Pentacyclic Triterpenoids with Nitrogen-Containing Heterocyclic Moiety,Privileged Hybrids in Anticancer Drug Discovery

Pentacyclic triterpenoids are well-known phytochemicals with various biological activities commonly found in plants as secondary metabolites. The wide range of biological activities exhibited by triterpenoids has made them the most valuable sources of pharmacological agents. A number of novel triterpenoid derivatives with many skeletal modifications have been developed. The most important modifications are the formation of analogues or derivatives with nitrogen-containing heterocyclic scaffolds. The derivatives with nitrogen-containing heterocyclic compounds are among the most promising candidate for the development of novel therapeutic drugs. About 75% of FDA-approved drugs are nitrogen-containing heterocyclic moieties. The unique properties of heterocyclic compounds have encouraged many researchers to develop new triterpenoid analogous with pharmacological activities. In this review, we discuss recent advances of nitrogen-containing heterocyclic triterpenoids as potential therapeutic agents. This comprehensive review will assist medicinal chemists to understand new strategies that can result in the development of compounds with potential therapeutic efficacy.     

Highlights on Steroidal Arylidene Derivatives as a Source of Pharmacologically Active Compounds: A Review

Steroids constitute a unique class of chemical compounds, playing an important role in physiopathological processes, and have high pharmacological interest. Additionally, steroids have been associated with a relatively low toxicity and high bioavailability. Nowadays, multiple steroidal derivatives are clinically available for the treatment of numerous diseases. Moreover, different structural modifications on their skeleton have been explored, aiming to develop compounds with new and improved pharmacological properties. Thus, steroidal arylidene derivatives emerged as a relevant example of these modifications. This family of compounds has been mainly described as 17β-hydroxysteroid dehydrogenase type 1 and aromatase inhibitors, as well as neuroprotective and anticancer agents. Besides, due to their straightforward preparation and intrinsic chemical reactivity, steroidal arylidene derivatives are important synthetic intermediates for the preparation of other compounds, particularly bearing heterocyclic systems. In fact, starting from arylidenesteroids, it was possible to develop bioactive steroidal pyrazolines, pyrazoles, pyrimidines, pyridines, spiro-pyrrolidines, amongst others. Most of these products have also been studied as anti-inflammatory and anticancer agents, as well as 5α-reductase and aromatase inhibitors. This work aims to provide a comprehensive overview of steroidal arylidene derivatives described in the literature, highlighting their bioactivities and importance as synthetic intermediates for other pharmacologically active compounds.     

Structure and acidity of some heterocyclic nitrosazones

Several new heterocyclic nitrosazones were prepared and their acid dissociation constants determined in 50 volume percent ethanol-water solution at 25.0 ± 0.1° and μ of 0.10. Infrared, electronic, and pmr spectra of these compounds and some deuterated nitrosazones were also examined and compared with their O-methyl derivatives. It is concluded that all compounds have the azo oxime structure and that the stereochemistry around the azo group is trans. The data revealed also that the nitrosazones derived from pyridine aldehydes show the existence of equilibria between zwitterionic and neutral molecules. No evidence for the tautomeric nitroso-hydrazone form could be obtained.     

Selective formation of heteroaryl thioethers via a phosphonium ion coupling reaction

Heteroaryl thioethers, comprised of pyridines and diazines, are an important class of compounds with relevance to medicinal chemistry. Metal-catalyzed cross-couplings and S_NAr reactions are traditionally used to form C–S bonds in these systems but are limited by available halogenated precursors. An alternative approach is presented where pyridines and diazines are transformed into heterocyclic phosphonium salts and then C–S bonds are formed by adding thiolate nucleophiles. The process is 4-selective for pyridines, simple to execute and can be used to make derivatives of complex pharmaceuticals.     

