Compounds 4n Research Articles

An Efficient Copper-Mediated Route for the Synthesis of 2-Substituted Benzothiazoles from Dithioesters and Investigation of Their Antibacterial Activities

AbstractAn efficient one-pot synthesis of 2-aryl/2-aroylbenzothiazoles through copper-mediated condensation of 2-chloroanilines with dithioesters has been developed. The method provides good isolated yields and exhibits broad functional group tolerance, accommodating both electron-donating and electron-withdrawing groups on the substrates. A series of synthesized compounds was evaluated for their antibacterial activity against Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella paratyphi. Among the series, three compounds exhibited a significant inhibitory effect against the tested pathogens, with one also demonstrating potential as an effective compound in both the agar well diffusion assay and broth microdilution assay. Additionally, the three compounds displayed strong inhibitory effects on biofilm formation of the pathogens in both the crystal violet assay and MTT assay at a concentration of 10 mM. These findings highlight the promising antimicrobial and antibiofilm properties of these compounds, indicating the potential for their further investigation as potential therapeutic agents against the tested pathogens.

Orthosteric and allosteric modulation of human HCAR2 signaling complex

Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors (HCARs). HCAR2 is one such receptor, activated by endogenous β-hydroxybutyrate (3-HB) and butyrate, and is the target for Niacin. Interest in HCAR2 has been driven by its potential as a therapeutic target in cardiovascular and neuroinflammatory diseases. However, the limited understanding of how ligands bind to this receptor has hindered the development of alternative drugs able to avoid the common flushing side-effects associated with Niacin therapy. Here, we present three high-resolution structures of HCAR2-Gi1 complexes bound to four different ligands, one potent synthetic agonist (MK-6892) bound alone, and the two structures bound to the allosteric agonist compound 9n in conjunction with either the endogenous ligand 3-HB or niacin. These structures coupled with our functional and computational analyses further our understanding of ligand recognition, allosteric modulation, and activation of HCAR2 and pave the way for the development of high-efficiency drugs with reduced side-effects.

Design, synthesis and antitubercular assessment of 1, 2, 3-triazole incorporated thiazolylcarboxylate derivatives

A library of 1, 2, 3-triazole incorporated thiazolylcarboxylate derivatives (7a-q) and (8a-j) were synthesized and evaluated for their in-vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. The two compounds 7h and 8h have displayed excellent antitubercular activity with MIC values of 3.12 and 1.56 µg/mL respectively (MIC values of standard drugs; Ciprofloxacin 1.56 μg/mL & Ethambutol 3.12 μg/mL). Whereas, the four compounds 7i, 7n, 7p and 8i displayed noticeable antitubercular activity with a MIC value of 6.25 µg/mL. The active compounds of the series were further studied for their cytotoxicity against RAW264.7 cell line using MTT assay. Furthermore, to study the probable mechanism of antitubercular action, physicochemical property profiling, DFT calculation and molecular docking study were executed on mycobacterial cell wall target Decaprenylphosphoryl-β-d-ribose 2′-epimerase 1 (DprE1). Among all the compounds, 7h (-10 kcal/mol) and 8h (-10.1 kcal/mol) exerted the highest negative binding affinity against the targeted DprE1 (PDB: 4NCR) protein.

Synthesis, Antifungal Ergosterol Inhibition, Antibiofilm Activities, and Molecular Docking on β-Tubulin and Sterol 14-Alpha Demethylase along with DFT-Based Quantum Mechanical Calculation of Pyrazole Containing Fused Pyridine-Pyrimidine Derivatives.

Multidrug-resistant fungal infections have become much more common in recent years, especially in immune-compromised patients. Therefore, researchers and pharmaceutical professionals have focused on the development of novel antifungal agents that can tackle the problem of resistance. In continuation to this, a novel series of pyrazole-bearing pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives (4a-4o) have been developed. These compounds have been screened against Candida albicans, Aspergillus niger, and Aspergillus clavatus. The synthesized compounds were characterized by well-known spectroscopic techniques, i.e., IR, 1H NMR, 13C NMR, and mass spectrometry. In vitro antifungal results revealed that compound 4n showed activity against C. albicans having MIC value of 200 μg/mL. To know the plausible mode of action, the active derivatives were screened for anti-biofilm and ergosterol biosynthesis inhibition activities. The compounds 4h, 4j, 4k, and 4n showed greater ergosterol biosynthesis inhibition than the control DMSO. To comprehend how molecules interact with the receptor, studies of molecular docking of 4k and 4n have been performed on the homology-modeled protein of β-tubulin. The molecular docking revealed that the active compounds 4h, 4j, 4k, 4l, and 4n interacting with the active site amino acid of sterol 14-alpha demethylase (PDB ID: 5v5z) indicate one of the possible modes of action of ergosterol inhibition activity. The synthesized compounds 4c, 4e, 4h, 4i, 4j, 4k, 4l, and 4n inhibited biofilm formation and possessed the potential for anti-biofilm activity. DFT-based quantum mechanical calculations were carried out to optimize, predict, and compare the vibration modes of the molecule 4a.

