Heterocyclic Systems Research Articles

Synthesis of Tetrahydronaphthoazetidinones, 2,5‐Dioxo‐1,4‐methanobenzoazepines and 3‐Hydroxypyrrolidinones Through Copper‐Assisted Post‐Ugi Reactions

AbstractCopper‐assisted post‐Ugi reactions enable access to different heterocyclic systems, tetrahydronaphthoazetidinone, 2,5‐dioxo‐1,4‐methanobenzoazepine and 3‐hydroxypyrrolidinone derivatives. The described process affords complex scaffolds from readily available acyclic precursors using simple protocols.

One-pot synthesis of fused-rings heterocyclic systems based on symmetrically benzofuran annulated 1,8-naphthalimides

A useful and straightforward synthetic approach to afford heteroarenes by symmetrical annulation of two benzofuran units to 1,8-naphthalene anhydrides, through a regioselective one-pot Sn–Ar/C–H activation tandem reaction is introduced herein. Two synthetic pathways are compared, highlighting that the utilization of diester derivatives improves: (i) the compatibility with the key ring expansion step, (ii) the solubility of the intermediate thus facilitating its purification, and (iii) the versatility of the final imidization. The electrochemical and spectral properties of this new class of compounds are investigated.

A convenient one-pot synthesis of novel heterocyclic systems of 9-chloro-4-methyl-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepine and inhibitory evaluation against bromodomain-containing protein 4 (BRD4) enzyme by molecular docking

A convenient one-pot synthesis of novel heterocyclic systems of 9-chloro-4-methyl-6,11-dihydro-5H-benzo[b]pyrimido[4,5-e][1,4]diazepine and inhibitory evaluation against bromodomain-containing protein 4 (BRD4) enzyme by molecular docking

Templated Total Synthesis of Cu(I)-Methanobactin OB3b.

Methanobactin OB3b (Mbn-OB3b) is a unique natural product with stunning affinity for copper ions (Ka ≈Cu(I) 1034 ). Here, we report the first total synthesis of Cu(I)-bound methanobactin OB3b featuring as key transformations a cyclodehydration-thioacylation sequence, to generate the conjugated heterocyclic systems, and a copper-templated cyclization, to complete the caged structure of the very sensitive target compound.

Synthesis of Thiazoloquinolines with Diverse Molecular Skeletons: A Review

AbstractThiazoloquinolines are an important class of heterocyclic molecules having a wide variety of biological activities. Since the first synthesis of this fused heterocyclic ring system in 1937, quite a good number of research works have been accomplished in designing and achieving the synthesis of various substituted thiazoloquinolines. These molecules possess diverse structural features and bioactive potentials. A thorough survey of literature, available in this field, clearly indicates that there are certain fused thiazoloquinolines whose syntheses have been largely dealt with while the synthesis of some other fusion pattern remains comparatively less explored. The objective of this review is to present a concise overview of the methods towards the synthesis of thiazoloquinolines in a chronological manner.

Templated Total Synthesis of Cu(I)‐Methanobactin OB3b**

AbstractMethanobactin OB3b (Mbn‐OB3b) is a unique natural product with stunning affinity for copper ions (Ka≈Cu(I) 1034). Here, we report the first total synthesis of Cu(I)‐bound methanobactin OB3b featuring as key transformations a cyclodehydration‐thioacylation sequence, to generate the conjugated heterocyclic systems, and a copper‐templated cyclization, to complete the caged structure of the very sensitive target compound.