Preparation of 2-aryl and 2-aryloxymethyl imidazo[1,2-a]pyridines and related compounds

A series of substituted 2-aryl imidazo[1,2-a]pyridines has been prepared in which a variety of substituents are introduced on the 4′-position of the phenyl ring and on the 3, 5 , 6 or 7 position of the heterocyclic ring. Most examples have acetamido, bromo, cyano, or formyl substituents at the 4′-position. Analogous imidazo-[2,1-b]fhiazoles and imidazo[1,2-a]pyrimidines have also been prepared. Another series of compounds consisting of 4′-formylphenoxymethyl derivatives of imidazole, the three positional isomers of pyridine, thiazole, benzimidazole and ring-substituted imidazo[1,2-a]pyridines has been prepared. 2-(4′-Formylphenylethenyl) derivatives of imidazole and imidazo[1,2-a]pyridine were also prepared.     

An Overview on Synthetic 2-Aminothiazole-Based Compounds Associated with Four Biological Activities

Amongst sulfur- and nitrogen-containing heterocyclic compounds, the 2-aminothiazole scaffold is one of the characteristic structures in drug development as this essential revelation has several biological activities abiding it to act as an anticancer, antioxidant, antimicrobial and anti-inflammatory agent, among other things. Additionally, various 2-aminothiazole-based derivatives as medical drugs have been broadly used to remedy different kinds of diseases with high therapeutic influence, which has led to their wide innovations. Owing to their wide scale of biological activities, their structural variations have produced attention amongst medicinal chemists. The present review highlights the recently synthesized 2-aminothiazole-containing compounds in the last thirteen years (2008–2020). The originality of this proposal is based on the synthetic strategies developed to access the novel 2-aminothiazole derivatives (N-substituted, 3-substituted, 4-substituted, multi-substituted, aryl/alkyl substituents or acyl/other substituents). The literature reports many synthetic pathways of these 2-aminothiazoles associated with four different biological activities (anticancer, antioxidant, antimicrobial and anti-inflammatory activities). It is wished that this review will be accommodating for new views in the expedition for rationalistic designs of 2-aminothiazole-based medical synthetic pathways.     

The mass spectra of some 1H-imidazo[1,2-a]pyrrolo[3,2-e]pyridines

We report here the mass spectral fragmentations of some derivatives of a new heterocyclic system 1H-imidazo[1,2-a]pyrrolo[3,2-e]pyridine. These compounds combine structural features of 1H-pyrrolo[2,3-b]pyridines and imidazo[1,2-a]pyridines, but follow fragmentation pathways similar to the former.     

Microwave-assisted synthesis and transformations of sterically hindered 3-(5-tetrazolyl)pyridines

Sterically hindered 2,4-disubstituted 3-(5-tetrazolyl)pyridines were synthesized from corresponding nicotinonitriles using microwave technology. 2-Methylnicotinonitriles were converted into the 2-azidomethyl-3-cyanopyridines via 2-hydroxymethyl and 2-chloromethyl derivatives. Intramolecular [3+2] cycloaddition of an heteroaromatic cyano group to side azido group was carried out to form a novel heterocyclic system containing a (tetrazolo)azaisoindole unit. Condensation of the 2-methylnicotinonitriles and aldehydes gave rise to the corresponding 2-vinyl derivatives, which were then transformed into novel heterocyclic system (5,6-dihydrotetrazolo[5,1-f]-1,6-naphthyridine) by intramolecular N-alkylation reaction of tetrazole ring with olefinic fragment. The 3-(5-tetrazolyl)pyridines obtained were alkylated to give the various N- and C-benzyl derivatives as well as acylated to afford the 3-(1,3,4-oxadiazol-2-yl)pyridines in good yields. A majority of above-mentioned reactions was carried out under microwave irradiation.     

Synthesis and Anti‐Avian Influenza Virus (H5N1) Evaluation of Some Novel Nicotinonitriles and Their N‐Acylic Nucleosides

Pyridine and fused pyridines derivatives are interesting compounds with diverse chemical properties and pharmacological activities. Herein, the synthesis and antiviral evaluation of some new pyridines are described.     

