Enantiopure 4‐oxazolin‐2‐ones and 4‐methylene‐2‐oxazolidinones as chiral building blocks in a divergent asymmetric synthesis of heterocycles

Enantiopure 3‐((R)‐ and 3‐((S)‐1‐phenylethyl)‐4‐oxazoline‐2‐ones were evaluated as chiral building blocks for the divergent construction of heterocycles with stereogenic quaternary centers. The N‐(R)‐ or N‐(S)‐1‐phenylethyl group of these compounds proved to be an efficient chiral auxiliary for the asymmetric induction of the 4‐ and 5‐positions of the 4‐oxazolin‐2‐one ring through thermal and MW‐promoted nucleophilic conjugated addition to Michael acceptors and alkyl halides. The resulting adducts were transformed via a cascade process into fused six‐membered carbo‐ and heterocycles. The structure of the reaction products depended on the electrophiles and reaction conditions used. Alternative isomeric 4‐methylene‐2‐oxazolidinones served as chiral precursors for a versatile and divergent approach to highly substituted cyclic carbamates. DFT quantum calculations showed that the formation of bicyclic pyranyl compounds was generated by a diastereoselective concerted hetero‐Diels‐Alder cycloaddition.     

Synthesis and biological evaluation of some acyclic alpha-(1H-pyrazolo-[3,4-d]pyrimidin-4-yl)thioalkylamide nucleosides

The chemical synthesis of some acyclic alpha-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)thioalkylamide nucleosides (10-12)a-c is described. The treatment of IH-pyrazolo[3,4-d]pyrimidin-4-thione 1 with compounds 2a-c gave, regioselectively, ethyl alpha-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)thioalkylates 3a-c, respectively. These heterocycles were alkylated, separately, with alkylating agents 4, 5 and 6 to give, regioselectively, the N1-acyclic nucleosides (7-9)a-c which were deprotected to afford the desired products (10-12)a-c. All synthetic compounds were characterized on the basis of their physical and spectroscopic properties. The products (10-12)a-c were evaluated for their inhibitory effects against the replication of HIV-1 (III(B)), HIV-2 (ROD), various DNA viruses, a variety of tumor-cell lines and M. tuberculosis. No marked biological activity was found.     

Stereoselective synthesis of enantiopure N-substituted pyrrolidin-2,5-dione derivatives by 1,3-dipolar cycloaddition and assessment of their in vitro antioxidant and antibacterial activities

1,3-Dipolar cycloaddition between a chiral nitrone and N-substituted maleimides afforded unprecedented enantiopure spiro-fused heterocycles in good yields with a high enantio- and diastereoselectivity. The reaction was taking place on the less hindered face of the nitrone. The obtaining heterocycles were screened for their in vitro antioxidant properties and the results revealed that the potent antioxidant activity was generally recorded to compounds (3g) and (3e). The in vitro antibacterial activities of these two compounds were also investigated and the results demonstrated the strongest potential of compound (3g) against all the tested bacteria. Molecular properties were analyzed and showed good oral drug candidate like properties and that could be exploited as a potential antioxidant and antimicrobial agent. Finally, the preliminary results obtained from this investigation attempted to clarify if the structurally different side chains of active compounds interfere with their biological properties.     

Design and synthesis of novel D-ring fused steroidal heterocycles

Using dehydroepiandrosterone as the starting material, we have synthesized a series of steroid analogs possessing a D-ring fused with heterocycles which are pyridine, imidazo [2,1-b]thiazoles or substituted thiazole imines. All the final structures are first reported and identified by NMR and MS spectroscopys, the yields of these products are moderate to good and the reaction conditions are mild. The cytotoxicity of the synthesized compounds against EC-109(human esophageal carcinoma), EC-9706(human esophageal carcinoma), MGC-803(human gastric carcinoma) were investigated.     

Synthesis and antimicrobial activity of new heterocyclic compounds containing thieno[3,2-c]coumarin and pyrazolo[4,3-c]coumarin frameworks

Reaction of 4-chlorocoumarin-3-carbonitrile with ethyl thioglycolate and ethyl glycinate hydrochloride leads to a series of title products. Hydrazinolysis of amino thienocoumarin carboxylate afforded the hydrazino derivative which underwent various reactions to build new heterocyclic rings containing thienocoumarin moiety. Chloro acetylation of aminoester compound afforded the chloro acetyl amino which underwent nucleophilic substitution reactions with various amines. The following treatment with formaldehyde under Mannich conditions afforded the corresponding imidazo derivatives. Reaction of chloroacetylamino with potassium thiocyanate yielded ethylpyrimidothieno coumarin sulfanylacetate which was used as a versatile precursor for synthesis of other heterocycles. On the other hand, reaction of chloro coumarin carbonitrile with hydrazine gave the aminopyrazolocoumaine which reacted with bifunctionally compounds to give the substituted pyrimido derivatives. Diazotization and coupling of aminopyrazole with ethylcyanoacetate yielded ethylaminotriazinopyrazolocoumarine carboxylate. Several of the compounds obtained demonstrated considerable antifungal and antibacterial activity in the in vitro test systems.     

