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7-Azaindoles are compounds of considerable medicinal interest. During development of the structure–activity relationship for inhibitors of the colony stimulated factor 1 receptor tyrosine kinase (CSF1R), a specific 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amine was needed. Two different synthetic strategies were evaluated, in which the order of the key C-C and C-N cross-coupling steps differed. The best route relied on a chemoselective Suzuki–Miyaura cross-coupling at C-2 on a 2-iodo-4-chloropyrrolopyridine intermediate, and subsequently a Buchwald–Hartwig amination with a secondary amine at C-4. Masking of hydroxyl and pyrroles proved essential to succeed with the latter transformation. The final trimethylsilylethoxymethyl (SEM) deprotection step was challenging, as release of formaldehyde gave rise to different side products, most interestingly a tricyclic eight-membered 7-azaindole. The target 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amine (compound 3c) proved to be 20-fold less potent than the reference inhibitor, confirming the importance of the N-3 in the pyrrolopyrimidine parent compound for efficient CSF1R inhibition. [ABSTRACT FROM AUTHOR]

Molecular structures of 5-chloro-7-azaindole-3-carbaldehyde (5Cl7AICA) and 4-chloro-7-azaindole-3-carbaldehyde (4Cl7AICA) were investigated using infrared and Raman spectroscopy supported by density functional theory (DFT) calculations. Theoretical studies were carried out with three DFT methods, which include dispersion corrections: B3LYP-D3, PBE0-D3, and ωB97X-D. A single-crystal X-ray diffraction analysis was performed for 5Cl7AICA. The compound crystallizes in the monoclinic system, space group P21/c, with lattice parameters a = 3.82810(12) Å, b = 12.7330(3) Å, c = 15.9167(5) Å, and β = 94.539(3)°, with Z = 4. Within the crystal lattice, 5Cl7AICA molecules form dimers via dual and strong N1–H1⋅⋅⋅N7′ hydrogen bonds, accompanied by other intermolecular interactions. In the DFT calculations, two types of dimers of the investigated molecules were analyzed: dimer 1, which is present in the crystal structure of 5Cl7AICA, and dimer 2 displaying a 180° rotation of the aldehyde group compared to dimer 1. Computational results indicate that dimer 1 is more stable than dimer 2 for 5Cl7AICA, whereas dimer 2 is more stable than dimer 1 for 4Cl7AICA molecules. Furthermore, experimental and theoretical vibrational spectra were examined to elucidate the influence of internal rotation of the aldehyde group on spectroscopic properties. [ABSTRACT FROM AUTHOR]

7-Azaindoles are compounds of considerable medicinal interest. During development of the structure–activity relationship for inhibitors of the colony stimulated factor 1 receptor tyrosine kinase (CSF1R), a specific 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amine was needed. Two different synthetic strategies were evaluated, in which the order of the key C-C and C-N cross-coupling steps differed. The best route relied on a chemoselective Suzuki–Miyaura cross-coupling at C-2 on a 2-iodo-4-chloropyrrolopyridine intermediate, and subsequently a Buchwald–Hartwig amination with a secondary amine at C-4. Masking of hydroxyl and pyrroles proved essential to succeed with the latter transformation. The final trimethylsilylethoxymethyl (SEM) deprotection step was challenging, as release of formaldehyde gave rise to different side products, most interestingly a tricyclic eight-membered 7-azaindole. The target 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amine (compound 3c) proved to be 20-fold less potent than the reference inhibitor, confirming the importance of the N-3 in the pyrrolopyrimidine parent compound for efficient CSF1R inhibition.

Molecular structures of 5-chloro-7-azaindole-3-carbaldehyde (5Cl7AICA) and 4-chloro-7-azaindole-3-carbaldehyde (4Cl7AICA) were investigated using infrared and Raman spectroscopy supported by density functional theory (DFT) calculations. Theoretical studies were carried out with three DFT methods, which include dispersion corrections: B3LYP-D3, PBE0-D3, and ωB97X-D. A single-crystal X-ray diffraction analysis was performed for 5Cl7AICA. The compound crystallizes in the monoclinic system, space group P21/c, with lattice parameters a = 3.82810(12) Å, b = 12.7330(3) Å, c = 15.9167(5) Å, and β = 94.539(3)°, with Z = 4. Within the crystal lattice, 5Cl7AICA molecules form dimers via dual and strong N1–H1⋅⋅⋅N7′ hydrogen bonds, accompanied by other intermolecular interactions. In the DFT calculations, two types of dimers of the investigated molecules were analyzed: dimer 1, which is present in the crystal structure of 5Cl7AICA, and dimer 2 displaying a 180° rotation of the aldehyde group compared to dimer 1. Computational results indicate that dimer 1 is more stable than dimer 2 for 5Cl7AICA, whereas dimer 2 is more stable than dimer 1 for 4Cl7AICA molecules. Furthermore, experimental and theoretical vibrational spectra were examined to elucidate the influence of internal rotation of the aldehyde group on spectroscopic properties.

