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1.
Medicine (Baltimore) ; 103(24): e38496, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38875413

ABSTRACT

As a subtype of the 5-hydroxytryptamine (5-HT) receptor, 5-HT1A receptors are involved in the pathological process of psychiatric disorders and is an important target for antidepressants. The research groups focus on these area have tried to design novel compounds to alleviate depression by targeting 5-HT1A receptor. The heterocyclic structures is an important scaffold to enhance the antidepressant activity of ligands, including piperazine, piperidine, benzothiazole, and pyrrolidone. The current review highlights the function and significance of nitrogen-based heterocyclics 5-HT1AR represented by piperazine, piperidine, benzothiazole, and pyrrolidone in the development of antidepressant.


Subject(s)
Antidepressive Agents , Receptor, Serotonin, 5-HT1A , Serotonin 5-HT1 Receptor Agonists , Humans , Serotonin 5-HT1 Receptor Agonists/pharmacology , Serotonin 5-HT1 Receptor Agonists/therapeutic use , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Receptor, Serotonin, 5-HT1A/drug effects , Receptor, Serotonin, 5-HT1A/metabolism , Piperazines/pharmacology , Piperazines/chemistry , Benzothiazoles/pharmacology , Benzothiazoles/chemistry , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/therapeutic use , Piperidines/pharmacology , Piperidines/therapeutic use , Piperidines/chemistry , Pyrrolidinones/pharmacology , Pyrrolidinones/therapeutic use , Pyrrolidinones/chemistry , Depression/drug therapy
2.
Bioorg Med Chem ; 107: 117756, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38759255

ABSTRACT

Herein, four silver(I) complexes bearing acetylated d-galactopyranoside-based N-heterocyclic carbene ligands were synthesized and fully characterized by elemental analysis, NMR, and X-ray photoelectron spectroscopy. All complexes were obtained with an anomeric ß-configuration and as monocarbene species. In this study, we investigated the biological effects of the silver(I) complexes 2a-d on the human rhabdomyosarcoma cell line, RD. Our results show concentration-dependent effects on cell density, growth inhibition, and activation of key signaling pathways such as Akt 1/2, ERK 1/2, and p38-MAPK, indicating their potential as anticancer agents. Notably, at 35.5 µM, the complexes induced mitochondrial network disruption, as observed with 2b and 2c, whereas with 2a, this disruption was accompanied by nuclear content release. These results provide insight into the utility of carbohydrate incorporated NHC complexes of silver(I) as new agents in cancer therapy.


Subject(s)
Antineoplastic Agents , Cell Proliferation , Drug Screening Assays, Antitumor , Rhabdomyosarcoma , Silver , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Silver/chemistry , Silver/pharmacology , Cell Proliferation/drug effects , Rhabdomyosarcoma/drug therapy , Rhabdomyosarcoma/pathology , Structure-Activity Relationship , Molecular Structure , Methane/chemistry , Methane/analogs & derivatives , Methane/pharmacology , Methane/chemical synthesis , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Dose-Response Relationship, Drug , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemical synthesis , Cell Line, Tumor , Acetylation , Galactose/chemistry , Galactose/pharmacology
3.
J Chromatogr A ; 1727: 464988, 2024 Jul 19.
Article in English | MEDLINE | ID: mdl-38749348

ABSTRACT

In this research, a novel magnetic nanocomposite (Fe3O4@Zn/Al-LABSA-LDH/ZIF-8) was synthesized using Fe3O4 as the magnetic core, layered double hydroxide (LDH) with linear alkylbenzene sulfonic acid (LABSA) intercalation and zeolitic imidazolate framework-8 (ZIF-8) as the shell. Benefiting from the intercalation of LABSA into LDH combined with ZIF-8, the multiple interactions, including π-π stacking, hydrogen bonding, and electrostatic interactions, conferred high selectivity and good extraction capability to the material towards heterocyclic aromatic amines (HAAs). Fe3O4@Zn/Al-LABSA-LDH@ZIF-8 was used as an adsorbent for magnetic solid-phase extraction (MSPE) to enrich HAAs in thermally processed meat samples, followed by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) detection. The method exhibited a low detection limit (0.021-0.221 ng/g), good linearity (R2 ≥ 0.9999), high precision (RSD < 7.2 %), and satisfactory sample recovery (89.7 % -107.5 %). This research provides a promising approach for developing novel adsorbents in sample preparation and improving analytical performance.


