Heterocyclic Derivatives Research Articles

Quinoline incorporating pyrimidine heterocyclic azo dye derivatives: Synthesis, characterization and applications

In the present study, novel quinoline substituted pyrimidine heterocyclic azo dye derivatives (IVa-x) have been synthesized. All the prepared compounds have been characterized by several spectroscopic analyses and evaluated for in vitro antimicrobial activity. Furthermore, the dyeing performances of all the compounds have been estimated on cotton and silk fabrics. Colour and rubbing fastness properties of all the dyed fabrics have been examined by referencing to standard gray scale. These newly synthesized azo dyes exhibit various hues with good to excellent fastness properties. Out of all the phenol derivatives, Naphthol substituted compounds have come out as remarkably active antimicrobial scaffolds with excellent dye characteristics.

Discovery of highly potent proapoptotic antiestrogens in a series of androst-5,16-dienes D-modified with imidazole-annulated pendants

Heterocyclic derivatives of steroid hormones are potent anticancer agents, which are used in the chemotherapy of breast and prostate cancers. Here, we describe a novel series of androstenes, D-modified with imidazole-annulated pendants, with significant anticancer activity. Novel C17-linked imidazole-annulated heterocyclic derivatives of dehydropregnenolone acetate were synthesized by the cyclocondensation with amidines using 3β-acetoxy-21-bromopregna-5,16-dien-20-one as the substrate. The antiproliferative potency of all the synthesized compounds was evaluated against human prostate (22Rv1) and human breast (MCF7) cancer cell lines and cytochromes P450. The lead compound, imidazo[1,2-a]pyridine derivative 3h, was revealed to be a promising candidate for future anticancer drug design, particularly against ERα-positive breast cancer. Lead compound 3h was found to be selective against MCF7 cells with IC50 of 0.1 μM and to act as both a potent selective agent blocking estrogen receptor α, which is involved in the stimulation of breast cancer growth, and an effective apoptosis inducer. The potential ability of compound 3h to bind to ERα was studded using molecular docking and molecular dynamics simulation. The selectivity analysis showed that lead steroid 3h produces no effects on cytochromes P450 CYP17A1, CYP7A1, and CYP21A2.

Quinolines: Privileged Scaffolds for Developing New Anti‐neurodegenerative Agents

AbstractThe burden of neurodegenerative diseases is emerging with the increase in life expectancy. It is a great challenge to develop effective methods of preventing these diseases and to treat them. Quinoline and its derivatives have numerous biological effects. They show significant anti‐neurodegenerative activity. Quinoline compounds are used to develop various anti‐neurodegenerative drugs as they have demonstrated fantastic effects through numerous mechanisms of action. A lot of quinoline compounds have been studied till now for their anti‐neurodegenerative properties. Quinoline scaffold among all heterocyclic compounds has emerged as a critical building block for the production of a variety of novel medications. Many heterocyclic substituent quinoline derivatives with good anti‐neurodegenerative activity are discussed in this review. Such as PBT2 that has shown potential to reduce cerebrospinal fluid Aβ, and improve cognitive functions, quinoline‐chromenone and acridine‐chromenone hybrids that act as anti AChE agents. Further molecules like coumarin‐quinoline derivatives, 1,2,3,4‐tetrahydroquinoline‐2,3,4‐trione 3‐oximes and Clioquinol has been discussed as a possible anti‐Neurodegeneration medication. The efficacy of quinoline derivatives to cure neurodegenerative diseases and save the central nervous system in early stage has nurtured the interest of researchers to increase the search in this area.

Identification of Flavone Derivative Displaying a 4′-Aminophenoxy Moiety as Potential Selective Anticancer Agent in NSCLC Tumor Cells

Five heterocyclic derivatives were synthesized by functionalization of a flavone nucleus with an aminophenoxy moiety. Their cytotoxicity was investigated in vitro in two models of human non-small cell lung cancer (NSCLC) cells (A549 and NCI-H1975) by using MTT assay and the results compared to those obtained in healthy fibroblasts as a non-malignant cell model. One of the aminophenoxy flavone derivatives (APF-1) was found to be effective at low micromolar concentrations in both lung cancer cell lines with a higher selective index (SI). Flow cytometric analyses showed that APF-1 induced apoptosis and cell cycle arrest in the G2/M phase through the up-regulation of p21 expression. Therefore, the aminophenoxy flavone-based compounds may be promising cancer-selective agents and could serve as a base for further research into the design of flavone-based anticancer drugs.