Privileged structure-based ligands for melanocortin receptors-tetrahydroquinolines, indoles, and aminotetralines

Substitution of the aryl sulfonamide moiety contained in MC4 agonist 1 with bicyclic heterocycles and aminotetralines produced compounds with MC4 activity. The heterocycles represent alternative privileged structures to that contained in 1. Compounds in which the polar group of the privileged structure was displayed in an endocyclic fashion were not as active as the parent agonist 1, while those with an exocyclic polar group afforded activity competitive with 1.     

Imino [4+4] cycloaddition products as exclusive and biologically relevant acrolein-amine conjugates are intermediates of 3-formyl-3,4-dehydropiperidine (FDP), an acrolein biomarker

We demonstrated synthetically that the eight-membered heterocycles 2,6,9-triazabicyclo[3.3.1]nonanes and 1,5-diazacyclooctanes are the initial and exclusive products of the reaction, through an imino [4+4] cycloaddition, of biologically relevant amines with acrolein. The stabilities of the aminoacetals within the eight-membered heterocycles determined whether the product was subsequently transformed gradually into the 3-formyl-3,4-dehydropiperidine (FDP), which is widely used as an oxidative stress marker. The reactivity profiles discovered in this study suggested that some of the imino [4+4] cycloaddition products are reactive intermediates of FDP and contribute to the mechanisms underlying the oxidative stress response to acrolein.     

Quantitative relationships of structure and antimicrobial activity in azole-containing chemotherapeutics

Several novel azole-containing compounds belonging to condensed heterocycles were studied in vitro within the program of screening antimicrobial substances. Changes in the activity of the compounds against 8 representatives of the microbial genera dependent on the chemical structure were followed up. The changes in the structure referred to the radicals at positions 1 and 3.     

Bis(phosphine) Pd(II)–azido complexes containing heterocyclic ligands: Reactivity toward organic isocyanides

Bis(phosphine) Pd–azido complexes containing heterocycles such as tetrazolyl, pyrazinyl, and thienyl groups reacted with aryl isocyanides to give the corresponding Pd–carbodiimido or –imidoyl carbodiimido complexes. These products were formed by the insertion of the isocyanides into the Pd–N (azido) or the Pd–C (heterocycles) bond.     

Synthesis and antibacterial activity of arylpiperazinyl oxazolidinones with diversification of the N-substituents

A series of 4-arylpiperazin-1-yl-3-phenyloxazolidin-2-one derivatives with diversification of the N-substituents such as methylene O-linked heterocycles, thioamide, dithiocarbamate, thiourea, and thiocarbamate were synthesized and evaluated as antibacterial agents. Their in vitro activities (MIC) were evaluated against MRSA and VRE resistant Gram-positive strains such as Staphylococcus and Enterococcus. Most of the compounds were more potent in vitro but less active in vivo than linezolid.     

Cytotoxic heterocyclic triterpenoids derived from betulin and betulinic acid

The aim of this work was to synthesize a set of heterocyclic derivatives of lupane, lup-20(29)-ene, and 18α-oleanane, and to investigate their cytotoxic activities. Some of those heterocycles were previously known in the oleanane (allobetulin) group; however, to our knowledge the syntheses and biological activities of lupane heterocycles have not been reported before. Starting from betulin (1) and betulinic acid (2), we prepared 3-oxo compounds and 2-bromo-3-oxo compounds 3-10, 2-hydroxymethylene-3-oxo compounds 11-13 and β-oxo esters 14-16. Condensation of these intermediates with hydrazine, phenylhydrazine, hydroxylamine, or thiourea yielded the pyrazole and phenylpyrazole derivatives 17-22, pyrazolones 23-25, isoxazoles 26 and 27, and thiazoles 28-31. Fifteen compounds (14-16, 18-25, and 29-32) have not been reported before. The cytotoxicity was measured using panel of seven cancer cell lines with/without MDR phenotype and non tumor MRC-5 and BJ fibroblasts. The preferential cytotoxicity to cancer cell lines, particularly to hematological tumors was observed, the bromo acids 5, 6 showed highest activity and selectivity against tumor cells.     