Synthesis, characterization of new α‐quinolin‐3‐yl‐α‐(aminoamides, aminoesters) and bi‐heterocyclic aromatic systems from gem‐dicyanoepoxides and their pharmacological activity as antioxidant and antifungal agents

AbstractNew series of quinoline coupled to diversely functionalized heterocyclic cores were synthesized, via appropriate synthetic routes, using 3‐(quinolin‐3‐yl) oxirane‐2,2‐carbonitriles as key intermediates. The epoxide ring opening gave bi‐heterocyclic hybrids such as α‐quinolin‐3‐yl‐α‐aminoacetic acid derivatives, quinoxaline‐ and benzimidazole‐quinoline hybrids, and quinoline‐1,3‐oxathioles. Some selected bi‐heterocyclic hybrids were evaluated in vitro for their antioxidant potential using DPPH• and ABTS•+ methods, and their antifungal activity against Fusarium oxysporum f. sp. Lycopersici. It was demonstrated that bi‐heterocyclic aromatic systems exhibited significant antioxidant activities, which are similar in magnitude to those of standards BHT and BHA with important IC50 values. The SAR study of the antifungal activity revealed that only compounds bearing a 2‐imino‐1,3‐oxathiole nucleus are active showing interesting results. Crystal X‐ray structures for two compounds are also reported.

Synthesis and properties of methanesulfonyl derivatives of diethyl esters of 5-(hydroxyalkylamino)-1,3-oxazol-4-yl-phosphonic acids

A number of {[4-(diethoxyphosphoryl)-2-R-1,3-oxazol-5-yl]amino}alkyl methanesulfonates were synthesized and the peculiarities of their reaction with triethylamine were studied. The influence of the structure of the 5-alkanolamine substituent on the efficiency of their transformation into 7-R-1-ethoxy-5-methyl-1,3,4,5-tetrahydro-1λ5-[1,3]oxazolo[4,5-c][1,5,2]oxazaphosphepine-1-ones was clarified. The structure of the [1,3]oxazolo[4,5-c][1,5,2]oxazaphosphepine derivatives has been reliably proven by elemental analysis, IR, 1H, 13C, and 31P NMR spectroscopy (including 1D and 2D experiments), mass spectrometry and single crystal X-ray diffraction. The oxazole cycle in [1,3]oxazolo[4,5-c][1,5,2]oxazaphosphepines is easily cleaved by water in an acidic environment, which leads to the formation of derivatives of the new heterocyclic system – N-(2-ethoxy-5-methyl-2-oxido-4-oxo-1,5,2-oxazaphosphepan-3-yl)arylamides.

The Synthesis and Base-Induced Breakdown of Triaryl 1,4-Oxathiins-An Experimental and DFT Study.

1,4-Oxathiins are valued for a breadth of bioactivities and are known commercial fungicides. This article explores a novel preparation of 2,3,6-trisubstituted 1,4-oxathiin-S,S-dioxides via the reaction of benzyl 1-alkynyl sulfones and aryl aldehydes under basic conditions. A total of 20 examples possessing exclusively a trans arrangement of the 2,3-diaryl substituents are exhibited; the products demonstrate a variation of functional groups on the aryl ring attached to the heterocyclic ring system. The preparation is hindered by the base sensitivity of the products, and a ring-opened by-product typically contaminates the reaction mixture. A DFT assessment of the overall system includes a lithium counterion and offers possible pathways for the incorporation of the aldehyde, the cyclization step and the requisite proton transfers. In addition, the DFT work reveals options for the ring opening chemistry. It appears the trans 2,3-diaryl selectivity is set during the cyclization stage of the reaction sequence. The practical work uncovers a new reaction pathway to create a family of novel 1,4-oxathiin-S,S-dioxides whereas the computational work offers an understanding of the structures and possible mechanisms involved.

Recent Advances in Design and Synthesis of 1,3-Thiaselenolane and 1,3-Thiaselenole Derivatives

Recent advances in the design and synthesis of five-membered heterocycles containing both sulfur and selenium atoms—1,3-thiaselenolane and 1,3-thiaselenole derivatives—are discussed in this review. These heterocyclic systems are of interest as intermediates for organic synthesis and compounds that can exhibit various useful properties, including biological activity and electrical conductivity. The main focus of the review is on the works of the last 20 years that make use of catalytic reactions. Synthetic methods for the preparation of structurally related 1,4,5,8-diselenadithiafulvalenes based on catalytic cross-coupling reactions are also presented. To date, the design and synthesis of 1,3-thiaselenolane and 1,3-thiaselenole derivatives have not been discussed in a separate review.