Synthesis of 3-aryl pyrrolidines: A highlights

Pyrrolidine derivatives are very important families of heterocyclic compounds that show diverse biological activity. The substitution pattern and functionalization on these derivatives show different biological activities. Different substituted pyrrolidines shown to have different antibacterial effects. They are also used as scaffolds in the synthesis of unnatural oligomers which have various biological applications in the field of antidiabetic, anticancer, antimalarial, antiviral, antimicrobial, anti-inflammatory, and antibacterial activities . Numerous groups have synthesized substituted pyrrolidines and they constructed the pyrrolidine ring by the formation of various different bonds from acyclic precursors. Some of the groups have synthesized that derivatives only by reduction.     

Synthesis of tetracyclic thienotriazolopyridines based on hydrazine derivatives of fused pyridinethiones

A method for the synthesis of hydrazine derivatives of fused pyridinethiones based on alicyclic and heterocyclic ketones has been developed. Successive heterocyclization of these hydrazine derivatives was carried out in order to obtain new derivatives of tricyclic triazolo[4,3-a]pyridines, tetracyclic thieno[3,2-e][1,2,4]triazolo[4,3-a]pyridines, as well as a new heterocyclic system of thieno[2,3-c][1,2,4]triazolo[3,4-a]-2,7-naphthyridine.

     

Novel one step synthesis of imidazo[1,2-a]pyridines and Zolimidine via iron/iodine-catalyzed Ortoleva-King type protocol

Imidazo[1,2-a]pyridines form versatile scaffolds in pharmaceutical industry arising from their diverse biological activities. The synthesis of these molecules thus has been of great interest and resulted in the development of a large number of new methodologies. Herein we describe the first iron-catalyzed Ortoleva-King type protocol towards the synthesis of these fused heterocyclic compounds. This methodology employs cheap and easily available FeCl₃·6H₂O and molecular iodine as the catalytic system. The procedure has been well explored by extending the substrate scope with a variety of aromatic ketones and 2-aminopyridines to furnish different imidazo[1,2-a]pyridine derivatives in moderate to good yields. A successful application of this protocol was also demonstrated by achieving direct one step synthesis of the gastro protective drug, Zolimidine.     

Mutagenic heterocyclic nitrogen compounds related to protein pyrolysates. 1. Derivatives of dipyrido[1,2-a:3′,2′-d]imidazole

2-Amino-6-methyldipyrido[1,2-a:3′-2′-d]imidazole is one of the mutagenic principles of L-glutamic acid and casein pyrolysates. We prepared several isomeric amines of this compound, as well as their homologues methylated in different positions on the heterocyclic ring, either by nitration of the ring followed by reduction or from appropriate 4-azidodipyrido[1,2-a:3′,2′-d]imidazoles. The latter compounds, the heterocyclic ring itself and various functional derivatives (hydroxylated, carboxylated, hydrazinic) were synthesized from 2-aminoimidazo[1,2-a]pyridines via various reactions which are described herein.     

Further heterocyclic analogs of polyaryls

A series of indoles, indolizines, imidazo[1,2-a]pyridines, and quinolines, all of them heterocyclic analogs of polyaryls, have been prepared from diacetyl derivatives of aromatic hydrocarbons.     

Synthesis,characterization, and dyeing performance of some azo thienopyridine and thienopyrimidine dyes based on wool and nylon

A string of novel heterocyclic mono azo dyes were synthesized and their utilization in dyeing different fabrics as wool and nylon were discussed. Thienopyridine azo dyes 4 and 6 were prepared by reaction of chloro acetamidederivative 2 with diamino compounds to yield 3 and 5 , followed by reaction with NaNO₂/HCl and coupling with nucleophilic reagent. One-pot reaction of chloro acetamide 2 with ammonium thiocyanat in solvent ethanol gave the unexpected thienopyrimidine derivative 7 , which contain two active sites, the former is primary amine that was able to form diazonium salt that coupled with N,N-dimethylaniline, resorcinol, and/or self-coupling to afford the azo dyes 8-10 , and the latter is active methylene group that underwent coupling with different diazonium salts to give the azo thienopyrimidine derivative dye 11-15 . The dyeing performance of these azo dyes had been investigated in terms of their dyeing behavior and fastness properties on different fabrics. Results showed that the color strength (K/S) values, as well as, washing, rubbing, and resistance to acid, alkali and light showed high efficiency of these heterocyclic mono azo dyes to dye wool rather than nylon fibers.     