Cytochrome P450 oxidations in the generation of reactive electrophiles: epoxidation and related reactions

Much of the interest in the cytochrome P450 (P450) enzymes has been because of oxidation of chemicals to reactive products. The epoxides (oxiranes) have been a major topic of interest with olefins and aryl compounds. Epoxides vary considerably in their reactivity, with t(1/2) varying from 1s to several hours. The stability and reactivity influences not only the overall damage to biological systems but also the site of injury. Transformations of some xenobiotic chemicals may involve products other than epoxides. Chemicals considered here include olefins, aromatic hydrocarbons, heterocycles, vinyl halides, ethyl carbamate, vinyl nitrosamines, and aflatoxin B(1). These compounds either are unsaturated or are transformed to unsaturated products. The epoxides and other products provide a view of the landscape of P450-generated reactive products and the myriad of chemistry involved in the metabolism of drugs and protoxicants. Understanding the chemical nature of reactive products is necessary to develop rational strategies for intervention.     

Synthesis and biological evaluation of some alpha-[6-(1'-carbamoylalkylthio)-1 H-pyrazolo[3,4-D]pyrimidin-4-yl]thioalkylcarboxamide acyclonucleosides

The reaction of 1H-pyrazolo[3,4-d]pyrimidin-4,6-dithione 11 with compounds 12a-c produces ethyl alpha-[6-(1'-carboethoxyalkylthio)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]thioalkylates 13a-c, respectively. These heterocycles were alkylated, separately, with alkylating agents 14, 15, and 16 to afford, predominately, the N(1)-acyclic nucleosides (17-19)a-c, which were deprotected to give the desired products (20-22)a-c. All synthetic compounds were characterized on the basis of their physical and spectroscopic properties. The acyclic nucleosides (20-22)a-c were evaluated for their inhibitory effects against the replication of varicella-zoster virus, human cytomegalovirus and M. tuberculosis. No marked biological activity was found.     

A reusable magnetic nickel nanoparticle based catalyst for the aqueous synthesis of diverse heterocycles and their evaluation as potential anti-bacterial agent

A library of biologically important heterocycles, viz. pyrazolyl pyrimidine-triones, bis(heterocyclyl)methanes were successfully synthesised by the condensation of barbituric acid, pyrazolone with an aldehyde and dimedone/4-hydoxy coumarin with various substituted aldehydes in aqueous medium at room temperature catalysed by nickel nanoparticles which proved to be an efficient magnetically recyclable catalyst. The method is simple, eco-friendly and gave excellent yields of the products without taking recourse to column chromatographic separation procedures. Computational method was employed to elucidate the selective formation of uncyclised product in reaction course. The biological activity of the synthesized compounds were investigated and the results demonstrated profound antibacterial activity.     

Actions of a versatile fluorene-degrading bacterial isolate on polycyclic aromatic compounds.

Pseudomonas cepacia F297 grew with fluorene as a sole source of carbon and energy; its growth yield corresponded to an assimilation of about 40% of fluorene carbon. The accumulation of a ring meta-cleavage product during growth and the identification of 1-indanone in growth media and washed-cell suspensions suggest that strain F297 metabolizes fluorene by mechanisms analogous to those of naphthalene degradation. In addition to fluorene, strain F297 utilized for growth a wide variety of polycyclic aromatic compounds (PACs), including naphthalene, 2,3-dimethylnaphthalene, phenanthrene, anthracene, and dibenzothiophene. Fluorene-induced cells of the strain also transformed 2,6-dimethylnaphthalene, biphenyl, dibenzofuran, acenaphthene, and acenaphthylene. The identification of products formed from those substrates (by gas chromatography-mass spectrometry) in washed-cell suspensions indicates that P. cepacia F297 carries out the following reactions: (i) aromatic ring oxidation and cleavage, apparently using the pyruvate released for growth, (ii) methyl group oxidations, (iii) methylenic oxidations, and (iv) S oxidations of aromatic sulfur heterocycles. Strain F297 grew with a creosote-PAC mixture, producing an almost complete removal of all aromatic compounds containing 2 to 3 rings in 14 days, as demonstrated by gas chromatography analysis of the remaining PACs recovered from cultures. The identification of key chemicals confirmed that not only are certain compounds depleted but also the anticipated reaction products are found.     

Preparation of New Spiropyrazole,Pyrazole and Hydantoin Derivatives and Investigation of Their Antioxidant and Antibacterial Activities.