[Display omitted] • Azaindole derivative was grafted to TiO 2 as a novel photocatalyst. • TiO 2 sensitization was achieved by a bipolar electron-donor and -acceptor molecule. • Grafted-TiO 2 allowed the photodegradation of different pharmaceuticals in water. • Grafting leads to the TiO 2 band gap narrowing and favors the charge separation. • Photocatalytic performance was maintained in continuous flow regime. The application of metal-free organic molecules grafted titanium dioxide (TiO 2) as photocatalysts for the degradation of pharmaceuticals under solar light has been scarcely studied. Herein, a novel photocatalyst was synthesized anchoring a bipolar electron-donor and -acceptor molecule based on azaindole derivative (AZA4) onto TiO 2 aiming to improve the photoactivity under simulated solar irradiation. The TiO 2 -azaindole (TiO 2 -AZA4) was fully characterized, confirming that AZA4 was successfully grafted onto TiO 2 and improving the light absorption. The grafted TiO 2 was applied in the photodegradation of acetaminophen in water, showing a significantly better photocatalytic performance compared to that of pure TiO 2 under both solar and visible irradiations. AZA4 grafting leads to the TiO 2 band gap narrowing and favors the charge separation, thus improving the TiO 2 photoactivity. The photocatalytic performance of TiO 2 -AZA4 was evaluated using different conditions such as photocatalyst dose or initial pH of the solution, and the radical species involved in the process were investigated. The high activity of TiO 2 -AZA4 was confirmed in the photodegradation of a mixture of pharmaceuticals, namely acetaminophen, ibuprofen, and antipyrine, further demonstrating its stability and catalytic performance in a novel continuous flow test under simulated solar irradiation, thus finding a new strategy to design solar-light driven photocatalysts for the degradation of pollutants in water. [ABSTRACT FROM AUTHOR]

[Display omitted] Emerging clinical evidence indicates that selective CDK9 inhibition may provide clinical benefits in the management of certain cancers. Many CDK9 selective inhibitors have entered clinical developments, and are being investigated. No clear winner has emerged because of unforeseen toxicity often observed in clinic with these agents. Therefore, a novel agent with differentiated profiles is still desirable. Herein, we report our design, syntheses of a novel azaindole series of selective CDK9 inhibitors. SAR studies led to a preclinical candidate YK-2168. YK2168 exhibited improved CDK9 selectivity over AZD4573 and BAY1251152; also showed differentiated intravenous PK profile and remarkable solid tumor efficacy in a mouse gastric cancer SNU16 CDX model in preclinical studies. YK-2168 is currently in clinical development in China (CTR20212900). [ABSTRACT FROM AUTHOR]

Vinyl sulfides accessed via Wittig olefination with thioalkylphosphonium salts are used as aldehyde- or ketone surrogates in Fischer indole reactions. These vinyl sulfides react with arylhydrazines in the presence of TsOH·H2 O in refluxing ethanol or dichloroethane to yield diverse 3-substituted and 2,3-disubstituted indoles or azaindoles. The utility of this chemistry is highlighted with the efficient preparation of three biomedically relevant compounds: 4-aza-melatonin, a furoindoline, and an indomethacin-like CRTh2 antagonist. [ABSTRACT FROM AUTHOR]

Herein, we synthesized some new 4‐azaindole‐morpholine‐1,3,4‐oxadiazole conjugates (11 a–n) and evaluated for their in vitro anticancer potency towards three human cancer cell lines namely MCF‐7, A549 and HepG2 using MTT assay. Among all, compounds (1‐((5‐(4‐methoxyphenyl)‐1,3,4‐oxadiazol‐2‐yl)methyl)‐1H‐pyrrolo[3,2‐b]pyridin‐3‐yl) (morpholino) methanone (11 d), 4‐(5‐((3‐(morpholine‐4‐carbonyl)‐1H‐pyrrolo[3,2‐b]pyridin‐1‐yl)methyl)‐1,3,4‐oxadiazol‐2‐yl) benzonitrile (11 f) and (1‐((5‐(4‐chloro‐3,5‐dimethoxyphenyl)‐1,3,4‐oxadiazol‐2‐yl)methyl)‐1H‐pyrrolo[3,2‐b]pyridin‐3‐yl)(morpholino) methanone (11 k) displayed greater in vitro activity against all the cell lines than the erlotinib with IC50 values ranging from 1.12 to 14.15 μM. The active compounds 11 d, 11 f and 11 k were also screened for their inhibiting power of tyrosine kinase EGFR and results revealed that the compounds 11 d and 11 f exhibited more inhibition than the standard erlotinib. Further, docking studies of compounds 11 d, 11 f and 11 k on EGFR revealed that compound 11 d had highest binding energy (−10.37 kcal/mol). Finally, compounds 11 d and 11 f followed the rules of Lipinski, Ghose, Veber, Egan rule and Muegge rules without any deviation. [ABSTRACT FROM AUTHOR]

Azaindole scaffold is a privileged structure in medicinal chemistry and some derivatives have demonstrated to be potential anticancer drugs. Herein, a set of novel azaindoles, comprising the four regioisomers, bearing a morpholine (azaindoles 3 a-d) and N-methyl-N-benzylamine (azaindoles 4 a-d) groups were prepared. Among these compounds, azaindoles 4 exhibited higher cytotoxicity against the ovarian cancer cell line A2780 and normal dermal fibroblasts compared to azaindoles 3. Furthermore, azaindoles 4 b and 4 c promoted a delay in the cell cycle of the cancer cell line, inspiring an investigation into the intracellular localization of these derivatives., (© 2024 Wiley-VCH GmbH.)