Subject(s)
Amines , Limit of Detection , Nanocomposites , Solid Phase Extraction , Tandem Mass Spectrometry , Chromatography, High Pressure Liquid/methods , Tandem Mass Spectrometry/methods , Amines/analysis , Amines/chemistry , Nanocomposites/chemistry , Solid Phase Extraction/methods , Imidazoles/chemistry , Heterocyclic Compounds/analysis , Heterocyclic Compounds/chemistry , Hydroxides/chemistry , Zeolites/chemistry , Meat/analysis , Metal-Organic Frameworks/chemistry , Adsorption , Food Contamination/analysis , Liquid Chromatography-Mass Spectrometry
4.
J Agric Food Chem ; 72(23): 12915-12924, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38807027

ABSTRACT

Plant pathogenic fungi pose a significant threat to agricultural production, necessitating the development of new and more effective fungicides. The ring replacement strategy has emerged as a highly successful approach in molecular design. In this study, we employed the ring replacement strategy to successfully design and synthesize 32 novel hydrazide derivatives containing diverse heterocycles, such as thiazole, isoxazole, pyrazole, thiadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, thiophene, pyridine, and pyrazine. Their antifungal activities were evaluated in vitro and in vivo. Bioassay results revealed that most of the title compounds displayed remarkable antifungal activities in vitro against four tested phytopathogenic fungi, including Fusarium graminearum, Botrytis cinerea, Sclerotinia sclerotiorum, and Rhizoctonia solani. Especially, compound 5aa displayed a broad spectrum of antifungal activity against F. graminearum, B. cinerea, S. sclerotiorum, and R. solani, with the corresponding EC50 values of 0.12, 4.48, 0.33, and 0.15 µg/mL, respectively. In the antifungal growth assay, compound 5aa displayed a protection efficacy of 75.5% against Fusarium head blight (FHB) at a concentration of 200 µg/mL. In another in vivo antifungal activity evaluation, compound 5aa exhibited a noteworthy protective efficacy of 92.0% against rape Sclerotinia rot (RSR) at a concentration of 100 µg/mL, which was comparable to the positive control tebuconazole (97.5%). The existing results suggest that compound 5aa has a broad-spectrum antifungal activity. Electron microscopy observations showed that compound 5aa might cause mycelial abnormalities and organelle damage in F. graminearum. Moreover, in the in vitro enzyme assay, we found that the target compounds 5aa, 5ab, and 5ca displayed significant inhibitory effects toward succinate dehydrogenase, with the corresponding IC50 values of 1.62, 1.74, and 1.96 µM, respectively, which were superior to that of boscalid (IC50 = 2.38 µM). Additionally, molecular docking and molecular dynamics simulation results revealed that compounds 5aa, 5ab, and 5ca have the capacity to bind in the active pocket of succinate dehydrogenase (SDH), establishing hydrogen-bonding interactions with neighboring amino acid residues.


Subject(s)
Ascomycota , Botrytis , Drug Design , Fungicides, Industrial , Fusarium , Plant Diseases , Rhizoctonia , Succinate Dehydrogenase , Succinate Dehydrogenase/antagonists & inhibitors , Fusarium/drug effects , Fusarium/growth & development , Fungicides, Industrial/pharmacology , Fungicides, Industrial/chemical synthesis , Fungicides, Industrial/chemistry , Structure-Activity Relationship , Ascomycota/drug effects , Botrytis/drug effects , Botrytis/growth & development , Rhizoctonia/drug effects , Plant Diseases/microbiology , Molecular Docking Simulation , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Fungal Proteins/antagonists & inhibitors , Fungal Proteins/chemistry , Fungal Proteins/metabolism , Microbial Sensitivity Tests , Hydrazines/pharmacology , Hydrazines/chemistry , Hydrazines/chemical synthesis , Molecular Structure , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/chemical synthesis
5.
Top Curr Chem (Cham) ; 382(2): 18, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38758483

ABSTRACT

Indole, a ubiquitous and structurally versatile aromatic compound, has emerged as a key player in the synthesis of diverse heterocyclic frameworks via cycloaddition reactions. These reactions are completely atom-economical and, hence, are considered as green reactions. This review article provides a comprehensive overview of the pivotal role played by indole in the construction of complex and biologically relevant heterocyclic compounds. Here we explore the chemistry of indole-based cycloadditions, highlighting their synthetic utility in accessing a wide array of heterocyclic architectures, including cyclohepta[b]indoles, tetrahydrocarbazoles, tetrahydroindolo[3,2-c]quinoline, and indolines, among others. Additionally, we discuss the mechanistic insights that underpin these transformations, emphasizing the strategic importance of indole as a building block. The content of this article will certainly encourage the readers to explore more work in this area.