Wang resin catalyzed sonochemical synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines as potential inhibitors of SIRT1

The search of new approaches / strategies for the identification of potential anticancer agents prompted us to focus on SIRT1, which is considered as an emerging pharmacological target for cancer. The 2-amino-3,5-dicarbonitrile-6-thio-pyridine was chosen as a framework for the design of new and possible inhibitors of SIRT1. Firstly, the in silico docking of a number of molecules based on this framework not only showed their promising interactions with SIRT1 but also indicated their potential selectivity towards this protein over SIRT2. The study also suggested VAL412, PHE414, ILE347, ALA262, ILE411, HIS363, GLN345, ASN346, ILE270, ILE316, PHE273 and PHE297 as the common interacting residues for these molecules of which VAL412, and PHE414 were mostly involved in the H-bond interactions. A convenient access to these molecules was established via the 3-component reaction (3-CR) of appropriate aliphatic or (hetero)aromatic aldehyde, malononitrile and thiophenol under ultrasound. The reaction was catalyzed by the sulphonic acid-functionalized Wang resin (Wang-OSO3H) and proceeded in aqueous media under open air for 1 h to afford the desired products in 65–86 % yields. The recoverability and recyclability of the catalyst was established and application potential of the methodology was examined. The synthesized 2-amino-3,5-dicarbonitrile-6-thio-pyridines showed encouraging (> 50 %) SIRT1 inhibition in vitro that was in agreement with the findings of docking studies. Indeed, the compound 4n noted as the most encouraging in the in silico docking studies was also found to be the most active hit molecule in the in vitro assay. The Structure-Activity-Relationship (SAR) suggested encouraging activities when the R group at C-4 position was chosen as a t‑butyl group or the 4-NCC6H4 or 3-HOC6H4 or 2-Cl-6-FC6H3 moiety. However, a linear alkyl chain at the C-4 position was found to be unfavorable for SIRT1 inhibition. Collectively, the current research efforts identified the compound 4n as a promising inhibitor of SIRT1 among the current series of 3,5-dicarbonitrile-6-thio-pyridines examined.

Benzimidazole derivatives as tubulin polymerization inhibitors: Design, synthesis and in vitro cytotoxicity studies

A new class of benzimidazole derivatives as tubulin polymerization inhibitors has been designed and synthesized in this study. The in vitro anticancer profile of the developed molecules was reconnoitred on selected human cancer cells. The highest cytotoxicity was illustrated by compounds 7n and 7u with IC50 values ranging from 2.55 to 17.89 µM with specificity toward SK-Mel-28 cells. They displayed 5-fold less cytotoxicity towards normal rat kidney epithelial NRK52E cells, which implies that they are not harmful to normal, healthy cells. The cellular staining procedures like AO/EB, DCFDA, and DAPI were applied to comprehend the inherent mechanism of apoptosis which displayed nuclear and morphological alterations. The Annexin V binding and JC-1 studies were executed to evaluate the extent of apoptosis and the decline in mitochondrial transmembrane potential in SK-Mel-28 cell lines. Compound 7n dose-dependently arrested the G2/M phase of the cell cycle and the target-based outcomes proposed tubulin polymerization inhibition by 7n (IC50 of 5.05±0.13 μM). Computational studies were also conducted on the tubulin protein (PDB ID: 3E22) to investigate the stabilized binding interactions of compounds 7n and 7u with tubulin, respectively.

Synthesis and Antifungal Evaluation of New Azole Derivatives against Candida albicans.