Synthesis of phenylthiourea-based pyrazole, thiazole and/or pyran compounds: molecular modeling and biological activity

The significant biological activity of phenylthiourea derivatives prompted the synthesis of a new phenylthiourea-based heterocyclic ring systems (pyrazole, thiazole, and pyran), and their chemical structures were elucidated by spectral data. The DFT/B3LYP methodology was applied to explore the configuration and energetic features of the FMO’s of the compounds. The derivatives exhibited comparable energy gap, ranging from 2.13 to 2.56 eV, and were arranged in the following order: 5 < 8 < 7 < 6 < 4b < 4a. The antitumor activity of the new phenylthiourea-based derivatives was investigated against diverse cell lines, such as HepG2, HCT-116, MCF-7, PC3, and WI38, using Doxorubicin as a reference drug. The hybrids 5, 6, and 8 revealed strong cytotoxic against HCT-116 (IC50 = 2.29 ± 0.46-9.71 ± 0.34 µM). Furthermore, the molecular docking studies of the compounds indicated that the hybrids 5, 6 and 8 exhibited the greatest docking score values, in accordance to the antitumor activity.

Synthesis of pyran-annulated heterocyclic system under catalyst-solvent-free conditions using solar energy as renewable energy source

Synthesis of pyran-annulated heterocyclic system under catalyst-solvent-free conditions using solar energy as renewable energy source

Benzimidazole: A Promising target for the development of novel drug molecules against breast cancer

Breast cancer is considered as one of the deadliest diseases dominantly in developed and developing countries. Continuous research is required in order to design and develop better therapeutic agents for cancer treatment with more selectivity, efficacy and reduced toxicity. Fused heterocyclic ring system has been identified as a privileged structure by several researchers that can be used as a template for drug discovery and development in Medicinal Chemistry. Wide range of drugs with therapeutic potential contain hetero-aromatic bicyclic ring system as pharmacophore. According to various research outputs in the literature substituted benzimidazoles have wide range of pharmacological profiles with multi-targeting ability, making them an important basic nucleus for the design and development of novel therapeutic agents for the treatment of complex cancers including breast cancer, skin cancer, and blood cancer. In the presented article we have discussed research outputs by many scientists in the last few years that support the candidature of benzimidazole scaffold for the development of novel therapeutic agents against breast cancer along with their mechanism of action. This review also focuses on little introductory idea about benzimidazole nucleus and types of breast cancer.

Design, synthesis, and anticancer evaluation of novel imidazo[1,2-c]thieno[3,2-e]pyrimidin derivatives

Derivatives of a novel heterocyclic system ethyl 2-(2-(aryl)-9-(aryl)imidazo [1,2-c]thieno [3,2-e]pyrimidin-3-yl)acetate have been obtained by successive reactions in four stages; Knoevenagel condensation between acetophenone derivatives with malononitrile to give 2-(1-arylethylidene)malononitrile, closing the thiophene ring in the latter to form 3-amino-2-5-arylthieno [2,3-d]pyrimidin-4-amines by using formamid, and one-pot three-component reaction of the 3-amino-2-5-arylthieno [2,3-d]pyrimidin-4-amine ring, Meldrum's acid, and various aryl glyoxal. The structure of the new compounds was confirmed based on elemental analysis and spectral data. The anticancer activity of some selected synthesized compounds was also examined. Although the compounds 10a-j are not considerable effective against the three cell lines tested, in comparison to etoposide, compound 10c is somewhat potential.

