylates via Branch-Selective Pd/Cu Catalyzed Allylic Substitution.

Asymmetric desymmetrization has been demonstrated to be a powerful strategy for building stereocenters in asymmetric synthesis. Herein, a Pd/Cu catalyzed asymmetric desymmetrization reaction with a simple geminal dicarboxylate is reported. A wide scope of imino esters bearing an aryl or heteroaromatic group were compatible with this bimetallic catalytic system. The reactions proceeded smoothly, giving the desired products in good yields with high to excellent regio-, diastereo-, and enantioselectivity (up to 20 : 1 branched:linear, >20 : 1 dr, >99 % ee). Notably, the reaction favored branched selectivity, which is unusual for the Pd-catalyzed allylic alkylation reaction. In addition, the standard product could be easily transformed to other valuable molecules such as chiral allylic alcohols, carbamates, and organic boron compounds. Furthermore, DFT calculations were conducted to explain the origin of the branched selectivity.

Synthesis of 1-Silabenzo[d,e]isochromanes via Electrophilic Aromatic Substitution of Aldehydes Activated by Silylium Ion.

A strong Lewis acid silylium ion was utilized for dehydrogenative annulation between dialkyl(1-naphthyl)silanes 1 and aldehydes 2. Silane 1a was reacted with [Ph3C][B(C6F5)4] in the presence of 2,6-di-tert-butyl-4-methylpyridine and aldehydes 2 to afford the annulation product, 1-silabenzo[d,e]isochromanes 3, in moderate isolated yields. The annulation occurred only at the 8-position on the 1-naphthyl group. The silylium ion-promoted hydrosilylation proceeded competitively to afford silyl ethers 4 via the same intermediates, silylcarboxonium ions, in the dehydrogenative annulation. The ratio of 3 and 4 was affected by solvents and the electronic properties of aromatic aldehydes; for example, the use of less polar solvents and that of benzaldehydes with an electron-withdrawing group at the para-position predominantly yielded 3. This annulation reaction was applicable to aldehydes bearing a heteroaromatic group and aliphatic alkyl groups. Judging from these results, both the formation of silylcarboxonium ions by in situ-generated silylium ions and the electrophilic aromatic substitution are important for this annulation reaction.

A facile synthesis of a novel family of heterotricyclic hybrids: Spiro-pyrrolopyridazines

An efficient strategy for the synthesis of spiro-pyrrolopyridazines has been developed. When reacted with hydrazine monohydrate, spiro-2H-pyrroles with a 1,4-diketone functionality produced a novel family of heterotricyclic hybrids, spiro-pyrrolopyridazines, specifically spiro{cyclohexane-1,5'-pyrrolo[3,4-d]pyridazine} systems. The condensation reaction of spiro-2H-pyrroles with hydrazine monohydrate in refluxing 1-butanol proceeded well and afforded spiro-pyrrolopyridazines in good to high yields. The reaction was found to be general for variety of spiro-2H-pyrroles and demonstrated good tolerance to a variety of aromatic and heteroaromatic groups with electron-withdrawing and electron-donating substituents. The synthesis of heterotricyclic spiro-pyrrolopyridazine hybrids may exhibit potential to deliver diverse structural motifs that aid the drug discovery efforts.

Effect of heteroaromatics on the photochromic properties of Bindone-Aryl SpiroCyclohexadienes

In the last decade, photochromes activated by visible light have garnered increased interest due to their ability to modulate the properties of materials via the most benign stimulus available, light. This interest has focused on the development of new photochromic classes and thorough study of how to selectively tune their properties. Currently, the dominant class arising from these efforts are Donor-Acceptor Stenhouse Adducts, which display negative T-type behavior. The recently discovered Bindone-Aryl SpiroCyclohexadienes, which display positive T-type behavior, are poised to serve as a complementary class to DASAs. Herein, we show that the spectral and kinetic characteristics of the emergent Bindone-Aryl SpiroCyclohexadiene class can be modulated via the introduction of heteroaromatic donor groups.

Catalyst-free carbosilylation of alkenes using silyl boronates and organic fluorides via selective C-F bond activation

A regioselective carbosilylation of alkenes has emerged as a powerful strategy to access molecules with functionalized silylated alkanes, by incorporating silyl and carbon groups across an alkene double bond. However, to the best of our knowledge, organic fluorides have never been used in this protocol. Here we disclose the catalyst-free carbosilylation of alkenes using silyl boronates and organic fluorides mediated by tBuOK. The main feature of this transformation is the selective activation of the C-F bond of an organic fluoride by the silyl boronate without undergoing potential side-reactions involving C-O, C-Cl, heteroaryl-CH, and even CF3 groups. Various silylated alkanes with tertiary or quaternary carbon centers that have aromatic, hetero-aromatic, and/or aliphatic groups at the β-position are synthesized in a single step from substituted or non-substituted aryl alkenes. An intramolecular variant of this carbosilylation is also achieved via the reaction of a fluoroarene with a ω-alkenyl side chain and a silyl boronate.