In this study, we designed and prepared a series of new azole derivatives by recombination of fluconazole (FLC) and ketoconazole units, and in vitro antifungal activities against Candida albicans were evaluated. The results indicated that most azoles showed good antifungal activity against the drug-sensitive C. albicans strain, especially compounds 6a, 6e, 6n, 6p, 6r, 6s, 6t, and 6v, which displayed better antifungal activity (MIC50 < 1.0 μg/mL) than FLC against SC5314. The further mechanism study showed that compound 6r could significantly inhibit the formation of C. albicans biofilm, increase the permeability of the cell membrane, reduce the ergosterol level of the cell membrane, damage the membrane structure, and destroy the integrity of the cell structure to exert excellent antifungal activity. Subsequently, a molecular docking study indicated that azole compounds could inhibit cytochrome P450 14α-demethylase (CYP51). Therefore, these azole derivatives can be considered as potent antifungal drugs to treat fungal infections.

Design, Synthesis, and Molecular Docking Studies of 1,3,4-Oxadiazole Scaffolds as Potential Antimicrobial Agents

In search of suitable antimicrobial compounds, we report here the synthesis, characterization, and biological activities of 2-((5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl)thio)-N-arylacetamide (5a-5p). The molecules were characterized by infrared, mass, hydrogen-1 nuclear magnetic resonance (1H NMR), 13C NMR, and elemental analysis. The in vitro antimicrobial activity was investigated against pathogenic Gram-positive and Gram-negative bacterial and fungal strains. The results were explained with a molecular docking study against microbial DNA gyrase. It was found that the compounds 5h, 5i, 5j, 5k, 5l, 5n, and 5p showed significant activities against tested organisms as compared to standard drugs (fluconazole and ciprofloxacin).

Synthesis and in vitro Antimicrobial Screening of Benzofuran-3(2H)-one Linked Geminal bis 1,2,3-Triazole Hybrid Derivatives

A series of novel hybrid derivatives, 2,2-di(1H-1,2,3-triazol-1-yl)benzofuran-3(2H)-ones, were synthesized from o-hydroxyacetophenones via a two-step process involving sodium azide, iodine and sodium bicarbonate, followed by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) in aqueous conditions. These compounds were characterized using 1H NMR, 13C NMR and mass spectra and analyzed in vitro against bacteria (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa) and fungi (Candida albicans, Aspergillus niger). Compounds 3f, 3h and 3n showed notable antibacterial activity (MIC = 50 μg/mL), comparable to streptomycin, while compounds 3b, 3f and 3h exhibited similar antifungal activity (MIC = 50 μg/mL), comparable to standard clotrimazole. Compound 3f displayed superior antimicrobial efficacy among the tested compounds.

Orthosteric ligand selectivity and allosteric probe dependence at Hydroxycarboxylic acid receptor HCAR2

Hydroxycarboxylic acid receptor 2 (HCAR2), a member of Class A G-protein-coupled receptor (GPCR) family, plays a pivotal role in anti-lipolytic and anti-inflammatory effects, establishing it as a significant therapeutic target for treating dyslipidemia and inflammatory diseases. However, the mechanism underlying the signaling of HCAR2 induced by various types of ligands remains elusive. In this study, we elucidate the cryo-electron microscopy (cryo-EM) structure of Gi-coupled HCAR2 in complex with a selective agonist, MK-6892, resolved to a resolution of 2.60 Å. Our structural analysis reveals that MK-6892 occupies not only the orthosteric binding pocket (OBP) but also an extended binding pocket (EBP) within HCAR2. Pharmacological assays conducted in this study demonstrate that the OBP is a critical determinant for ligand selectivity among the HCARs subfamily. Moreover, we investigate the pharmacological properties of the allosteric modulator compound 9n, revealing its probe-dependent behavior on HCAR2 in response to varying orthosteric agonists. Collectively, our findings provide invaluable structural insights that contribute to a deeper understanding of the regulatory mechanisms governing HCAR2 signaling transduction mediated by both orthosteric and allosteric ligands.

Design, Synthesis, Antitumour Evaluation, and In Silico Studies of Pyrazolo-[1,5-c]quinazolinone Derivatives Targeting Potential Cyclin-Dependent Kinases.