Synthesis of azo compounds by nanosized iron-promoted reductive coupling of aromatic nitro compounds

Treatment of a variety of aromatic nitro compounds with the active-iron based reducing system composed of FeCl₂·4H₂O, an excess of lithium powder and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 5 mol %) in THF at room temperature, led to the formation of the corresponding symmetrically substituted azo compounds in good yield, resulting from a reductive coupling process. Some other functionalities including carbonyl, halogen, amino and hydroxyl groups, demonstrated to be compatible with the reaction conditions, giving none reduced or coupled by-products. In all cases, the azo compounds formed have not experienced over-reduction to the corresponding hydrazo or amino derivatives even upon prolonged heating or using an excess of the reducing system.     

Annelated Pyridines as Highly Nucleophilic and Lewis Basic Catalysts for Acylation Reactions

New heterocyclic derivatives of 9‐azajulolidine have been synthesized and characterized with respect to their nucleophilicity and Lewis basicity. The Lewis basicity of these bases as quantified through their theoretically calculated methyl‐cation affinities correlate well with the experimentally measured reaction rates for addition to benzhydryl cations. All newly synthesized pyridines show exceptional catalytic activities in benchmark acylation reactions, which correlate only poorly with Lewis basicity or nucleophilicity parameters. A combination of Lewis basicity with charge and geometric parameters in the framework of a three‐component quantitative structure–activity relationship (QSAR) model is, however, highly predictive.     

Theoretical Study of 2-(Trifluoromethyl)phenothiazine Derivatives with Two Hydroxyl Groups in the Side Chain-DFT and QTAIM Computations

Phenothiazines are known as synthetic antipsychotic drugs that exhibit a wide range of biological effects. Their properties result from the structure and variability of substituents in the heterocyclic system. It is known that different quantum chemical properties have a significant impact on drug behavior in the biological systems. Thus, due to the diversity in the chemical structure of phenothiazines as well as other drugs containing heterocyclic systems, quantum chemical calculations provide valuable methods in predicting their activity. In our study, DFT computations were applied to show some thermochemical parameters (bond dissociation enthalpy—BDE, ionization potential—IP, proton dissociation enthalpy—PDE, proton affinity—PA, and electrontransfer enthalpy—ETE) describing the process of releasing the hydrogen/proton from the hydroxyl group in the side chain of four 2-(trifluoromethyl)phenothiazine (TFMP) derivatives and fluphenazine (FLU). Additional theoretical analysis was carried out based on QTAIM theory. The results allowed theoretical determination of the ability of compounds to scavenge free radicals. In addition, the intramolecular hydrogen bond (H-bond) between the H-atom of the hydroxyl group and the N-atom located in the side chain of the investigated compounds has been identified and characterized.     

Current perspectives on quinazolines with potent biological activities: A review

Quinazoline is a heterocyclic compound having biological activities. It is aromatic in nature having bicyclic structure containing benzene ring and pyrimidine ring. Quinazoline and its derivatives are found to have wide range of biological activities that is anticancer, analgesic, antimicrobial, antihypertensive, anticonvulsant, antimalarial, antitumor, and anti-tubercular activities. The purpose of this review is to highlight the recent researches made by researchers on various biological activities of quinazoline derivatives on different targets.     

Bidentate and tridentate heterocyclic azo compounds having long alkyl chains as coating reagents for ion chromatography of manganese, zinc, and cadmium ions.

Bidentate and tridentate heterocyclic azo compounds with and without a long alkyl chain were prepared and examined for cation exchange chromatography of manganese, zinc, and cadmium; these ions could not be separated by reversed phase HPLC following precolumn derivatization with heterocyclic azo compounds owing to the dissociation of the complexes. The newly prepared azo compounds having a long alkyl chain favorably orientate in the reversed-phase stationary phase such that the coordinating parts of the ligand may make contact with metal ions in the mobile phase. Bidentate ligands showed sharp peaks but almost no resolution of manganese and cadmium. A tridentate ligand strongly retained all the three metal ions, which could be separated within 10 min by a competing ligand and by optimizing the pH.