Five-Membered Heterocyclic Sulfonamides as Carbonic Anhydrase Inhibitors

The development of heterocyclic derivatives has progressed considerably over the past decades, and many new carbonic anhydrase inhibitors (CAIs) fall into this field. In particular, five-membered heterocyclic sulfonamides have been generally shown to be more effective inhibitors compared to six-membered rings ones. Despite the importance of oxygen and nitrogen five-membered heterocyclic aromatic rings in medicinal chemistry, the installation of sulfonamide moiety on such heterocycles has not received much attention. On the other hand, 1,3,4-thiadiazole/thiadiazoline ring-bearing sulfonamides are the scaffolds which have been widely used in a variety of pharmaceutically important CAIs such as acetazolamide, metazolamide and their many derivatives obtained by using the tail approach. Here, we reviewed the field focusing on the diverse biological activities of these CAIs, such as antiglaucoma, antiepileptic, antitumor and antiinfective properties. This review highlights developments involving five-membered heterocyclic sulfonamides over the last years, with a focus on their pharmacological/clinical applications.

Urease Inhibition and Structure‐Activity Relationship Study of Thiazolidinone‐, Triazole‐, and Benzothiazole‐Based Heterocyclic Derivatives: A Focus Review

AbstractUrease has a long and distinguished history in the development of enzymology since it was the first enzyme crystallized by Sumner in 1926. The present review article is focused on the urease inhibitory potential of thiazolidinone, triazole, and benzothiazole‐based heterocyclic derivatives. The study begins with the historical developments in the discovery of urease and its substrate, urea, along with the active site architecture of ureases of different origins. The two pathways for the urease‐catalyzed hydrolysis of urea are explained in detail. The urease inhibitory potential of the aforementioned heterocyclic derivatives is reviewed and arranged systematically. Structure‐activity relationships (SARs) study provided the substituents necessary for urease inhibition and will be useful for the researchers working in the field of anti‐ulcer agents. To a step further, important binding interactions were identified with the amino acid residues at the active site of the enzyme. The information gathered is anticipated to offer logical direction and an effective method for creating innovative, potent, and efficient urease inhibitors that will have greater practical uses in the future.

Novel Benzo Five-Membered Heterocycle Derivatives as P-Glycoprotein Inhibitors: Design, Synthesis, Molecular Docking, and Anti-Multidrug Resistance Activity.

A proposed strategy to overcome multidrug resistance (MDR) of anticancer drugs in chemotherapy is to disable the efflux function of P-glycoprotein (P-gp). In this study, based on ring-merging and fragment-growing strategies, 105 novel benzo five-membered heterocycle derivatives were designed, synthesized, and screened. Exploration of the structure-activity relationship (SAR) led to the identification of d7 with low cytotoxicity and promising reversal activity to doxorubicin in MCF-7/ADR cells. Furthermore, the mechanism studies revealed that the reversal activity of d7 stemmed from the inhibition of P-gp efflux. Molecular docking further clarified the observed trends in SAR with d7 displaying potent affinity to P-gp. Additionally, coadministration of d7 with doxorubicin achieved stronger antitumor activity in a xenograft model than doxorubicin alone. These results suggest that d7 is a potential MDR reveal agent acting as a P-gp inhibitor and provides guidelines for the future development of new P-gp inhibitors.

Synthesis and Biological Activity of 2,6-Naphthyridine Derivatives: A Mini Review

Abstract: The broad spectrum of biological activity of 2,6-naphthyridine, one of the six structural isomers of pyridopyridine, is the main reason for the development of new compounds containing this scaffold. This review paper aims to present various methods for obtaining 2,6-naphthyridine analogues and their biological activity, which have been reported in the scientific literature. Compounds containing the 2,6-naphthyridine moiety can be isolated from plants or obtained synthetically from various substrates: pyridine derivatives, other heterocyclic derivatives, or acyclic compounds. Biological investigations have shown that these compounds exhibit various biological activity; among others, they have an effect on the central nervous system or anticancer or antimicrobial activity.