An efficient, straightforward, and metal-free methodology to rapidly access functionalised pyrazolo-[1,5-c]quinazolinones via a [3 + 2] dipolar cycloaddition and regioselective ring expansion process was developed. The synthesised compounds were characterised by methods such as NMR, HRMS, and HPLC. The in vitro antiproliferative activity against A549 cells (non-small cell lung cancer) was significant for compounds 4i, 4m, and 4n with IC50 values of 17.0, 14.2, and 18.1 μM, respectively. In particular, compounds 4t and 4n showed inhibitory activity against CDK9/2. Predicted biological target and molecular modelling studies suggest that the compound 4t may target CDKs for antitumour effects. The synthesised derivatives were considered to have moderate drug-likeness and sufficient safety in silico. In summary, a series of pyrazolo-[1,5-c]quinazolinone derivatives with antitumour activity is reported for the first time. We provide not only a simple and efficient synthetic method but also helpful lead compounds for the further development of novel cyclin-dependent kinase (CDK) inhibitors.

Design, synthesis and anti-inflammatory activity study of lansiumamide analogues for treatment of acute lung injury

Acute lung injury (ALI) is an inflammation-mediated respiratory disease with a high mortality rate. Medications with anti-inflammatory small molecules have been demonstrated in phase I and II clinical trials to considerably reduce the ALI mortality. In this study, two series of lansiumamide analogues were designed, synthesized, and evaluated for anti-inflammatory activity for ALI treatment. We found that compound 8n exhibited the best anti-inflammatory activity through inhibiting LPS-induced expression of the proinflammatory cytokines interleukin-6 (IL-6) and interleukin-1β (IL-1β) in Raw264.7 cells and activating the Nrf2/HO-1 pathway. Furthermore, we discovered in a LPS-induced ALI mice model that compound 8n significantly reduced the infiltration of inflammatory cells into lung tissue to achieve the effect of protecting lung tissues and improving ALI. Additionally, our mice model study revealed that compound 8n had a good expectorant effect. These results consistently support that lansiumamide analogue 8n represents a new class of anti-inflammatory agents with potential as a lead compound for further development into a therapeutic drug for ALI treatment.

Novel spiro[pyrrolidine-2,3′-quinoline]-2′-one derivatives containing piperazine fragment as potential chitin synthase inhibitors and antifungal agents: Design, synthesis and biological evaluation

A series of spiro[pyrrolidine-2,3′-quinoline]-2′-one derivatives were designed and synthesized for the discovery of novel antifungal drugs. The bioactivities of all derivatives were screened by evaluating their inhibitory effects against chitin synthase (CHS) and antimicrobial activities in vitro. Enzyme inhibition experiments showed that all the synthesized compounds inhibited the chitin synthase. Compounds 4d, 4k, 4n and 4o showed inhibitory effects against CHS with IC50 values which were close to that of the control drug (polyoxin B). The results of enzyme kinetics experiment showed that these compounds were non-competitive inhibitors of chitin synthase (Ki of compound 4o is 0.14 mM). Antimicrobial experiments showed that these compounds exhibited moderate to excellent antifungal activity against pathogenic fungal strains while the compounds showed little potency against bacteria. Among them, compounds 4d, 4f, 4k and 4n showed stronger antifungal activities against C. albicans than those of fluconazole and polyoxin B. Compounds 4f, 4n and 4o showed better antifungal activities against A. flavus than those of fluconazole and polyoxin B. Compound 4d showed similar activity to that of fluconazole and stronger activity than those of polyoxin B against C. neoformans and A. fumigatus. It is also showed that these compounds have the potency against drug-resistant fungal variants. The results of sorbitol protection assay and evaluation of antifungal activity against micafungin-resistant strains experiment further illustrated that these compounds inhibited the synthesis of chitin of fungal cell wall. Drug combination experiments showed that these compounds had synergistic or additive effects when combined with fluconazole or polyoxin B. The synergistic effects with polyoxin B further confirmed the compounds were non-competitive inhibitors of chitin synthase. Additionally, docking studies showed that these compounds had strong affinity with chitin synthase from C. albicans (CaChs2). These results indicate that the target of these synthesized compounds is chitin synthase, and these compounds had excellent antifungal activity while possessed the potency against drug-resistant fungal variants.