Ground- and excited-state properties of Re(I) carbonyl complexes – Effect of triimine ligand core and appended heteroaromatic groups

In this work, a series of six rhenium(I) complexes bearing 2,2′:6′,2″-terpyridine (terpy), 2,6-di(thiazol-2-yl)pyridine (dtpy), and 2,6-di(pyrazin-2-yl)pyridine (dppy) with appended quinolin-2-yl and N-ethylcarbazol-3-yl groups were prepared and spectroscopically investigated to evaluate the photophysical consequences of both the trisheterocyclic core (terpy, dtpy and dppy) and the heterocyclic substituent. The [ReCl(CO)3(Ln-κ2N)] complexes are regarded as ideal candidates for getting structure–property relationships, while terpy-like framework represents an excellent structural backbone for structural modifications. The replacement of the peripheral pyridine rings of 2,2′:6′,2″-terpyridine by thiazoles and pyrazines resulted in a significant red-shift of the absorption and emission of [ReCl(CO)3(Ln-κ2N)] due to stabilization of the ligand-centred LUMO orbital. Both quinoline and N-ethylcarbazole are extended π-conjugation organic chromophores, but they differ in electron-donating abilities. The low-energy absorption band of Re(I) complexes with the triimine ligands bearing quinolin-2-yl group was contributed by the metal-to-ligand charge-transfer (MLCT) electronic transitions. The introduction of electron-donating N-ethylcarbazol-3-yl substituent into the triimine acceptor core resulted in the change of the character of the HOMO of Re(I) complexes and a significant increase of molar absorption coefficients of the long-wavelength absorption, which was assigned to a combination of 1MLCT and 1ILCT (intraligand charge-transfer) transitions. Regardless of the appended heteroaromatic group, the emitting excited state of Re(I) terpy-based complexes was demonstrated to have predominant 3MLCT character, as evidenced by comprehensive studies including static and time-resolved emission spectroscopy along with ultrafast transient absorption measurements. The diodes with Re(I) complexes dispersed molecularly in a PVK:PBD matrix were emissive and effects of the complex structure on colour of emitted light and its intensity was pronounced.

The effects of long and bulky aromatic pendent groups with flexible linkages on the thermal, mechanical and electrical properties of the polyimides and their nanocomposites with functionalized silica.

A novel diamine bis(4-aminophenyl)bis{3,4[(4-(8-quinolyloxymethyl carbonyl)]}methane, containing two long/bulky aromatic pendent chains was synthesized by incorporating aromatic and hetero aromatic groups with flexible linkages. Flexible, stretchable, thermally stable and processable polyimides were prepared by reacting this newly synthesized diamine with commercial tetracarboxylic acid dianhydrides like 3,3′,4,4′-benzophenone tetra carboxylic acid dianhydride (BTDA) and 4,4′-(4,4′-isopropylidenediphenoxy)diphthalic Anhydride (BPADA). Nanocomposites of polyimides were prepared using aromatic amine functionalized silica as a filler by solution casting method. The current work investigates the effects of incorporating long/bulky aromatic side chains and flexible linkages on the thermal, mechanical, electrical and optical properties of the polyimides and nanocomposites. The polyimides showed good thermal stability (T10% = 364 & 388), high flame resistance, low glass transition temperatures (Tg = 130 °C & 156 °C), very low dielectric constants (2.5 & 2.8 at 1 MHz) and good optical transparency. The neat polyimides displayed good elongation at break (133–155%) but possessed low tensile strength. The chemically imidized polyimides showed good solubility in low and high boiling solvents. Nanocomposites of polyimides based on aromatic amine functionalized silica exhibited enhanced properties with T10% values varying between 409–482 °C, Tg between 165–280 °C and higher dielectric constants (3–5.7 at 1 MHz).

Positional Analogue Scanning: An Effective Strategy for Multiparameter Optimization in Drug Design.

Minimizing the number and duration of design cycles needed to optimize hit or lead compounds into high-quality chemical probes or drug candidates is an ongoing challenge in biomedical research. Small structure modifications to hit or lead compounds can have meaningful impacts on pharmacological profiles due to significant effects on molecular and physicochemical properties and intra- and intermolecular interactions. Rapid pharmacological profiling of an efficiently prepared series of positional analogues stemming from the systematic exchange of methine groups with heteroatoms or other substituents in aromatic or heteroaromatic ring-containing hit or lead compounds is one approach toward minimizing design cycles (e.g., exchange of aromatic or heteroaromatic CH groups with N atoms or CF, CMe, or COH groups). In this Perspective, positional analogue scanning is shown to be an effective strategy for multiparameter optimization in drug design, whereby substantial improvements in a variety of pharmacological parameters can be achieved.