Subject(s)
Cycloaddition Reaction , Heterocyclic Compounds , Indoles , Indoles/chemistry , Indoles/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/chemical synthesis , Molecular Structure
6.
J Inorg Biochem ; 257: 112603, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38749081

ABSTRACT

Numerous heterocyclic moieties serve as the foundational structure for clinically employed drugs, underscoring the significance of heterocycles in the innovation of pharmacologically active compounds. In the present investigation, a heterocyclic skeleton of thiophene-clubbed benzimidazole (tmb) was developed and utilized to synthesize seven novel series of metal (M(II) = Co, Ni, Cu, and Zn) complexes to explore diverse applications including pharmacological and photocatalytic performance. A sharp singlet peak appeared at 5.72 ppm (tmb) and 5.94 ppm for the Zn(II)-tmb complex corresponding to -CH2 protons, as evidenced by 1H NMR results, confirming the formation of targeted compounds. Antimicrobial assay and docking studies confirmed that the mixed metal complex; [Cu(tmb)2(1,10-phen)Cl2] possesses the highest activity and displayed significant biofilm inhibition, achieving 86.35 and 89.8% at concentrations of 1 and 0.020 mg/mL, respectively against E. coli. Furthermore, the photocatalytic activity was monitored by the degradation of methylene blue dye under direct sunlight and [Cu(tmb)2Cl2] exhibited a maximum degradation efficiency of 96.15% in 45 min. These findings could serve as inspiration for the development of benzimidazole-based metal complexes as effective anti-biofilm and photocatalytic agents.


Subject(s)
Coordination Complexes , Escherichia coli , Light , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemical synthesis , Catalysis , Escherichia coli/drug effects , Benzimidazoles/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Heterocyclic Compounds/chemistry , Sulfur/chemistry , Photochemical Processes , Molecular Docking Simulation , Microbial Sensitivity Tests
7.
Eur J Med Chem ; 273: 116520, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38788299

ABSTRACT

The absence of effective active pockets makes traditional molecularly targeted drug strategies ineffective against 80 % of human disease-related proteins. The PROTAC technology effectively makes up for the deficiency of traditional molecular targeted drugs, which produces drug activity by degrading rather than inhibiting the target protein. The degradation of PROTAC is not only affected by POI ligand and E3 ligand, but by the selection of suitable linker which can play an important role in the efficiency and selectivity of the degradation. In the early exploring stage of the PROTAC, flexible chains were priorly applied as the linker of PROTAC. Although PROTAC with flexible chains as linkers sometimes perform well in vitro bioactivity evaluations, the introduction of lipophilic flexible chains reduces the hydrophilicity of these molecules, resulting in generally poor pharmacokinetic characteristics and pharmacological activities in vivo. In addition, recent reports have also shown that some PROTAC with flexible chains have some risks to causing hemolysis in vivo. Therefore, PROTAC with flexible chains show less druggability and large difficulty to entering the clinical trial stage. On the other hand, the application of nitrogen heterocycles in the design of PROTAC linkers has been widely reported in recent years. More and more reports have shown that the introduction of nitrogen heterocycles in the linker not only can effectively improves the metabolism of PROTAC in vivo, but also can enhance the degradation efficiency and selectivity of PROTAC. These PROTAC with nitrogen heterocycle linkers have attracted much attention of pharmaceutical chemists. The introduction of nitrogen heterocycles in the linker deserves priority consideration in the primary design of the PROTAC based on various druggabilities including pharmacokinetic characteristics and pharmacological activity. In this work, we summarized the optimization process and progress of nitrogen heterocyclic rings as the PROTAC linker in recent years. However, there were still limited understanding of how to discover, design and optimize PROTAC. For example, the selection of the types of nitrogen heterocycles and the optimization sites of this linker are challenges for researchers, choosing between four to six-membered nitrogen heterocycles, selecting from saturated to unsaturated ones, and even optimizing the length and extension angle of the linker. There is a truly need for theoretical explanation and elucidation of the PROTAC to guide the developing of more effective and valuable PROTAC.


