Pyrrole Series Research Articles

Discovery of pyrrolo[2,3-d]pyrimidin-4-one derivative YCH3124 as a potent USP7 inhibitor for cancer therapy

USP7 is one of the most studied deubiquitinating enzymes, which is involved in the regulation of multiple cell signaling pathways and has been shown to be associated with the occurrence and progression of a variety of cancers. Inhibitors targeting USP7 have been studied by several teams, but most of them lack selectivity and have low activities. Herein, we reported a serious of pyrrole[2,3-d]pyrimidin-4-one derivatives through scaffold hopping of recently reported 4-hydroxypiperidine compounds. The representative compound Z33 (YCH3124) exhibited highly potent USP7 inhibition activity as well as anti-proliferative activity against four kinds of cancer cell lines. Further study revealed that YCH3124 effectively inhibited the downstream USP7 pathway and resulted in the accumulation of both p53 and p21 in a dose-dependent manner. Notably, YCH3124 disrupted cell cycle progression through restricting G1 phase and induced significant apoptosis in CHP-212 cells. In summary, our efforts provided a series of novel pyrrole[2,3-d]pyrimidin-4-one analogs as potent USP7 inhibitors with excellent anti-cancer activity.

Structure-Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials.

Controlling malaria requires new drugs against Plasmodium falciparum. The P. falciparum cGMP-dependent protein kinase (PfPKG) is a validated target whose inhibitors could block multiple steps of the parasite's life cycle. We defined the structure-activity relationship (SAR) of a pyrrole series for PfPKG inhibition. Key pharmacophores were modified to enable full exploration of chemical diversity and to gain knowledge about an ideal core scaffold. In vitro potency against recombinant PfPKG and human PKG were used to determine compound selectivity for the parasite enzyme. P. berghei sporozoites and P. falciparum asexual blood stages were used to assay multistage antiparasitic activity. Cellular specificity of compounds was evaluated using transgenic parasites expressing PfPKG carrying a substituted "gatekeeper" residue. The structure of PfPKG bound to an inhibitor was solved, and modeling using this structure together with computational tools was utilized to understand SAR and establish a rational strategy for subsequent lead optimization.

Modified porphyrin chromophores: Synthesis and spectroscopic properties of nitronaphtho[1,2-b]porphyrins, benzothieno[2,3-b]porphyrins and their metalated derivatives

A series of c-annulated pyrroles were prepared by reacting isocyanoacetate esters with dinitronaphthalenes in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene. The resulting nitronaphthopyrroles esters condensed with an acetoxymethylpyrrole to afford dipyrrylmethanes and following cleavage of the ester groups, acid-catalyzed condensation with a dipyrrylmethane dialdehyde afforded four isomeric nitronaphthoporphyrins. Three of these isomers showed only minor differences in their electronic spectra compared to a known naphtho[1,2-b]porphyrin, although in two cases the intensities of the Soret band absorptions were reduced. However, when the nitro group was placed at a position one removed from the porphyrin nucleus, the UV–vis spectrum showed two very broad peaks in the Soret band region as well as distorted Q bands. This effect was also noted for the corresponding nickel(II), copper(II) and zinc complexes. An example of a benzo[b]thiophene-fused porphyrin was also prepared in three steps from 3-nitrothiophene, but the fused heterocyclic unit had virtually no effect on the porphyrin chromophore. This study demonstrates that while fused naphthalene and benzo[b]thiophene units do not significantly affect the electronic structure of porphyrins, the introduction of a suitably placed electron-withdrawing group can induce profound changes.

Visible-light-induced synthesis of N-disulfanyl indoles, pyrroles or carbazoles via the construction of stable S-S-N bonds.

A simple and efficient visible-light-induced approach for the formation of stable S-S-N bonds has been developed. Through these photocatalytic reactions, a series of N-disulfanyl indoles, pyrroles and carbazoles were afforded with good to excellent yields. Moreover, the gram-scale experiment has confirmed the practicability of this approach.

A Method for Pyrrole Synthesis through Intramolecular Cyclization of γ-Alkynyl Oximes Promoted by SmI2

AbstractA new strategy for the synthesis of pyrrole through intramolecular cyclization of γ-alkynyl oximes promoted by SmI2 is reported for the first time. In contrast to the prior methods, the selection of oxime instead of oxime ether or ester as substrate makes the synthetic method without accompaniment of organic waste (ArCO2H, AcOH, or ROH) because the hydroxyl group in oxime acts as the leaving group and is finally removed in the form of water molecule in the reaction. From a synthetic point of view, a series of pyrroles were obtained in this one-pot reaction with a broad scope of substrates and feasible reaction conditions.

Catalyst‐free one‐pot three‐component rapid synthesis of polysubstituted pyrroles by liquid‐assisted grinding

AbstractA series of polysubstituted pyrroles were rapidly synthesized in moderate to good yields via catalyst‐free one‐pot three‐component reaction of 1,3‐dicarbonyl compounds with primary amines and nitrostyrenes by using liquid‐assisted grinding. This protocol provides several advantages over the conventional chemical synthesis, such as simple work‐up procedure, wide substrate scope, short reaction time, and environmental friendliness. Structures of polysubstituted pyrroles were confirmed by1H NMR,13C NMR, and ESI‐MS studies.