Biocatalytic C-H halogenation is becoming increasingly attractive due to excellent catalyst-controlled selectivity and environmentally benign reaction conditions. Significant efforts have been made on enzymatic halogenation of industrial arenes in a cost-effective manner. Here we report an unprecedented enzymatic halogenation of a panel of industrially important indole, azaindole and anthranilamide derivatives using a thermostable RebH variant without addition of any external flavin reductase enzyme. The reactions were catalyzed by the RebH variant 3-LSR enzyme with the help of a co-purified E. coli reductase identified as alkyl hydroperoxide reductase F (AhpF).

cesium carbonate mediated synthesis of desired 1 N‐substituted phenylethanone analogue of 4‐azaindole is carried out in Dimethylformamide. Further formation of derivatives of 6 is produced from desired analogue of 4‐azaindole. The mechanistic pathway is analyzed with density functional theory calculations which supported the experimental results. Due to structural similarity of azaindole core nucleus with purine ring of ATP, it is a promising /attractive molecule to be explored for its biological potential. [ABSTRACT FROM AUTHOR]

The preparation of various 5‐ and 6‐azaindoles, heterocyclic structures that are frequently part of molecules in clinical development, and their monohydroxy analogues were described. Different strategies, relying on the de novo pyrrole ring formation, were investigated and, thanks to Hemetsberger–Knittel, Bartoli and Leimgruber–Batcho approaches, 4‐ and 7‐monohydroxy 5‐ and 6‐azaindoles were obtained. The crucial introduction of the oxygen atom was carried out from halogen derivatives, using nucleophilic substitution reactions under basic conditions with or without a copper catalyst. Some preliminary oxidation reactions have shown that it was yet not possible to synthesize the azaquinone indole structure from monohydroxy azaindole, using molecular oxygen in the presence of salcomine as a catalyst. [ABSTRACT FROM AUTHOR]

The repeated and improper use of antibiotics had led to an increased number of multiresistant bacteria. Therefore, new lead structures are needed. Here, the synthesis and an expanded structure–activity relationship of the simple and antistaphylococcal amide nematophin from Xenorhabdus nematophila and synthetic derivatives are described. Moreover, the synthesis of intrinsic fluorescent derivatives, incorporating azaindole moieties was achieved for the first time.

Purpose: To investigate the effect of azaindole on proliferation of liver cancer cells, as well as the underlying mechanism. Methods: Colony forming and 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) assays were used to determine the effect of azaindole on cell proliferation. A tumor model was established through subcutaneous administration of HEPG2 cells to rats. Thereafter, in vivo tumor development was measured using Vernier caliper. Results: The proliferation potential of HEPG2 and SNU-398 cells was markedly and dose-dependently suppressed by treatment with azaindole at doses of 2, 4, 8, 16 and 20 µM (p < 0.05). The expression levels of Ki67 and PCNA levels were significantly down-regulated in HEPG2 and SNU-398 cells on treatment with 20 µM azaindole. Moreover, azaindole significantly suppressed mRNA and protein expressions of KIFC1 in HEPG2 and SNU-398 cells (p < 0.05). Tumor volume in azaindole-treated rats on day 21 was greatly reduced, while KIFC1 expression in azaindole-treated rat tumor tissue was significantly down-regulated, when compared to the model group (p < 0.05). Conclusion: Azaindole targets proliferation of liver cancer cells in vitro and inhibits tumor growth in vivo through a mechanism involving down-regulation of KIFCI expression. Thus, azaindole is a potential therapeutic candidate for liver cancer. [ABSTRACT FROM AUTHOR]

Synthetic cannabinoid receptor agonists (SCRAs) first appeared on the international recreational drug market in the early 2000s in the form of SCRA‐containing herbal blends. Due to the cannabimimetic effects associated with the consumption of SCRAs, they have acquired an ill‐informed reputation for being cheap, safe, and legal alternatives to illicit cannabis. Possessing high potency and affinity for the human cannabinoid receptor subtype‐1 (CB1) and ‐2 (CB2), it is now understood that the recreational use of SCRAs can have severe adverse health consequences. The major public health problem arising from SCRA use has pressed legislators around the world to employ various control strategies to curb their recreational use. To circumvent legislative control measures, SCRA manufacturers have created a wide range of SCRA analogs that contain, more recently, previously unencountered azaindole, γ‐carbolinone, or carbazole heterocyclic scaffolds. At present, little information is available regarding the chemical syntheses of these newly emerging classes of SCRA, from a clandestine perspective. When compared with previous generations of indole‐ and indazole‐type SCRAs, current research suggests that many of these heterocyclic SCRA analogs maintain high affinity and efficacy at both CB1 and CB2 but largely evade legislative control. This review highlights the importance of continued research in the field of SCRA chemistry and pharmacology, as recreational SCRA use remains a global public health issue and represents a serious control challenge for law enforcement agencies. [ABSTRACT FROM AUTHOR]

A series of amide derivatives of azaindole-oxazoles (11a–n) were designed and synthesized and their structures were confirmed by 1HNMR, 13CNMR and mass spectral analysis. Further, these derivatives were screened for their anticancer activity against human cancer cell lines viz; MCF7 (breast), A549 (lung) and A375 (melanoma). In vitro anticancer activity screening indicated that most of the hybrids exhibited potent inhibitory activities in a variety of cancer cell lines. Among the compounds 11d, 11e, 11f, 11j, 11k, 11l, 11m, and 11n were exhibited more potent activity than standard, in those mainly two compounds 11m and 11j were exhibited excellent activity in MCF-7 cell line with IC50 values 0.034 and 0.036 µM. Moreover, all these compounds were carried out their molecular docking studies on EGFR receptor results indicated that two potent compounds 11m and 11j were strongly binds to protein EGFR (PDB ID: 4hjo). It was found that the energy calculations were in good agreement with the observed IC50 values. [ABSTRACT FROM AUTHOR]