Subject(s)
Heterocyclic Compounds , Nitrogen , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemical synthesis , Humans , Nitrogen/chemistry , Molecular Structure , Animals , Ligands
8.
J Food Sci ; 89(6): 3494-3505, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38700357

ABSTRACT

The abilities of Chinese quince free proanthocyanidins (FP) and bound proanthocyanidins (BP) at different levels (0.1%, 0.15%, and 0.3%) to mitigate heterocyclic aromatic amine (HAA) formation in fried chicken patties were investigated for the first time and compared with vitamin C (Vc). FP and BP reduced HAAs in a dose-dependent manner. Significantly, high concentrations of FP (0.3%) resulted in a reduction of PhIP, harman, and norharman levels by 59.84%, 22.91%, and 38.21%, respectively, in chicken patties. The addition of proanthocyanidins significantly (p < 0.05) reduced the weight loss of fried chicken patties. Furthermore, a positive correlation was observed among pH, weight loss, and total HAA formation in all three groups (FP, BP, and Vc). Multivariate analysis showed that FP had a more pronounced effect than BP from the perspective of enhancing the quality of fried chicken patties and reducing the formation of HAAs. These results indicate that proanthocyanidins, both BP and FP, but especially FP, from Chinese quince can inhibit the formation of carcinogenic HAAs when added to protein-rich foods that are subsequently fried.


Subject(s)
Amines , Chickens , Cooking , Proanthocyanidins , Proanthocyanidins/analysis , Proanthocyanidins/pharmacology , Animals , Amines/chemistry , Cooking/methods , Heterocyclic Compounds/chemistry , Rosaceae/chemistry , East Asian People
9.
J Food Sci ; 89(6): 3759-3775, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38706376

ABSTRACT

Heterocyclic amines (HCAs) have potential carcinogenic and mutagenic activity and are generated in cooked protein-rich foods. Adding proanthocyanidins (PAs) to these foods before frying is an effective way to reduce HCAs. In this study, polymeric PAs (PPA) and ultrasound-assisted acid-catalyzed/catechin nucleophilic depolymerized PAs (UAPA, a type of oligomeric PA) were prepared from Chinese quince fruits (CQF). Different levels of PPA and UAPA (0.05%, 0.1%, and 0.15%) were added to chicken meatballs and tofu; then these foods were fried, and the content of HCAs in them after frying was investigated. The results showed that PPA and, particularly, UAPA significantly inhibited the formation of HCAs in fried meatballs and tofu, and this inhibition was dose-dependent. The inhibition of HCAs by both PPA and UAPA was stronger in the chicken meatballs than in fried tofu. The level of total HCAs was significantly reduced by 57.84% (from 11.93 to 5.03 ng/g) after treatment of meatballs with 0.15% UAPA, with inhibition rates of 78.94%, 50.37%, and 17.81% for norharman, harman, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), respectively. Of note, there was a negative correlation between water, lipid, protein, creatine, and glucose content and HCA content in the crust, interior, and whole (crust-plus-interior) measurements of all fried samples. Interestingly, PPA and UAPA were found more effective in inhibiting HCAs in the exterior crust than in the interior of the fried chicken meatballs. These results provide evidence that further studies on the reduction of the formation of harmful HCAs in fried foods by adding CQF PAs could be valuable to the fried food industry. PRACTICAL APPLICATION: Chinese quince proanthocyanidins treatments significantly inhibited the generation of heterocyclic amines (HCAs) in chicken meatballs and tofu when deep-fried. These results suggest that Chinese quince proanthocyanidins can be used as natural food additive for reducing HCAs in fried foods, laying the foundation for using Chinese quince fruit proanthocyanidins for HCA inhibition in the food industry.


Subject(s)
Amines , Chickens , Cooking , Proanthocyanidins , Proanthocyanidins/pharmacology , Proanthocyanidins/analysis , Animals , Cooking/methods , Amines/chemistry , Fruit/chemistry , Meat Products/analysis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/analysis , Hot Temperature , East Asian People
10.
Bioorg Med Chem Lett ; 108: 129801, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-38777279

ABSTRACT

Novel saturated 6-(4'-aryloxy phenyl) vinyl 1,2,4-trioxanes 12a(1-3)-12d(1-3) and 13a(1-3)-13d(1-3) have been designed and synthesized, in one single step from diimide reduction of 11a(1-3)-11d(1-3). All the newly synthesized trioxanes were evaluated for their antimalarial activity against multi-drug resistant Plasmodium yoelii nigeriensis via oral route. Cyclopentane-based trioxanes 12b1, 12c1 and 12d1, provided 100 % protection to the infected mice at 24 mg/kg × 4 days. The most active compound of the series, trioxane 12b1, provided 100 % protection even at 12 mg/kg × 4 days and 60 % protection at 6 mg/kg × 4 days. The currently used drug, ß-arteether provides only 20 % protection at 24 mg/kg × 4 days.