2,2′‐Bis(arylamino)‐1,1′‐biaryls as Building Blocks for the Synthesis of Dibenzo[d,f][1,3]diazepines, Dibenzo[d,f][1,3]diazepinones, and Dibenzo[c,e][1,2,7]thiadiazepine 6‐Oxides

AbstractThe iron‐catalyzed oxidative C−C homocoupling of diarylamines affords 2,2′‐bis(arylamino)‐1,1′‐biaryls which represent crucial synthetic building blocks for an access to a range of seven‐membered heterocyclic ring systems. Reaction with paraformaldehyde, diphenyl carbonate, and diphenyl sulfite as efficient 1,1‐dielectrophiles led to dibenzo[d,f][1,3]diazepines, dibenzo[d,f][1,3]diazepinones, and dibenzo[c,e][1,2,7]thiadiazepine 6‐oxides. The synthetic procedures enable short and practical routes to these 1,3‐diazepine derivatives under mild reaction conditions and with a high tolerance of various functional groups.

Thermal and oxidative syntheses, structure, and optical properties of 2,6,8-trisubstituted 1,2,3-triazolo[4′,5′:3,4]pyrazolo[1,5-a]pyrimidin-2-ium-1(3)-ides

This study reports the unexpected synthesis of eight examples of a new heterocyclic system, which is composed of a charged triazole ring fused to the pyrazolo[1,5-a]pyrimidine, named 2,8-(diaryl)-6-(trifluoromethyl)-[1,2,3]triazolo[4′,5′:3,4]pyrazolo[1,5-a]pyrimidin-2-ium-1(3)-ides (2). Compounds 2 were successfully synthesized from the reactions of E-3-(aryldiazenyl)-7-(trifluoromethyl)-pyrazolo[1,5-a]pyrimidin-2-amines (1) in yields of up to 85% by employing two different method: thermal azide decomposition and oxidative cyclization. In general, derivatives 2a–h presented absorption bands at the ultraviolet region (250–380 nm) and green emission properties with large Stokes shifts. Moreover, TD-DFT calculations were performed, and redox analysis was conducted by cyclic voltammetry.

Synthesis of (2-Aminopyrimidin-4-yl)(pyridin-4-yl)methanone and Derivatives

AbstractPyrido[3,4-g]quinazoline was previously identified as a relevant scaffold for protein kinase inhibition. In order to assess if the planarity of this heterocyclic system was essential to the protein kinase inhibitory potency observed in this series, new compounds were synthesized and evaluated, in which the central cycle was opened to provide (pyridin-4-yl)(pyrimidin-4-yl)methane derivatives, which were prepared from the corresponding ketone precursor. After preparing (2-aminopyrimidin-4-yl)(pyridin-4-yl)methanone, derivatives were synthesized and evaluated toward a panel of protein kinases. The results demonstrated that the planar pyrido[3,4-g]quinazoline tricyclic system was mandatory to maintain the protein kinase inhibitory potency in this series.

Benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole)-4-carbonitrile

Electron-withdrawing heterocyclic units are found in most organic optoelectronic materials. Benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole) is an interesting new heterocyclic system, the chemical properties of which are much less studied than other fused thiadiazoles. Cyano derivatives of electron-accepting heterocycles are known as potential components of photoluminescent materials. In this communication, benzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole)-4-carbonitrile was successfully obtained via the cyanation of 4-bromobenzo[1,2-d:4,5-d′]bis([1,2,3]thiadiazole) with copper(I) cyanide in DMF. The structure of the newly synthesized compound was established by means of elemental analysis, high-resolution mass spectrometry, 1H and 13C NMR, and IR spectroscopy.