Synthesis of Some New Substituted Dihydro-5-(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazole) Heterocyclic Derivatives and Evaluation of Their Pharmacological Activities

Synthesis of Some New Substituted Dihydro-5-(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazole) Heterocyclic Derivatives and Evaluation of Their Pharmacological Activities

Synthesis, Characterization and Studying Biological Activity of Heterocyclic Compounds

Heterocyclic moiety was mentioned to present diverse biological activities such as inhibitors of protein glycation, antibacterial, antifungal, anticancer, antidepressant, anti-inflammatory, antituberculosis, antioxidant, and as antiviral agents, in addition to other biological activities; therefore, many medicines containing heterocyclic moiety have been observed. Due to the pharmacological importance of heterocyclic derivatives, the present work comes as attempt to synthesis of heterocyclic compound involved (tetrazole and pyrazole rings) by series of steps starting from pyrimidin-2-amine, which reacted with 2-chloroacetyl chloride gave compound (1) [2-chloro-N-(pyrimidin-2-yl) acetamide], then the refl ex reaction of the compound (1) with the hydrazine hydrate in ethanol led to compound (2) [2-hydrazinyl-N-(pyrimidin-2-yl)acetamide], the last one reacted with acetyl acetone to form pyrazole ring compound (3) [2-(3,5-dimethyl-1H-pyrazol-1-yl)-N-(pyrimidin-2-yl)acetamide]. In other line another pyrazole derivative was prepared by diazotization of pyrimidin-2-amine with NaNO2/HCl to azo derivative compound (4), which is reacted with acetyl acetone gave compound (5) [3-(2-(pyrimidin-2-yl)hydrazono)pentane-2,4-dione] to react with hydrazine gave pyrazole moiety compound (6) [(2-((1H-pyrazol-4-yl)diazenyl)pyrimidine]. Pyrimidin-2-amine was reacted with 4-hydroxybenzaldehyde in ethanol and glacial acetic acid gave Schiff base compound (7) , which reacted with sodium azide in dioxane to form tetrazole ring compound (8) [4-(1-(pyrimidin-2-yl)-4,5-dihydro-1H-tetrazol-5-yl)phenol]. The spectroscopic techniques were used to confi rmed the chemical structures are FTIR, 1H-NMR. The biological study of pyrazole and tetrazole derivative was evaluated as anti-bacterial against gram-negative (Klebsiella pneumoniae), gram-positive (Enterococcus faecalis) and as anti-fungal against the Candida trichomonas and Candida dubliniensis in concentration 25, 75, 50, and 100 mg/mL. It was found that pyrazole and tetrazole derivative have biological activity against the bacteria and fungi where the tetrazole ring has biological eff ect more than pyrazole ring.

Design, Synthesis and In Vitro Biological Activity of Novel C-7 Methylene Congeners of Furanoallocolchicinoids.

A series of novel heterocyclic colchicine derivatives bearing a C-7 methylene fragment were synthesized via Wittig, Horner-Wadsworth-Emmons and Nenajdenko-Shastin olefination approaches. The in vitro biological activities of the most promising compounds were investigated using MTT assays and cell cycle analyses. Compounds with an electron withdrawing group on the methylene fragment exhibited substantial antiproliferative activity towards COLO-357, BxPC-3, HaCaT, PANC-1 and A549 cell lines. The spatial orientation of the substituent at the double bond significantly influenced its biological activity.

LA multiple PAHs-degrading Shinella sp. strain and its potential bioremediation in wastewater

Polycyclic aromatic hydrocarbons (PAHs) and heterocyclic derivatives are organic pollutants which threaten ecosystems and human beings. In this study, a new strain, Shinella sp. FLN 14, was isolated and characterized. It can utilize fluorene as its sole carbon source and effectively co-metabolize multiple PAHs and heterocyclic derivatives, including phenanthrene, acenaphthene, and fluoranthene. Two possible metabolic pathways are proposed (i.e., salicylic acid pathway and phthalic acid pathway). Whole-genome sequencing revealed that strain FLN14 possesses a chromosome and four plasmids. However, when combined with ensemble genetic information, novel fluorene-degrading functional gene clusters were not located within the genome of FLN 14, except for some new dioxygenases and electron transport chains, which typically initiate the oxidation of aromatic compounds. In wastewater bioremediation, strain FLN14 removed nearly 95 % of PAHs within 5 days and maintained high degrading activity during the 18-day reaction compared to the control. Overall, our study provides a promising candidate to achieve bioremediation of PAHs-contaminated environments.