Subject(s)
Antimalarials , Drug Resistance, Multiple , Heterocyclic Compounds , Malaria , Plasmodium yoelii , Animals , Plasmodium yoelii/drug effects , Antimalarials/pharmacology , Antimalarials/chemistry , Antimalarials/chemical synthesis , Mice , Administration, Oral , Drug Resistance, Multiple/drug effects , Malaria/drug therapy , Structure-Activity Relationship , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemical synthesis , Molecular Structure , Disease Models, Animal , Parasitic Sensitivity Tests
11.
Molecules ; 29(9)2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38731412

ABSTRACT

Skeleton editing has rapidly advanced as a synthetic methodology in recent years, significantly streamlining the synthesis process and gaining widespread acceptance in drug synthesis and development. This field encompasses diverse ring reactions, many of which exhibit immense potential in skeleton editing, facilitating the generation of novel ring skeletons. Notably, reactions that involve the cleavage of two distinct rings followed by the reformation of new rings through ring insertion play a pivotal role in the construction of novel ring skeletons. This article aims to compile and systematize this category of reactions, emphasizing the two primary reaction types and offering a thorough exploration of their associated complexities and challenges. Our endeavor is to furnish readers with comprehensive reaction strategies, igniting research interest and injecting fresh impetus into the advancement of this domain.


Subject(s)
Heterocyclic Compounds , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/chemical synthesis , Molecular Structure , Chemistry Techniques, Synthetic
12.
Molecules ; 29(9)2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38731481

ABSTRACT

As the use of antibiotics increases, the increasing resistance of bacteria is the main reason for the reduced efficiency of antibacterial drugs, making the research of new antibacterial materials become new hot spot. In this article, two novel coordination polymers (CPs), namely, [Cd2(L)2(bibp)2]n (1) and [Ni(L)(bib)]n (2), where H2L = N,N'-bis(4-carbozvlbenzvl)-4-aminotoluene, bibp = 4,4'-bis(imidazol-1-yl)biphenyl, and bib = 1,3-bis(1-imidazoly)benzene, have been synthesized under solvothermal and hydrothermal condition. Structural clarification was performed through infrared spectrum and single-crystal X-ray diffraction analysis, while thermal analysis and XRD technology were used for the performance assessment of compounds 1 and 2. In addition, antibacterial performance experiments showed that compounds 1 and 2 have certain selectivity in their antibacterial properties and have good antibacterial properties against S. aureus. As the concentration of the compound increases, the inhibitory effect gradually strengthens, and when the concentration of the compound reaches 500 µg/mL and 400 µg/mL, the concentration of the S. aureus solution no longer increases and has been completely inhibited.


Subject(s)
Anti-Bacterial Agents , Microbial Sensitivity Tests , Polymers , Staphylococcus aureus , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Staphylococcus aureus/drug effects , Polymers/chemistry , Polymers/pharmacology , Polymers/chemical synthesis , Ligands , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Molecular Structure , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemical synthesis , Models, Molecular , Crystallography, X-Ray
13.
Molecules ; 29(10)2024 May 10.
Article in English | MEDLINE | ID: mdl-38792094

ABSTRACT

Viruses are a real threat to every organism at any stage of life leading to extensive infections and casualties. N-heterocycles can affect the viral life cycle at many points, including viral entrance into host cells, viral genome replication, and the production of novel viral species. Certain N-heterocycles can also stimulate the host's immune system, producing antiviral cytokines and chemokines that can stop the reproduction of viruses. This review focused on recent five- or six-membered synthetic N-heterocyclic molecules showing antiviral activity through SAR analyses. The review will assist in identifying robust scaffolds that might be utilized to create effective antiviral drugs with either no or few side effects.


Subject(s)
Antiviral Agents , Heterocyclic Compounds , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemistry , Humans , Virus Replication/drug effects , Structure-Activity Relationship , Viruses/drug effects , Virus Diseases/drug therapy , Animals
14.
Int J Mol Sci ; 25(10)2024 May 18.
Article in English | MEDLINE | ID: mdl-38791560

ABSTRACT

A new, eco-friendly process utilising the green solvent propylene carbonate (PC) has been developed to perform N-alkylation of N-, O- and/or S-containing heterocyclic compounds. PC in these reactions served as both the reagent and solvent. Importantly, no genotoxic alkyl halides were required. No auxiliary was necessary when using anhydrous PC. Product formation includes nucleophilic substitution with the concomitant loss of water and carbon dioxide. Substrates prepared, including the newly invented PROTAC drugs, are widely used.