Synthesis, molecular docking, and ADME analysis of a series of 4-amino-3,5-dimethyl-1,2,4-triazole derivatives

The heterocyclic system of 1,2,4-triazole enables the successful creation of promising biologically active compounds. By creating a range of derivatives based on 4-amino-3,5-dimethyl-1,2,4-triazole, the spectrum of potential biologically active compounds can be expanded. The aim of the work was the synthesis and in silico justification of the prospects for the search for biologically active compounds among 4-amino-3,5-dimethyl-1,2,4-triazole derivatives. Materials and methods. The work uses modern methods for synthesizing organic compounds, followed by confirmation of their individuality and structure through the analysis of physical-chemical parameters and spectroscopic techniques such as 1H NMR, IR spectroscopy, elemental analysis, and chromatography-mass spectrometry. To assess the similarity of the synthesized compounds to medicinal products, the SwissADME online tool was employed. The probability of impact on a number of enzyme systems (cyclooxygenase-2, lanosterol 14α-demethylase, anaplastic lymphoma kinase) was estimated using molecular docking. Results. A series of newly synthesized derivatives of 4-amino-3,5-dimethyl-1,2,4-triazole was obtained, and the synthesis conditions were optimized and their structures were confirmed. It was determined that there is a high probability of influencing lanosterol 14α-demethylase, highlighting the significance of further research on the antifungal activity of the synthesized compounds. Additionally, the potential influence on the activity of cyclooxygenase-2 and anaplastic lymphoma kinase was discovered. However, the probability of exhibiting the corresponding activities, namely anti-inflammatory and anti-cancer, is low. Physical indicators, parameters of pharmacokinetics, and drug-likeness are important, which determines the prospects of creating biologically active substances based on the synthesized series of compounds. Conclusions. A series of 4-((R-iden)amino)-3,5-dimethyl-1,2,4-triazoles were synthesized, and their general physical-chemical properties were determined. The overall potential for creating innovative biological products based on these compounds was assessed using in silico methods for predicting the activity of substances.

Synthesis, Characterization, 'ADMET-SAR' Prediction, DPPH Assay, and Anti-Mycobacterium Study of 4-[(substituted benzyl) amino]benzo hydrazides and its Hydrazones as the Acyl-CoA Carboxylase, AccD5 Inhibitors.

Hydrazide-hydrazone derivatives have shown diverse biological activities, such as antitubercular (anti-TB), antibacterial, antifungal, anticancer, anti-inflammatory, antiviral, and antiprotozoal actions. Hydrazide-hydrazones contain azomethine (-NH-N=CH-) group connected with carbonyl group and are believed to be responsible for various pharmaceutical applications. They aid in the synthesis of different five-membered heterocyclic systems, such as oxadiazole, triazoles, etc. Methods: In the present study, various hydrazines/hydrazones were synthesized starting from 4- amino benzoic acid derivatives. Structures of all 9 newly synthesized compounds (6a-6d and 8a- 8e) were further characterized by using various spectroscopic methods, such as 1H-NMR (Nuclear Magnetic Resonance), FT-IR (Fourier-transform infrared spectroscopy), Gas chromatographymass spectrometry (GC-MS), etc. Furthermore, molecular docking analysis against the acyl-CoA carboxylase, AccD5 (PDB ID: 2A7S), was also carried out using the Glide module, which depicted good binding scores than standard drugs. The anti-tuberculosis activity of all the hydrazides and hydrazones (6a-6d and 8a-8e) were evaluated against the Mycobacterium tuberculosis H37 RV strain using the Alamar-Blue susceptibility (MABA) test. The activity was expressed as the minimum inhibitory concentration (MIC) in μg/mL values. The antioxidant activity was also carried out using a DPPH assay. Our findings demonstrated highly encouraging in-vitro results (MABA assay, MIC: 1.2 μg/mL) of hydrazones as depicted by good antimycobacterial activity. The antioxidant results showed a moderate to a good percentage of DPPH inhibition. Our in-silico ADMET analysis further suggested good pharmacokinetic and toxicity-free profiles of synthesized analogues (6a-6d and 8a-8e). Our results signify hydrazones/hydrazines as potential hit candidates against the future developments of potent and safer anti-TB agents.