After graduating with a master's degree from Faculty of Pharmaceutical Sciences, Hokkaido University in 1983, I worked in medicinal chemistry for 37 years at a pharmaceutical company and 4 years at a university. On this occasion of my retirement, I would like to summarize the memorable reactions from my life in research over more than 40 years. This includes an overview of my drug discovery research at pharmaceutical companies covering practical and effective synthetic methods of key intermediates for renin inhibitors, 1β-methylcarbapenem, neurokinin receptor antagonists and sphingosine-1-phosphate receptor agonists. I have also described microbial transformation reactions for phosphorylation and glucuronidation, as well as antibacterial cyclic peptide and ogipeptins. During this time, two years of studying at the Scripps Research Institute and three years of working in India were also very valuable experiences. Finally, I have summarized the results of synthetic research on indole and azaindole derivatives conducted at the Health Sciences University of Hokkaido over a period of four years.

Activation of the CB 2 receptor is an attractive therapeutic strategy for the treatment of a wide range of inflammatory diseases. However, receptor subtype selectivity is necessary in order to circumvent the psychoactive effects associated with activation of the CB 1 receptor. We aimed to use potent, non-selective synthetic cannabinoids designer drugs to develop selective CB 2 receptor agonists. Simple structural modifications such as moving the amide substituent of 3-amidoalkylindole synthetic cannabinoids to the 2-position and bioisosteric replacement of the indole core to the 7-azaindole scaffold are shown to be effective and general strategies to impart receptor subtype selectivity. 2-Amidoalkylindole 16 (EC 50 CB 1 > 10 μM, EC 50 CB 2 = 189 nM) and 3-amidoalkyl-7-azaindole 21 (EC 50 CB 1 > 10 μM, EC 50 = 49 nM) were found to be potent and selective agonists with favourable physicochemical properties. Docking studies were used to elucidate the molecular basis for the observed receptor subtype selectivity for these compounds. Image 1 • 2-Amidoalkylindoles are selective CB 2 agonists irrespective of amide substitution. • Amino acid derived amides improve potency and physicochemical properties. • 1-(5-Hydroxypentyl)-3-amidoalkyl-7-azaindoles are selective CB 2 agonists. • Docking studies explain the molecular basis for receptor subtype selectivity. [ABSTRACT FROM AUTHOR]

Purpose: This work reports the synthesis and pharmacological and analytical data for a new series of recently identified azaindole-adamantyl-derived synthetic cannabinoids (SCs). Methods: Each SC was synthesised using an efficient and divergent synthesis, and assessed by electron ionisation mass spectrometry (EIMS). The cannabimimetic activity of each compound was conducted using a fluorometric imaging plate reader (FLIPR) assay. Results: The described EIMS method and retention time by gas chromatography were able to effectively differentiate each of the analogues regardless of the bicyclic core. For the first time in these SC structures, the bicyclic ring system was shown to have an impact on the cannabimimetic activities in the fluorometric assay of membrane potential. Analogues ranged from moderately potent at both CB1 and CB2 (e.g., AP4AIC EC50 = 160 nM and EC50 = 64 nM, respectively) to not active at either cannabinoid receptor (AP4AICA, AP5AICA, and APIC). Conclusions: Further investigation into receptor selectivity surrounding these bicyclic cores could prove useful for future therapeutic applications. [ABSTRACT FROM AUTHOR]

Indole- and azaindole-based glyoxylyl amide derivatives have been described as HIV-1 attachment inhibitors (AIs) that act by blocking the interaction between the viral gp120 coat protein and the human host cell CD4 receptor. As part of an effort to more deeply understand the role of the indole/azaindole heterocycle in the expression of antiviral activity, a survey of potential replacements was conducted using parallel synthesis methodology. The design and optimization was guided by a simple 2-dimensional overlay based on an overall planar topography between the indole/azaindole and C-7 substituents that had been deduced from structure-activity studies leading to the discovery of temsavir (3). 2-Substituted naphthalene- and quinoline-derived chemotypes emerged as the most interesting prototypes, with C-5 and C-6 substituents enhancing antiviral potency. Despite the fact that neither of these chemotypes incorporated a H-bond donor that has been shown to engage the side chain carboxylate of Asp 113 in gp120, the antiviral potency of several analogues met or exceeded that of 3 , demonstrating that engaging Asp 113 is not a prerequisite for potent antiviral activity. [ABSTRACT FROM AUTHOR]

Abstract The synthesized and sensing capability of two novel azaindole substituted mono and distyryl BODIPY dyes against bisulfate anion were reported. Structural characterizations of the targeted compounds were conducted by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, 1H and 13C NMR spectroscopies. Photophysical properties of the azaindole substituted BODIPY compounds were investigated employing absorption and fluorescence spectroscopies in acetonitrile solution. It was found that the final compounds 3 and 4 exhibited exclusively selective and sensitive turn-off sensor behavior on HSO 4 − anion. Additionally, the stoichiometry ratio of the targeted compounds to bisulfate anion was measured 0.5 by Job's method. Also, density function theory was performed to the optical response of the sensor for targeted compounds. Furthermore, the cytotoxicity of Azaindole-BODIPYs was examined against living human leukemia K562 cell lines. Graphical Abstract Unlabelled Image Highlights • New azaindole substituted mono and distyryl BODIPYs have been synthesized. • The Fluorescence Sensing properties of the compounds have been studied in acetonitrile • The cytotoxicity of Azaindole-BODIPYs was examined against living human leukemia K562 cell lines. • Very selective and sensitive fluorescence sensor for detection of HSO4- anion has been obtained. [ABSTRACT FROM AUTHOR]