Subject(s)
Heterocyclic Compounds , Propane , Alkylation , Heterocyclic Compounds/chemistry , Propane/chemistry , Propane/analogs & derivatives , Solvents/chemistry , Green Chemistry Technology/methods
15.
Drug Des Devel Ther ; 18: 1547-1571, 2024.
Article in English | MEDLINE | ID: mdl-38737333

ABSTRACT

The Coronavirus disease 2019 (COVID-19) pandemic is one of the most considerable health problems across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the major causative agent of COVID-19. The severe symptoms of this deadly disease include shortness of breath, fever, cough, loss of smell, and a broad spectrum of other health issues such as diarrhea, pneumonia, bronchitis, septic shock, and multiple organ failure. Currently, there are no medications available for coronavirus patients, except symptom-relieving drugs. Therefore, SARS-CoV-2 requires the development of effective drugs and specific treatments. Heterocycles are important constituents of more than 85% of the physiologically active pharmaceutical drugs on the market now. Several FDA-approved drugs have been reported including molnupiravir, remdesivir, ritonavir, oseltamivir, favipiravir, chloroquine, and hydroxychloroquine for the cure of COVID-19. In this study, we discuss potent anti-SARS-CoV-2 heterocyclic compounds that have been synthesized over the past few years. These compounds included; indole, piperidine, pyrazine, pyrimidine, pyrrole, piperazine, quinazoline, oxazole, quinoline, isoxazole, thiazole, quinoxaline, pyrazole, azafluorene, imidazole, thiadiazole, triazole, coumarin, chromene, and benzodioxole. Both in vitro and in silico studies were performed to determine the potential of these heterocyclic compounds in the fight against various SARS-CoV-2 proteins.


Subject(s)
Antiviral Agents , COVID-19 Drug Treatment , Heterocyclic Compounds , SARS-CoV-2 , Humans , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/therapeutic use , SARS-CoV-2/drug effects , COVID-19
16.
Curr Pharm Des ; 30(4): 255-277, 2024.
Article in English | MEDLINE | ID: mdl-38711394

ABSTRACT

BACKGROUND: The escalation of cancer worldwide is one of the major causes of economy burden and loss of human resources. According to the American Cancer Society, there will be 1,958,310 new cancer cases and 609,820 projected cancer deaths in 2023 in the United States. It is projected that by 2040, the burden of global cancer is expected to rise to 29.5 million per year, causing a death toll of 16.4 million. The hemostasis regulation by cellular protein synthesis and their targeted degradation is required for normal cell growth. The imbalance in hemostasis causes unbridled growth in cells and results in cancer. The DNA of cells needs to be targeted by chemotherapeutic agents for cancer treatment, but at the same time, their efficacy and toxicity also need to be considered for successful treatment. OBJECTIVE: The objective of this study is to review the published work on pyrrole and pyridine, which have been prominent in the diagnosis and possess anticancer activity, to obtain some novel lead molecules of improved cancer therapeutic. METHODS: A literature search was carried out using different search engines, like Sci-finder, Elsevier, ScienceDirect, RSC etc., for small molecules based on pyrrole and pyridine helpful in diagnosis and inducing apoptosis in cancer cells. The research findings on the application of these compounds from 2018-2023 were reviewed on a variety of cell lines, such as breast cancer, liver cancer, epithelial cancer, etc. Results: In this review, the published small molecules, pyrrole and pyridine and their derivatives, which have roles in the diagnosis and treatment of cancers, were discussed to provide some insight into the structural features responsible for diagnosis and treatment. The analogues with the chromeno-furo-pyridine skeleton showed the highest anticancer activity against breast cancer. The compound 5-amino-N-(1-(pyridin-4- yl)ethylidene)-1H-pyrazole-4-carbohydrazides was highly potent against HEPG2 cancer cell. Redaporfin is used for the treatment of cholangiocarcinoma, biliary tract cancer, cisplatin-resistant head and neck squamous cell carcinoma, and pigmentation melanoma, and it is in clinical trials for phase II. These structural features present a high potential for designing novel anticancer agents for diagnosis and drug development. CONCLUSION: Therefore, the N- and C-substituted pyrrole and pyridine-based novel privileged small Nheterocyclic scaffolds are potential molecules used in the diagnosis and treatment of cancer. This review discusses the reports on the synthesis of such molecules during 2018-2023. The review mainly discusses various diagnostic techniques for cancer, which employ pyrrole and pyridine heterocyclic scaffolds. Furthermore, the anticancer activity of N- and C-substituted pyrrole and pyridine-based scaffolds has been described, which works against different cancer cell lines, such as MCF-7, A549, A2780, HepG2, MDA-MB-231, K562, HT- 29, Caco-2 cells, Hela, Huh-7, WSU-DLCL2, HCT-116, HBL-100, H23, HCC827, SKOV3, etc. This review will help the researchers to obtain a critical insight into the structural aspects of pyrrole and pyridine-based scaffolds useful in cancer diagnosis as well as treatment and design pathways to develop novel drugs in the future.