In this study, the synthesis of new spiropyrazoles, pyrazole and hydantoin heterocycles is reported by three component reactions of parabanic acids, hydrazine derivatives, and phenacyl bromides in the presence of triphenylphosphine as a nucleophile and triethylamine as a base in good to high yields (69–91 %). Evaluation of the synthesized compounds revealed a good to excellent antioxidant activities (37.6–96.2 %) using DPPH inhibitory potency. Among these compounds, hydantoin derivatives displayed higher antioxidant activities (93.7–96.2 %) comparing with spiropyrazoles and pyrazoles. The obtained results showed that Cl and Br substituents on the phenyl ring increased antioxidant activities of the related heterocycles. The antibacterial activities of the synthesized compounds were examined against two Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and two Gram-positive (Staphylococcus aureus and Bacillus subtilis) bacteria. Among the synthesized heterocycles, 2-[1,3-dimethyl-2,5-dioxo-4-(2-oxo-2-phenylethyl)imidazolidin-4-yl]hydrazine-1-carbothioamide exhibited the excellent antibacterial activity against both Gram-positive and Gram-negative bacteria.     

Mutagenic activity of methyl-substituted tri- and tetracyclic aromatic sulfur heterocycles

A number of polycyclic aromatic sulfur heterocycles have been identified in coal-derived products and in shale oils. The mutagenic activity of some of these compounds, including dibenzothiophene, benzo[b]naphtho[1,2-d]thiophene, benzo[b]naphtho[2,1-d]thiophene and benzo[b]naphtho[2,3-d]thiophene have been determined using the Salmonella/microsome mutagenicity test. These compounds demonstrated either very weak or no mutagenic activity. The methyl derivatives of each of these four compounds were assayed for mutagenic activity. Salmonella typhimurium TA98 was used as the tester strain. All assays required a rat-liver homogenate metabolic activator. Five of the methylated derivatives, 1-methylbenzo[b]naphtho[1,2-d]thiophene, 3-methylbenzo[b]naphtho[1,2-d]thiophene, 1-methylbenzo[b]-naphtho[2,1-d]thiophene, 6-methylbenzo[b]naphtho[2,1-d]thiophene and 4-methylbenzo[b]naphtho[2,3-d]thiophene demonstrated mutagenic activity. However, activity was observed only at high concentrations of the metabolic activator.     

Novel 1,3-dicarbonyl compounds having 2(3H)-benzazolonic heterocycles as PPARgamma agonists

A series of 1,3-dicarbonyl compounds having 2(3H)-benzazolonic heterocycles has been synthesized and tested for PPARgamma agonist activity. SAR were developed and revealed that 6-acyl-2(3H)-benzothiazolone derivatives with 1,3-dicarbonyl group were the most potent. IP administration of compound 22 exhibited comparable levels of glucose and triglyceride correction to PO administration of rosiglitazone in the ob/ob mouse studies.     

Interactions of nitrogen heterocycles with cytochrome P-450 and monooxygenase activity

Three groups of isomeric nitrogen heterocycles, phenylpyridines, phenylimidazoles and pyridylimidazoles were studied in relation to the effect of steric factors on type II binding to cytochrome P-450 and inhibition of aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH) activity in hepatic microsomes from phenobarbital(PB)- and β-naphthoflavone(βNF)-induced rats. Type II binding affinity was lower (higher K_s) in compounds with substituents on the carbon adjacent to the nitrogen undergoing ligand interaction than in those where steric hindrance near the nitrogen was minimal. Binding affinities of the compounds as measured by their K_s values, were quite similar in both PB- and βNF-induced microsomes. In PB-induced microsomes, type II binding affinity was generally reflected by the ability of the compounds to inhibit AHH activity. In contrast, most of the compounds evaluated were inactive as AHH inhibitors in βNF-induced microsomes.     

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

The 1,2,3-triazole ring is a major pharmacophore system among nitrogen-containing heterocycles. These five-membered heterocyclic motifs with three nitrogen heteroatoms can be prepared easily using ‘click’ chemistry with copper- or ruthenium-catalysed azide-alkyne cycloaddition reactions. Recently, the ‘linker’ property of 1,2,3-triazoles was demonstrated, and a novel class of 1,2,3-triazole-containing hybrids and conjugates was synthesised and evaluated as lead compounds for diverse biological targets. These lead compounds have been demonstrated as anticancer, antimicrobial, anti-tubercular, antiviral, antidiabetic, antimalarial, anti-leishmanial, and neuroprotective agents. The present review summarises advances in lead compounds of 1,2,3-triazole-containing hybrids, conjugates, and their related heterocycles in medicinal chemistry published in 2018. This review will be useful to scientists in research fields of organic synthesis, medicinal chemistry, phytochemistry, and pharmacology.