The high frequency of the synthetic cannabinoid receptor agonists (SCRAs) emergence renders this group of new psychoactive compounds particularly demanding in terms of detection, identification, and responding. Without the available reference material, one of the specific problems is differentiation and structure elucidation of constitutional isomers. Herein, we report a simple and efficient flow chart diagram applicable for a rapid nuclear magnetic resonance (NMR) identification and differentiation between azaindoles, 4‐, 5‐, 6‐, and 7‐azaindole, which is a common structural motif of synthetic cannabinoids. The flow chart diagram is based on 1H NMR and 1H–15N NMR spectra, and to prove the concept, it has been tested on 5F‐MDMB‐P7AICA (1). Spectral and analytical data including standard 1D and 2D NMR spectra, gas chromatography−mass spectrometry (GC−MS), Fourier transform infrared−attenuated total reflectant (FTIR−ATR), Raman, melting point, and combustion analysis are provided for compound 1. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of 7-azaindole-based PI3K inhibitors with enhanced CDK2 inhibition were developed for the discovery of anti-TNBC drug candidates. • SAR studies identified FD2056 as a novel potent PI3K inhibitor with enhanced CDK2 inhibition. • In vitro and in vivo studies validate its anti-TNBC efficacy. • FD2056 could serve as a lead compound for the development of PI3K/CDK2 dual inhibitor. Blocking the PI3K pathway has been recognized as a promising strategy for cancer therapy. Herein, we report the discovery of novel PI3K inhibitors utilizing 7-azaindole-based fragment-oriented growth. Among them, compound FD2056 stands out as the most promising candidate, maintaining potent inhibitory activity against PI3K and enhanced CDK2 inhibition, and showing moderate selectivity among 108 kinases. In cellular assays, the inhibitor FD2056 demonstrated superior anti-proliferative profiles over reference compounds against TNBC cells and significantly increased apoptosis of MDA-MB-231 cells in a dose-dependent manner. Moreover, FD2056 showed more efficacious anti-TNBC activity than the corresponding drugs BKM120 and CYC202 at an oral dose of 15 mg/kg in the MDA-MB-231 xenograft model, inhibiting tumor growth by 43% with no observable toxic effects. All these results suggest that FD2056 has potential for further development as a promising anticancr compound, and co-targeting PI3K and CDK2 pathways may provide an alternative therapeutic strategy for the treatment of TNBC. [ABSTRACT FROM AUTHOR]

Currently, heterocycles have occupied an important position in the fields of drug design. Among them, azaindole moiety is regarded as one privileged scaffold to develop therapeutic agents. Since two nitrogen atoms of azaindole increase the possibility to form hydrogen bonds in the adenosine triphosphate (ATP)-binding site, azaindole derivatives are important sources of kinase inhibitors. Moreover, some of them have been on the market or in clinical trials for the treatment of some kinase-related diseases (e.g., vemurafenib, pexidartinib, decernotinib). In this review, we focused on the recent development of azaindole derivatives as potential kinase inhibitors based on kinase targets, such as adaptor-associated kinase 1 (AAK1), anaplastic lymphoma kinase (ALK), AXL, cell division cycle 7 (Cdc7), cyclin-dependent kinases (CDKs), dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1A (DYRK1A), fibroblast growth factor receptor 4 (FGFR4), phosphatidylinositol 3-kinase (PI3K) and proviral insertion site in moloney murine leukemia virus (PIM) kinases. Meanwhile, the structure-activity relationships (SARs) of most azaindole derivatives were also elucidated. In addition, the binding modes of some azaindoles complexed with kinases were also investigated during the SARs elucidation. This review may offer an insight for medicinal chemists to rationally design more potent kinase inhibitors bearing the azaindole scaffold. [Display omitted] • Azaindole is an important structural motif in the design of kinase inhibitors. • The recent development of azaindole derivatives was summed up based on kinase targets. • The structure-activity relationships of most azaindole derivatives were elucidated. [ABSTRACT FROM AUTHOR]

2,3,4-Trioxo-1-(1H-pyrrolo[2,3-b]pyridin-7-ium-7-yl)-cyclobutan-1-ide was obtained by reaction of squaric acid with 7-azaindole in acetic anhydride.

Graphical abstract Highlights • Picomolar pan-RSK inhibitors developed. • Using modeling, phenol isosteres were evaluated in order to identify a tool compound for in vivo use. • Pyrazole yielded most potent phenol isostere replacement for this series. Abstract Utilizing the already described 3,4-bi-aryl pyridine series as a starting point, incorporation of a second ring system with a hydrogen bond donor and additional hydrophobic contacts yielded the azaindole series which exhibited potent, picomolar RSK2 inhibition and the most potent in vitro target modulation seen thus far for a RSK inhibitor. In the context of the more potent core, several changes at the phenol moiety were assessed to potentially find a tool molecule appropriate for in vivo evaluation. [ABSTRACT FROM AUTHOR]

The compound 6‐azaindole undergoes self‐assembly by formation of N(1)−H⋅⋅⋅N(6) hydrogen bonds (H bonds), forming a cyclic, triply H‐bonded trimer. The formation phenomenon is visualized by scanning tunneling microscopy. Remarkably, the H‐bonded trimer undergoes excited‐state triple proton transfer (ESTPT), resulting in a proton‐transfer tautomer emission maximized at 435 nm (325 nm of the normal emission) in cyclohexane. Computational approaches affirm the thermodynamically favorable H‐bonded trimer formation and the associated ESTPT reaction. Thus, nearly half a century after Michael Kasha discovered the double H‐bonded dimer of 7‐azaindole and its associated excited‐state double‐proton‐transfer reaction, the triply H‐bonded trimer formation of 6‐azaindole and its ESTPT reaction are demonstrated. [ABSTRACT FROM AUTHOR]