Subject(s)
Antineoplastic Agents , Neoplasms , Pyridines , Pyrroles , Humans , Neoplasms/drug therapy , Neoplasms/diagnosis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Pyridines/pharmacology , Pyridines/chemistry , Pyridines/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacology , Pyrroles/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemical synthesis , Animals
17.
Int J Mol Sci ; 25(9)2024 Apr 27.
Article in English | MEDLINE | ID: mdl-38731989

ABSTRACT

Drug candidates must undergo thermal evaluation as early as possible in the preclinical phase of drug development because undesirable changes in their structure and physicochemical properties may result in decreased pharmacological activity or enhanced toxicity. Hence, the detailed evaluation of nitrogen-rich heterocyclic esters as potential drug candidates, i.e., imidazolidinoannelated triazinylformic acid ethyl esters 1-3 (where R1 = 4-CH3 or 4-OCH3 or 4-Cl, and R2 = -COOC2H5) and imidazolidinoannelated triazinylacetic acid methyl esters 4-6 (where R1 = 4-CH3 or 4-OCH3 or 4-Cl, and R2 = -CH2COOCH3)-in terms of their melting points, melting enthalpy values, thermal stabilities, pyrolysis, and oxidative decomposition course-has been carried out, using the simultaneous thermal analysis methods (TG/DTG/DSC) coupled with spectroscopic techniques (FTIR and QMS). It was found that the melting process (documented as one sharp peak related to the solid-liquid phase transition) of the investigated esters proceeded without their thermal decomposition. It was confirmed that the melting points of the tested compounds increased in relation to R1 and R2 as follows: 2 (R1 = 4-OCH3; R2 = -COOC2H5) < 6 (R1 = 4-Cl; R2 = -CH2COOCH3) < 5 (R1 = 4-OCH3; R2 = -CH2COOCH3) < 3 (R1 = 4-Cl; R2 = -COOC2H5) < 1 (R1 = 4-CH3; R2 = -COOC2H5) < 4 (R1 = 4-CH3; R2 = -CH2COOCH3). All polynitrogenated heterocyclic esters proved to be thermally stable up to 250 °C in inert and oxidising conditions, although 1-3 were characterised by higher thermal stability compared to 4-6. The results confirmed that both the pyrolysis and the oxidative decomposition of heterocyclic ethyl formates/methyl acetates with para-substitutions at the phenyl moiety proceed according to the radical mechanism. In inert conditions, the pyrolysis process of the studied molecules occurred with the homolytic breaking of the C-C, C-N, and C-O bonds. This led to the emission of alcohol (ethanol in the case of 1-3 or methanol in the case of 4-6), NH3, HCN, HNCO, aldehydes, CO2, CH4, HCl, aromatics, and H2O. In turn, in the presence of air, cleavage of the C-C, C-N, and C-O bonds connected with some oxidation and combustion processes took place. This led to the emission of the corresponding alcohol depending on the analysed class of heterocyclic esters, NH3, HCN, HNCO, aldehydes, N2, NO/NO2, CO, CO2, HCl, aromatics, and H2O. Additionally, after some biological tests, it was proven that all nitrogen-rich heterocyclic esters-as potential drug candidates-are safe for erythrocytes, and some of them are able to protect red blood cells from oxidative stress-induced damage.


Subject(s)
Esters , Heterocyclic Compounds , Nitrogen , Esters/chemistry , Nitrogen/chemistry , Heterocyclic Compounds/chemistry , Drug Stability , Thermodynamics , Spectroscopy, Fourier Transform Infrared , Pyrolysis
18.
J Med Chem ; 67(10): 8271-8295, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38717088

ABSTRACT

A series of heterocyclic ring-fused derivatives of bisnoralcohol (BA) were synthesized and evaluated for their inhibitory effects on RANKL-induced osteoclastogenesis. Most of these derivatives possessed potent antiosteoporosis activities in a dose-dependent manner. Among these compounds, 31 (SH442, IC50 = 0.052 µM) exhibited the highest potency, displaying 100% inhibition at 1.0 µM and 82.8% inhibition at an even lower concentration of 0.1 µM, which was much more potent than the lead compound BA (IC50 = 2.325 µM). Cytotoxicity tests suggested that the inhibitory effect of these compounds on RANKL-induced osteoclast differentiation did not result from their cytotoxicity. Mechanistic studies revealed that SH442 inhibited the expression of osteoclastogenesis-related marker genes and proteins, including TRAP, TRAF6, c-Fos, CTSK, and MMP9. Especially, SH442 could significantly attenuate bone loss of ovariectomy mouse in vivo. Therefore, these BA derivatives could be used as promising leads for the development of a new type of antiosteoporosis agent.