Selective Detection of Copper Ions and Biological Activities of Isoniazid Schiff Bases

AbstractFollowing mechanical milling, the condensation reaction of the corresponding heterocyclic aldehydes with Isoniazid yields the Schiff base (E)‐N′‐((1H‐pyrrol‐2‐yl) methylene)isonicotinohydrazide (S1) and (E)‐N′‐(Thiophen‐2‐ylmethylene)isonicotinohydrazide (S2) supported heterocyclic derivatives. The structures of the Schiff bases, S1 and S2 were confirmed by 1H NMR, 13C NMR and IR spectroscopy. Copper ions (Cu2+) were trapped by S1 in DMSO to form the yellow‐coloured complex Cu‐(E)‐N′‐((1H‐pyrrol‐2‐yl)methylene) isonicotinohydrazide (Cu2++S1) with high sensitivity and selectivity. But the same ligand S1 could not be able to capture other metal ions tested for this work (namely, Co2+, Ni2+, Zn2+, Mn2+, Hg2+, Cd2+, Pb2+, Fe2+, and Fe3+) in DMSO. UV‐visible spectroscopic results confirmed the complex formation (Cu2++S1) with copper ions, but not with the other ions. Analysis of non‐covalent interactions (NCI) of ligand S1 with Ni2+, Cu2+ and Zn2+ in DMSO were investigated by density functional theory (DFT). NCI analysis of S1 by Cu2+ ions in DMSO was in good agreement with the experimental results. S2 did not react with any metal ions used in this study to form a complex in DMSO and the same was confirmed by UV‐Visible spectra. Reasonably good antibacterial activity was observed with S1, S2, Cu2++S1 compared to amoxicillin against Gram‐negative bacteria (K. pneumoniae, E. coli), Gram‐positive bacteria (S. aureus, S. pneumoniae), and fungal strain (C. albicans).

‘On Water’‐Promoted Three‐Component Tandem Michael Addition/D−A Cycloaddition Reaction to Construct Polycyclic N‐Heterocycles Derivatives

'On Water'-promoted the three-component tandem Michael addition/D-A cycloaddition reaction in 80 °C at 3 h has been developed without employing any catalyst and organic solvent. The process allows facile access to polycyclic N-heterocycles derivatives contain indole and maleimide from easily accessible starting materials in moderate to high yields (up to 91 %). Compared with conventional reaction conditions, this reaction not only improves the reaction efficiency and rate but also minimizes the side reaction.

Design, synthesis, and biological evaluation of diaryl heterocyclic derivatives targeting tubulin polymerization with potent anticancer activities

A series of diaryl heterocyclic analogues were designed and synthesized as tubulin polymerization inhibitors. Among them, compound 6y showed the highest antiproliferative activity against HCT-116 colon cancer cell line with an IC50 values of 2.65 μM. Compound 6y also effectively inhibited tubulin polymerization in vitro (IC50 of 10.9 μM), and induced HCT-116 cell cycle arrest in G2/M phase. In addition, compound 6y exhibited high metabolic stability on human liver microsomes (T1/2 = 106.2 min). Finally, 6y was also effective in suppressing tumor growth in a HCT-116 mouse colon model without apparent toxicity. Collectively, these results suggest that 6y represents a new class of tubulin inhibitors deserving further investigation.

Fluorescent Cd-MOFs for ion recognition constructed by 2, 5-dimethoxyterephthalic acid and nitrogen heterocyclic derivatives

Under solvothermal synthesis, 1,4-bis(4-methyl-1H-imidazole-1- yl)benzene(1,4-BMIB), 1,1'-(2,5-dimethyl-1,4-phenylene)bis(1H-imidazole)(1,1′- DPBI) and 1,3,5-tri(1H-imidazole-1-yl)benzene (1,3,5-TIB) were used to combine with 2,5-dimethoxyterephthalic acid (H2DTA) and Cd(Ⅱ) to obtain three luminescent complexes {[Cd(DTA)(1,4-BMIB)]‧H2O}n(1), {[Cd(DTA)(1,1′-DPBI)(H2O)] ‧H2O}n(2) and {[Cd(DTA)(1,3,5-TIB)]‧0.5H2DTA}n (3), respectively. Single-crystal diffraction tests revealed that complex 1 belongs to monoclinic crystal system with C2/c space group, where binuclear Cd2(CO2)4 units act as six-connected metal centers resulting in three-dimensional frame with topological symbol of (48.52.65). Complexes 2 and 3 crystallize in triclinic P-1 space group. Among them, complex 2 is a dia-type triple interspersed framework, while complex 3 is a 2-fold-interpenetrating structure. Comparing to the fluorescent emission spectra of ligands, the fluorescence of complexes is obviously enhanced. In addition, all complexes have good recognition capability for Fe3+ and Cr2O72− ions, and their detection curves fit with Stern-Volme equation (I0/I ​= ​1+Ksv[M]) in low concentration range. The fluorescent intensities from complexes indicate a good linear relationship with the concentration of detection ions, and the detection limit is also low. Through scanning for various ions, these complexes are expected to be fluorescent sensors for identifying Fe3+ and Cr2O72− ions.

Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH3, CH2D, CD2H, CD3and13CH3Groups onto (Hetero)Arenes

Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH₃, CH₂D, CD₂H, CD₃and¹³CH₃Groups onto (Hetero)Arenes

Computational and Pharmacokinetic Investigation of Some Heterocyclic Amide Derivatives as Cyclooxygenase Inhibitors: An In-Silico Approach

The two most significant as well as historically important non-steroidal and anti-inflammatory medications (NSAIDs), aspirin and ibuprofen, are frequently used to treat fever, pain, and inflammation. By blocking the activity of cyclooxygenase (COX), it can prevent the production of prostaglandin. In an effort to examine the physiochemical and biological properties of some heterocyclic amide derivatives and quantum mechanical computations have been used to analyze the compounds. To clarify the thermochemical, molecular orbital, and equilibrium geometrical features in the gas phase, density functional theory (DFT) with the B3LYP/6- 31G basis set has been used. Binding affinities and modes of heterocyclic amide analogs have been investigated on human cyclooxygenase (COX-1 and COX-2) proteins (6Y3C and 5F19) using molecular docking as well as nonbonding interactions. Results from geometry and thermochemical analysis support the chemical sustainability of all the structures. Most of the compounds exhibited a significant affinity for binding to the receptor protein (5F19) than the standard drugs aspirin and ibuprofen. The improved pharmacokinetic features of certain derivatives with reduced acute oral toxicity were revealed by ADMET prediction. Overall, four heterocyclic amide analogs 3-6 were found to be more efficient in inhibiting COX- 2 (5F19) than COX-1 (6Y3C), suggesting that they may be useful as COX-2-related inflammation drug candidates.

Serendipitous discovery of Pd-catalyzed intramolecular cyclization of ortho-bromo(hetero)aryl-substituted (hetero)aryl-1,2-diketones: Applications in the synthesis of carba- and heterocyclic benzoin derivatives

Carbaand heterocyclic benzoin derivatives were prepared by Sonogashira coupling of alkynes with 1,2-dihaloalkenes and subsequent oxidation of the alkyne to a 1,2-diketone. The Pd-catalyzed reaction of the product with (2-bromophenyl)boronic acid in the presence of phenylacetylene resulted in formation of cyclic benzoin derivatives by Suzuki-Miyaura reaction and subsequent Pd catalyzed nucleophilic addition to the carbonyl group. Hitherto unprecedented 5-hydroxy-5-phenylbenzo[b]naphtho[1,2-d]thiophene-6(5H)-ones and their regioisomers were prepared from 2,3-dibromobenzothiophene. Phenanthrene benzoin derivatives were prepared from 2-bromo-1-iodobenzene.

4-Bromo-1,8-Naphthalimide derivatives as Antifungal Agents: Synthesis, Characterization, DNA Binding, Molecular docking, Antioxidant and ADMET studies

A series of heterocyclic derivatives (2a-2n) was synthesized and characterized by melting point, FT-IR 1H, 13C NMR, UV-visible spectroscopy and mass spectrometry. In vitro antifungal activity of the heterocyclic derivatives (2a-2n) was evaluated against the fungal strains: C. albicans, C. glabrata and C. tropicalis. The results revealed that heterocyclic analog 2a exhibits significant activity against all three strains with MIC value of 200 μg/mL, 2b exhibits antifungal activity against C. albicans with MIC value of 400 μg/mL and C. glabrata and C. tropicalis with MIC value of 500 μg/mL. Analog 2m also shows antifungal activity against C. albicans with MIC values of 200 μg/mL and C. glabrata and C. tropicalis with a MIC value 250 μg/mL as compared to the standard drug fluconazole. The binding interaction study of promising heterocyclic derivatives 2a, 2b, and 2m with CT-DNA was carried out by using UV-visible, fluorescence, cyclic voltammetry, circular dichroism, and viscosity measurements. The molecular docking study of the heterocyclic derivatives (2a–2n) was done with PDB ID: 1BNA. The pharmacokinetics properties of the heterocyclic derivatives (2a–2n) showed good oral bioavailability. Antioxidant potential of heterocyclic derivatives (2a–2n) was further approximated through DPPH and H2O2 free radical and showed that all the derivatives exhibited remarkable antioxidant activity.