CSN5 is the zinc metalloprotease subunit of the COP9 signalosome (CSN), which is an important regulator of cullin-RING E3 ubiquitin ligases (CRLs). CSN5 is responsible for the cleavage of NEDD8 from CRLs, and blocking deconjugation of NEDD8 traps the CRLs in a hyperactive state, thereby leading to auto-ubiquitination and ultimately degradation of the substrate recognition subunits. Herein, we describe the discovery of azaindoles as a new class of CSN5 inhibitors, which interact with the active-site zinc ion of CSN5 through an unprecedented binding mode. The best compounds inhibited CSN5 with nanomolar potency, led to degradation of the substrate recognition subunit Skp2 in cells, and reduced the viability of HCT116 cells. [ABSTRACT FROM AUTHOR]

Azaindoles are rare in nature but extremely attractive for drug discovery programs. Azaindoles can be obtained by diverse methods, including those involving metal-catalyzed reactions. This important core has been fascinating the scientific community due to their challenging synthesis and relevant bioactivity. This paper highlights the diverse synthetic methodologies developed to date involving metal-catalyzed reaction to attain azaindoles and its functionalization.

High enantioselectivity was achieved for the hydrogenation of azaindoles by using the chiral catalyst, which was prepared from [Ru(η3-methallyl)2(cod)] and a trans-chelating bis(phosphine) ligand (PhTRAP). The dearomative reaction exclusively occurred on the five-membered ring, thus giving the corresponding azaindolines with up to 97:3 enantiomer ratio. [ABSTRACT FROM AUTHOR]

An azaindole based schiff base AzIm was synthesized that serve as a luminescent turn “off” switch for the detection of Fe 3+ ions. The photoluminescence intensity of AzIm was quenched significantly in the presence of 30 μM Fe 3+ ions. The sensing response of the probe was tested at different ranges of pH and at different cation concentrations between 2 and 25 μM. Analytical characteristics were evaluated using standard Benesi-Hildebrand equation and the system displayed micromolar sensitivity for these ions. The specific diminished emission signal upon Fe 3+ binding was interpreted in terms of the enhanced photoelectron transfer from azaindole group, which induces very fast and efficient non-radiative decay of the excited states of the sensor. In addition, practical utilization of luminescent AzIm was further supported by significant ion selective stability against the presence of extraneous charged species that makes this system compatible for quantitative analysis of environmental samples. [ABSTRACT FROM AUTHOR]

A series of 1-Sulfonyl-6-Piperazinyl-7-Azaindoles, showing strong antagonistic activity to 5-HT 6 receptor (5-HT 6 R) was synthesized and characterized. The series was optimized to reduce activity on D 2 receptor. Based on the selectivity against this off-target and the analysis of the ADME-tox profile, compound 1c was selected for in vivo efficacy assessment, which demonstrated procognitive effects as shown in reversal of scopolamine induced amnesia in an elevated plus maze test in mice. Compound 3 , the demethylated version of compound 1c , was profiled against a panel of 106 receptors, channels and transporters, indicating only D 3 receptor as a major off-target. Compound 3 has been selected for this study over compound 1c because of the higher 5-HT 6 R/D 2 R binding ratio. These results have defined a new direction for the design of our pseudo-selective 5-HT 6 R antagonists. [ABSTRACT FROM AUTHOR]

Five novel 1H-pyrrolo[2,3- b ]pyridine or 1H-pyrazolo[3,4- b ]pyridine derivatives, with a methylene, sulfur, sulfoxide or cyclopropyl group as a linker, were designed, synthesized and biologically evaluated against c-Met and ALK. The development of these methods of compound synthesis may provide an important reference for the construction of novel 7-azaindole and 7-azaindazole derivatives with a single atom linker. The enzyme assay and cell assay in vitro showed that compound 9 displayed strong c-Met kinase inhibition with IC 50 of 22.8 nM, moderate ALK kinase inhibition, and strong cell inhibition with MKN-45 IC 50 of 329 nM and EBC-1 IC 50 of 479 nM. In order to find the better candidate compounds, compounds 8 , 9 and 10 have been selected as tool compounds for further optimization. [ABSTRACT FROM AUTHOR]

A novel azaindole-based colorimetric and fluorescent sensor with an attached hydrazine group (L) was synthesized and characterized by FT-IR, NMR, and CHNS analyses. L exhibited high colorimetric selectivity and sensitivity toward Ag + ions over other common cation solutions (Ag + , Na + , K + , Ba 2+ , Cd 2+ , Co 2+ , Cu 2+ ,Cr 3+ , Fe 2+ , Mg 2+ , Mn 2+ , Ni 2+ , Sr 2+ , Zn 2+ , and Al 3+ ) in ethanol:HEPES buffer (1:9, v/v) solution. Upon addition of Ag + ions, the maximum absorption band of L displayed a red shift from 332 to 400 nm. The efficient electron transfer ability of the molecular receptor L lead to the easy formation of silver nanoparticles (AgNPs) that manifested naked eye detection through color change of solution from colorless to yellow. The AgNPs thus obtained using organic compound L as stabilizer were characterized by light scattering, zeta potential and transmission electron microscopy (TEM). Meanwhile, the results of fluorescence titration experiments illustrated that the sensor functions as “turn-off” receptor upon selective binding with Fe 2+ . Comparative studies revealed that quenched emission originated from selective chelation of Fe 2+ ions with the lone pair of the azaindole receptor's nitrogen atom and causes enhanced PET process Both B.-H. plot and emission spectra analysis reveals a 1:2 stoichiometric relationship between L and the added Fe 2+ ions. The designed probe L permitted accurate detection of respectiveAg + and Fe 2+ down to 2.8 nM and 2.17 × 10 −7 M with rapid response times. Finally, by using Ag + and Fe 2+ ions as chemical inputs and the absorbance and emission response as outputs, logic circuits are constructed at the nanoscale level. [ABSTRACT FROM AUTHOR]