Design and synthesis of 1H-pyrazolo[3,4-d]pyrimidine derivatives as hematopoietic progenitor kinase 1 (HPK1) inhibitors

Despite immune checkpoint inhibitors' tremendous success in the treatment of tumors, the moderate response rate limits their widespread use. Hematopoietic progenitor kinase 1 (HPK1) is served as an essential negative regulator of T-cell receptor, which has been identified as a promising target for enhancing antitumor immunity. However, the development of a selective HPK1 inhibitor is still challenging. Herein, we reported a novel series of 1H-pyrazolo[3,4-d]pyrimidine derivatives as HPK1 inhibitors by structure-based rational design. The optimal compound 10n significantly inhibited HPK1 with an IC50 value of 29.0 nM and the phosphorylation of SLP76 at a concentration as low as 0.1 μM. Furthermore, compound 10n exhibited good selectivity over a panel of 25 kinases, including GLK from the same MAP4K family. Together, the current study provided a novel, potent, and selective HPK1 inhibitor, acting as a lead compound for the future development of cancer immunotherapy.

Synthesis of Novel Carboxamide Derivatives: Insecticidal Activity, Acetylcholinesterase Activity and In Silico Calculations

The insecticidal activity of carboxamide derivatives was investigated against both larvae and adults of Myzus percisace (Sulzer) (Hemiptera: Aphididae), Leptinotarsa decemlineata (Coleoptera: Chrysomelidae), and Trialeurodes vaporariorum (Hemiptera: Aleyrodidae) in different concentrations. The synthesized compounds were obtained good yield, and their molecular structures were confirmed by FTIR, NMR, and MALDI-TOF/MS. The compound 3o was found to be the most active against Leptinotarsa decemlineata adults, while the compound 3l was found against larvae. Furthermore, the compounds were evaluated against acetylcholinesterase (AChE) enzyme, and two of the compounds (3n and 3o) showed moderate inhibitory effect against both commercial acetylcholinesterase (0.18 ± 0.01 and 0.13 ± 0.01 μM) and M. percisace adult homogenate (0.65 ± 0.02 and 0.24 ± 0.01 μM), respectively. In silico molecular docking and ADME properties were performed.

Design, Synthesis, In Silico Studies and In Vitro Evaluation of New Indole- and/or Donepezil-like Hybrids as Multitarget-Directed Agents for Alzheimer's Disease.

Alzheimer's disease (AD) is considered a complex neurodegenerative condition which warrants the development of multitargeted drugs to tackle the key pathogenetic mechanisms of the disease. In this study, two novel series of melatonin- and donepezil-based hybrid molecules with hydrazone (3a-r) or sulfonyl hydrazone (5a-l) fragments were designed, synthesized, and evaluated as multifunctional ligands against AD-related neurodegenerative mechanisms. Two lead compounds (3c and 3d) exhibited a well-balanced multifunctional profile, demonstrating intriguing acetylcholinesterase (AChE) inhibition, promising antioxidant activity assessed by DPPH, ABTS, and FRAP methods, as well as the inhibition of lipid peroxidation in the linoleic acid system. Compound 3n, possessing two indole scaffolds, showed the highest activity against butyrylcholinesterase (BChE) and a high selectivity index (SI = 47.34), as well as a pronounced protective effect in H2O2-induced oxidative stress in SH-SY5Y cells. Moreover, compounds 3c, 3d, and 3n showed low neurotoxicity against malignant neuroblastoma cell lines of human (SH-SY5Y) and murine (Neuro-2a) origin, as well as normal murine fibroblast cells (CCL-1) that indicate the in vitro biocompatibility of the experimental compounds. Furthermore, compounds 3c, 3d, and 3n were capable of penetrating the blood-brain barrier (BBB) in the experimental PAMPA-BBB study. The molecular docking showed that compound 3c could act as a ligand to both MT1 and MT2 receptors, as well as to AchE and BchE enzymes. Taken together, those results outline compounds 3c, 3d, and 3n as promising prototypes in the search of innovative compounds for the treatment of AD-associated neurodegeneration with oxidative stress. This study demonstrates that hydrazone derivatives with melatonin and donepezil are appropriate for further development of new AChE/BChE inhibitory agents.

Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation

Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body β-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 mediates distinct pathophysiological events by activating Gi/o protein or β-arrestin effectors. Here, we characterize compound 9n as a Gi-biased allosteric modulator (BAM) of HCAR2 and exhibit anti-inflammatory efficacy in RAW264.7 macrophages via a specific HCAR2-Gi pathway. Furthermore, four structures of HCAR2-Gi complex bound to orthosteric agonists (niacin or monomethyl fumarate), compound 9n, and niacin together with compound 9n simultaneously reveal a common orthosteric site and a unique allosteric site. Combined with functional studies, we decipher the action framework of biased allosteric modulation of compound 9n on the orthosteric site. Moreover, co-administration of compound 9n with orthosteric agonists could enhance anti-inflammatory effects in the mouse model of colitis. Together, our study provides insight to understand the molecular pharmacology of the BAM and facilitates exploring the therapeutic potential of the BAM with orthosteric drugs.