Subject(s)
Osteoclasts , Osteoporosis , Animals , Female , Mice , Bone Resorption/drug therapy , Cell Differentiation/drug effects , Coumarins/pharmacology , Coumarins/chemistry , Coumarins/chemical synthesis , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/chemical synthesis , Osteoclasts/drug effects , Osteoclasts/metabolism , Osteogenesis/drug effects , Osteoporosis/drug therapy , Ovariectomy , RANK Ligand/metabolism , RANK Ligand/antagonists & inhibitors , RAW 264.7 Cells , Small Molecule Libraries/pharmacology , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity Relationship
19.
Food Res Int ; 186: 114394, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38729737

ABSTRACT

The ability of spices (bay leaf, star anise, and red pepper) and their characteristic phenolic compounds (quercetin, kaempferol, and capsaicin) to inhibit Heterocyclic aromatic amines (HAAs) in roasted beef patties were compared. Density functional theory (DFT) was used to reveal phenolic compounds interacting with HAAs-related intermediates and free radicals to explore possible inhibitory mechanisms for HAAs. 3 % red chili and 0.03 % capsaicin reduced the total HAAs content by 57.09 % and 68.79 %, respectively. DFT demonstrated that this was due to the stronger interaction between capsaicin and the ß-carboline HAAs intermediate (Ebind = -32.95 kcal/mol). The interaction between quercetin and phenylacetaldehyde was found to be the strongest (Ebind = -17.47 kcal/mol). Additionally, DFT indicated that capsaicin reduced the carbonyl content by transferring hydrogen atoms (HAT) to eliminate HO·, HOO·, and carbon-centered alkyl radicals. This study provided a reference for the development of DFT in the control of HAAs.


Subject(s)
Amines , Cooking , Density Functional Theory , Heterocyclic Compounds , Phenols , Amines/chemistry , Cattle , Heterocyclic Compounds/chemistry , Animals , Phenols/analysis , Capsaicin/chemistry , Capsaicin/pharmacology , Capsaicin/analogs & derivatives , Capsicum/chemistry , Skatole/analysis , Spices/analysis , Red Meat/analysis , Meat Products/analysis , Hot Temperature , Quercetin/analogs & derivatives , Quercetin/analysis , Quercetin/pharmacology
20.
Int J Biol Macromol ; 269(Pt 2): 132027, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38702001

ABSTRACT

In this study, novel Cu-complexes of heterocyclic cellulose which were synthesized via the reaction of carboxymethyl cellulose (CMC) from bagasse pulp with NH2NH2 to give hydrazide cellulose which easily reacted with CS2 to form salt and then cyclized in the presence of HCl to afford cellulose oxadiazole, or with hydrazine hydrate to give cellulose triazole. Furthermore, the cellulose oxadiazole and triazole moieties acting as chelating agents with metal ion Cu (II), and all synthesized compounds were examined for their spectral analysis to show the adsorption of Cu (II) on the surface of cellulose through intramolecular hydrogen bonding. Results illustrated that cellulose oxadiazole and Cu- cellulose oxadiazole exhibited antimicrobial activities more than triazole and Cu- cellulose triazole. Furthermore, anticancer results showed that both cellulose oxadiazole and triazole exhibited activity higher than Cu-cellulose oxadiazole and Cu-cellulose triazole, where the cellulose triazole showed the highest activity (IC50 = 58.7 µg/µL). Additionally, the docking simulation of the synthesized cellulose complexes with different proteins such as PDBID:3t88, PDBID:4ynt, PDBID:1tgh, PDBID:2wje, and PDBID:4hdq and shortage bond length to confirm the experimental results. Optimization of metal complexes utilized the DFT/B3LYP/LANL2DZ basis set to confirm the stability of these metals theoretically and their physical descriptors and FMO analysis.


Subject(s)
Anti-Infective Agents , Antineoplastic Agents , Cellulose , Copper , Molecular Docking Simulation , Cellulose/chemistry , Copper/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Anti-Infective Agents/pharmacology , Anti-Infective Agents/chemistry , Humans , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemical synthesis , Density Functional Theory , Microbial Sensitivity Tests , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Cell Line, Tumor
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