[Display omitted] • New derivatives of the diyne-bridged 7-azaindole have been synthesized. • The diyne stretching vibrational mode appears to play a key role in excited-state deactivation in solution. • The diyne group allows great variability in the ground state, although it is restricted in the excited state. In this work we present the synthesis, X-ray diffraction analysis and photophysical characterization of two new diyne bridged azaindole derivatives. DFT and TD-DFT calculations were carried out to deepen the knowledge of the molecular structure and photophysics of diyne compounds. The presence of the diyne group joining two azaindole platforms leads to a low rotational barrier and a large conformational variability in the ground state. The vibrational stretching mode associated to the diyne bridge presents an unusual high reorganization energy and Huang-Rhys factor for a vibrational mode in the high energy region. This vibrational mode has a significant contribution to non-radiative relaxation and seems to be related to the weak fluorescence observed from these compounds in the solvated state or in aggregates. Stretching of the diyne bridge is not totally blocked in π-π stacked aggregates according to our computational studies, which also confirm weak exciton coupling. The interplay of the diyne bridge stretching mode in non-radiative relaxation in aggregates is explained as due to the type of molecular packing (parallel stacking and "head-to-tail" stacking) and leads to overall low fluorescence quantum yield values from both diyne derivatives in the solid state. Thus, the diyne bridge stretching mode acts as a driving force governing the final photophysical properties. This experimental and theoretical study contributes to shed light into the important role that the diyne bond plays in the final electronic and photophysical properties of this family of compounds. [ABSTRACT FROM AUTHOR]

Three new asymmetrical diarylethenes containing an azaindole moiety and a variable heteroaryl ring have been synthesized. Their properties, such as photochromism, fatigue resistance, thermal stability, acidichromism, and fluorescence, were systematically investigated to elucidate the effects of aromatic stabilization energies (ASE) of the heteroaryl moieties. The results indicated that thermal stability decreased with the increment of the aromatic stabilization energies of the variable heteroaryl rings in the order of thiazyl

The preparation of various 2-(7-azaindolyl)carboxylic esters by Pd-catalyzed coupling of Reformatsky reagents with TBDMS-protected 3-bromo-7-azaindoles leading to a wide range of arylated ester derivatives is reported. After removal of the protecting group, the corresponding free 2-(7-azaindolyl)carboxylic esters are obtained in satisfactory yields. [ABSTRACT FROM AUTHOR]

We hereby report the preparation of new azaindole derivatives starting from 2-(2-ethoxy-2-oxoethyl)nicotinic acid. Conversion of a half ester into acyl azide followed by Curtius rearrangement gave the corresponding isocyanate. Trapping of the isocyanate with different nucleophiles produced urea and urethane derivatives. Intramolecular cyclization reactions gave the target compounds. [ABSTRACT FROM AUTHOR]

[Display omitted] • Rosuvastatin based azaindole framework was designed to identify cytotoxic agents. • Sonochemical synthesis of target compounds involved coupling–cyclization strategy. • Several compounds showed significant cytotoxic effects on three cancer cell lines. • 5b inhibited Akt1 in vitro that was supported by its strong interaction with Akt1 in silico. • 5b is a potent inhibitor (MIA Paca-2 IC50 ∼ 19 nM) with NOAEL > 100 μM in Zebrafish. Addressing the increasing incidences of cancer worldwide along with the multifaceted problem of drug resistance via development of new anticancer agents has become an essential goal. Due to the known cytotoxic effects and reported Akt inhibitory potential of azaindoles we designed a new framework incorporating the structural features of rosuvastatin and 5- or 7-azaindole. The framework was used to construct a library of small molecules for further pharmacological evaluation. The design was supported by the docking studies of two representative molecules in silico. A one-pot sonochemical approach was established for the synthesis of these rosuvastatin based azaindoles that involved the coupling–cyclization of a rosuvastatin derived terminal alkyne with appropriate 3-iodopyridine derivatives under Pd/Cu-catalysis. When tested using an MTT assay, some of the synthesized compounds showed desirable cytotoxic effects against three cancer cell lines e.g. HCT 116, Hep G2 and PA-1 but no significant effects against the non-cancerous HEK cell line. According to the SAR the 5-azaindole ring appeared to be marginally better than the 7-azaindole whereas the activity was varied with the variation of sulfonamide moiety attached to the N-1 atom of the azaindole ring. Among all the groups present in the sulfonamide moiety the p -MeC 6 H 4 group appeared to be most effective in terms of activity. While 3b and 5b were identified as initial hit molecules the compound 5b (in addition to 3b) also showed significant inhibition of Akt1 in vitro that was reflected by its strong interaction with Akt1 in silico (with the docking score −11.7 kcal/mol) involving two H-bonding interactions with Ser7 and Asp439 residues. Further, a reasonable ADME was predicted for 5b in silico. Being a potent inhibitor (MIA Paca-2 IC 50 = 18.79 ± 0.17 nM) and with NOAEL (No Observed Adverse Effect Level) > 100 µM in Zebrafish, 5b emerged as a promising compound. [ABSTRACT FROM AUTHOR]