Novel pyrrolo[2,3-d]pyrimidine derivatives as multi-kinase inhibitors with VEGFR-2 selectivity

Since the discovery of imatinib, the first tyrosine kinase inhibitor, in 2001, targeted therapy has become mainstream of cancer therapeutics. Despite the advantages in efficacy and low side effects compared with conventional chemotherapy, the success of the targeted anticancer drugs is still limited by the drug resistance which happens due to the fact that the development of cancer is stimulated by several stimuli and therefore, defeating cancer may occur upon the inhibition of several targets. However, coadministration of multiple drugs always lead to many disadvantages including increased toxicity and less patient compliance. Therefore, the aim of research is to develop anticancer agents with multi-target action based on the modification of the chemical structure of sunitinib, a well-known multi-kinase inhibitor. A series of fifteen compounds comprising pyrrolo[2,3-d]pyrimidine and hydrazone have been designed and successfully synthesized. Among the synthesized compounds, compounds 6f, 6l and 6n inhibited the enzymatic activity of EGFR, Her2, VEGFR-2 and CDK2 kinase enzymes similar to sunitinib and the reference protein kinase inhibitors. Interestingly, remarkable results were revealed by compounds 6j and 6c that demonstrated selective VEGFR-2 inhibition activities and compound 6i that exhibited selective dual inhibition of Her2/VEGFR-2 enzymes. Further analysis revealed that compounds 6f and 6n suppressed cell cycle progression of HepG2 cells and induced early and late apoptosis. Moreover, those two compounds triggered a significant elevation in caspase 3 and Bax proapoptotic proteins and a notable reduction in Bcl-2 anti-apoptotic protein. Finally, molecular docking studies were conducted to predict the possible binding interactions of 6f and 6n with CDK2 and 6f, 6n, 6j and 6c with VEGFR-2.

The structural modification and biological evaluation of tetrahydrothienopyridine derivatives as selective BChE inhibitors

A series of tetrahydrothienopyridine derivatives have been designed, synthesized, and evaluated as selective BChE inhibitors. Compounds were analyzed via HRMS, 1H NMR, and 13C NMR. The inhibitory effects were evaluated according to the method of Ellman et al. 6n was the most potent and selective inhibitor against BChE (eeAChE IC50 = 686.4 ± 478.6 μM, eqBChE IC50 = 10.5 ± 5.0 nM, SI = 6.5*104, hBChE IC50 = 32.5 ± 6.5 nM). Cell-based assays have confirmed the low neurotoxicity of 6a and 6n and their moderate neuroprotective effects. Compounds 6a and 6n provide novel chemical entities for the treatment of Alzheimer’s disease.

Synthesis of 4-Pyridinylquinolines via Sugasawa and Friedlander Reaction from 4-Cyanopyridine with Anilines and Ketones

Abstract: Firstly, 2-amino aromatic ketones were synthesized by o-acylation of p-substituted anilines with nitrile under Sugasawa conditions, and the yield was up to 90.1%. Then, 4-pyridinylquinoline derivatives were synthesized by Friedlander reaction with α-methylene ketones, and the yield was up to 81.9%. The structures of five 2-amino aromatic ketones and eighteen substituted quinolines were characterized by MS, 1H NMR, and 13C NMR. The structures were further confirmed by single crystal X-ray diffraction, which was consistent with the expected structures. Analyzing the crystal structure, it was found that compounds 4j and 4q crystallized in the monoclinic with the P21/n space group, respectively. Compounds 2c, 2d, 2e, and 4n crystallized in the triclinic with the P-1 space group, respectively. Of which compound 4n crystallized in the triclinic space group P-1 with two crystallographically independent but chemically equivalent molecules in the asymmetric unit. The two independent molecules were found to possess different orientations of the chlorine, methyl, pyridyl, and acetyl groups relative to the core (quinoline) two-ring system. This work provides a simple, straightforward synthetic protocol for preparing 4-pyridinylquinoline derivatives.