Biocatalytic C-H halogenation is becoming increasingly attractive due to excellent catalyst-controlled selectivity and environmentally benign reaction conditions. Significant efforts have been made on enzymatic halogenation of industrial arenes in a cost-effective manner. Here we report an unprecedented enzymatic halogenation of a panel of industrially important indole, azaindole and anthranilamide derivatives using a thermostable RebH variant without addition of any external flavin reductase enzyme. The reactions were catalyzed by the RebH variant 3-LSR enzyme with the help of a co-purified E. coli reductase identified as alkyl hydroperoxide reductase F (AhpF)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hui, Sana, Ho, Ke, Ghadessy, Duong and Seayad.)

(Z)-2-(4-Chloro-5H-1,2,3-dithiazol-5-ylideneamino)-6-ethoxy-4-phenylpyridine-3,5-dicarbonitrile 1, when treated with either triphenylphosphine (4 equiv.) or polymer bound triphenylphosphine (5 equiv.) in dichloromethane at room temperature for 3 days affords 3‑amino-6-ethoxy-4-phenyl-1H-pyrrolo[2,3-b]pyridine-2,5-dicarbonitrile 2 in 60–62% yields.

Abstract: A series of aminooxadiazoles was optimized for inhibition of Cdc7. Early lead isoquinoline 1 suffered from modest cell potency (cellular IC50 =0.71μM measuring pMCM2), low selectivity against structurally related kinases, and high IV clearance in rats (CL=18 L/h/kg). Extensive optimization resulted in azaindole 26 (Cdc7 IC50 =1.1 nM, pMCM2 IC50 =32 nM) that demonstrated robust lowering of pMCM2 in a mouse pharmacodynamic (PD) model when dosed orally. Modifications to improve the pharmacokinetic profile of this series were guided by trapping experiments with glutathione in rat hepatocytes. [Copyright &y& Elsevier]

Abstract: Cdc7 kinase is responsible for the initiation and regulation of DNA replication and has been proposed as a target for cancer therapy. We have identified a class of Cdc7 inhibitors based on a substituted indole core. Synthesis of focused indole and azaindole analogs yielded potent and selective 5-azaindole Cdc7 inhibitors with improved intrinsic metabolic stability (ie 36). In parallel, quantum mechanical conformational analysis helped to rationalize SAR observations, led to a proposal of the preferred binding conformation in the absence of co-crystallography data, and allowed the design of 7-azaindole 37 as a second lead in this series. [Copyright &y& Elsevier]

Background and Purpose Drugs targeting microtubules are commonly used for cancer treatment. However, the potency of microtubule inhibitors used clinically is limited by the emergence of resistance. We thus designed a strategy to find new cell-permeable microtubule-targeting agents. Experimental Approach Using a cell-based assay designed to probe for microtubule polymerization status, we screened a chemical library and identified two azaindole derivatives, CM01 and CM02, as cell-permeable microtubule-depolymerizing agents. The mechanism of the anti-tumour effects of these two compounds was further investigated both in vivo and in vitro. Key Results CM01 and CM02 induced G2/ M cell cycle arrest and exerted potent cytostatic effects on several cancer cell lines including multidrug-resistant (MDR) cell lines. In vitro experiments revealed that the azaindole derivatives inhibited tubulin polymerization and competed with colchicines for this effect, strongly indicating that tubulin is the cellular target of these azaindole derivatives. In vivo experiments, using a chicken chorioallantoic xenograft tumour assay, established that these compounds exert a potent anti-tumour effect. Furthermore, an assay probing the growth of vessels out of endothelial cell spheroids showed that CM01 and CM02 exert anti-angiogenic activities. Conclusions and Implications CM01 and CM02 are reversible microtubule-depolymerizing agents that exert potent cytostatic effects on human cancer cells of diverse origins, including MDR cells. They were also shown to inhibit angiogenesis and tumour growth in chorioallantoic breast cancer xenografts. Hence, these azaindole derivatives are attractive candidates for further preclinical investigations. [ABSTRACT FROM AUTHOR]

Abstract: An efficient approach for the formation of 5-amino- and 7-amino-6-azaoxindole derivatives was developed. 2-Amino-4-chloro-3-nitropyridine (8), and its 5-nitro-substituted regioisomer (9), respectively, were obtained by reaction with ethyl malonate. The resulting 2-amino-3/5-nitropyridine derivatives substituted in the 4-position with malonic acid diethyl ester (10, 11) were subjected to reductive cyclization yielding 3-ethoxycarbonyl-6-azaoxindole derivatives 4a and 5a. Protection of the amino function was not required. Intermediates 10 and 11 could also be converted to the corresponding 4-acetic acid ethyl esters 12 and 13 by dealkoxycarbonylation with LiCl, and subsequently cyclized under reductive conditions yielding 3-unsubstituted 5-/7-aminooxazindoles. [Copyright &y& Elsevier]

Abstract: The lead optimization of a series of potent azaindole IKK2 inhibitors is described. Optimization of the human whole blood activity and selectivity over IKK1 in parallel led to the discovery of 16, a potent and selective IKK2 inhibitor showing good efficacy in a rat model of neutrophil activation. [Copyright &y& Elsevier]