Nitrogen–Sulfur–Oxygen compounds in the study of oil migration in Block TW, eastern flank of the Oriente Basin, Ecuador

Nitrogen–Sulfur–Oxygen compounds of crude-oil samples were analyzed to study oil migration in Block TW. The 15 crude-oil samples of the Upper Cretaceous Napo Formation M1ss Member had similar geochemical characteristics; a similar normal alkane distribution mode (forward peak-single peak model); and similar terpane, hopane, and regular sterane distribution characteristics, which are similar to those of the Upper Cretaceous marl in the eastern flank. The nitrogen compounds of the crude oils from the M1ss Member in Block TW show a prominent geochromatographic effect-an obvious decrease in the total absolute abundance of pyrrole (a kind of biomarker), absolute abundance of exposed pyrrolic hydrogen. The ratios of “shielded pyrrolic hydrogen/exposed pyrrolic hydrogen” and “partially shielded pyrrolic hydrogen/exposed pyrrolic hydrogen” increase with oil migration while the ratios of “shielded pyrrolic hydrogen/partially shielded pyrrolic hydrogen” exhibited almost no change. The ratios of 1,8-/2,6-dimethylcarbazole, 1,4-/2,6-dimethylcarbazole, and 1,5-/2,6- dimethylcarbazole were good indicators of oil migration, which greatly decreased in short-distance migration in the Johanna reservoir and Alice West reservoir and could be used to semiquantitatively analyze the oil migration direction within the same reservoir. The main oil migration in Block TW was from southwest to northeast, and the geochromatographic effects between different reservoirs were not obvious, which might be the results of different oil charging points, different migration pathways, or the simultaneous supply of local and far sources. Heteroatomic compounds of oxyfluorene and thiofluorene series have strong biodegradation resistance and can assist in identifying the direction of oil migration. The variation trend of total abundance of oxyfluorene and thiofluorene in Block TW is similar to that of carbazole series compounds, but the migration fractionation effect is not as obvious as that of pyrrole series compounds. A set of parameters should be used in studying oil migration, which can be determined according to most of their variation trends. The ratios of 1,8-/2,6-dimethylcarbazole, 1,4-/2,6-dimethylcarbazole, and 1,5-/2,6-dimethylcarbazole in the M1ss Reservoir of Block TW have similar and obvious geochromatographic effects, which can be used as regional oil and gas migration indicators. The pyrrole compounds (particularly the carbazole series) have obvious geochromatographic effects along with oil migration, which could be used to analyze its direction, particularly in highly explored areas with several wells.

Novel Structural Hybrids of Pyrrole and Thiazole Moieties: Synthesis and Evaluation of Antibacterial and Antifungal Activities.

One of the best ways to design new biocidal agents is synthesizing hybrid molecules by combining two or more bioactive moieties in a single molecular scaffold. So, new series of pyrroles bearing a thiazole moiety were synthesized using 1-methyl-1H-pyrrole-2-carbaldehyde thiosemicarbazones 1a-c. Cyclization of thiosemicarbazone derivatives 1a-c with ethyl chloroacetate, ethyl 2-chloropropanoate, chloroacetone and phenacyl bromide afforded the corresponding thiazolidin-4-ones 2a-c, 5-methylthiazolidin-4-ones 3a-c, 4-methyl-2,3-dihydrothiazoles 4a-c, and 4-phenyl-2,3-dihydrothiazoles 5a-c, respectively. The antimicrobial activity of the new thiazole derivatives was evaluated.

Pyrrole‐Fused Benzoxazinones/Quinoxalinones: Molecular Dynamic Simulation, Antiproliferative and Antibacterial Activities

AbstractA series of novel pyrrole fused benzoxazinones/quinoxalinones has been evaluated for antiproliferative activity against breast cancer cell line, MCF7 and treatment‐resistant triple‐negative breast cancer cell line MDA‐MB‐231. Among which pyrroloquinoxalinones exhibited higher cytotoxicity. Furthermore, they showed insignificant cellular cytotoxicity in normal human cell HEK293T when treated with their respective IC50 concentrations. In silico molecular docking, study suggests that the inhibitory mechanism of pyrroloquinoxalinones probably mediated via modulation of breast cancer targets such as VEGFR2 and EGFR. The stability of target protein (VEGFR2 and EGFR)‐ligand (pyrroloquinoxalinones) interactions was validated by Molecular dynamic simulation (50 ns). Additionally, pyrrolobenzoxazinones/quinoxalinones were evaluated for in vitro antibacterial activity against Gram‐positive and Gram‐negative bacterial strains. All the compounds exhibited significant antibacterial activity (IC50 0.034–15.4 μM) towards the tested bacterial strains. These findings indicate that pyrrolobenzoxazinones/quinoxalinones are valuable scaffolds for the development of potent anticancer and antibacterial compounds.

Selectively reductive amination of levulinic acid with aryl amines to N-substituted aryl pyrroles

Synthesizing nitrogen (N)-containing molecules from biomass derivatives is a new strategy for production of this kind of chemicals. Herein, for the first time we present the synthesis of N-substituted aryl pyrroles via reductive amination/cyclization of levulinic acid (LA) with primary aromatic amines and hydrosilanes (e.g., PMHS) over CsF, and a series of N-substituted aryl pyrroles could be obtained in good to excellent yields at 120 °C. The mechanism investigation indicates that the reaction proceeds in two steps: the cyclization between amine and LA occurs first to form intermediate 5-methyl-N-alkyl-1,3-dihydro-2H-pyrrolones and their isomeride (B), and then the chemo- and region-selective reduction of intermediates take place to produce the final products. This approach for synthesis of N-substituted aryl pyrroles can be performed under mild and green conditions, which may have promising applications.

4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines.

Various malignant human diseases show disturbed signaling pathways due to increased activity of proteins within the epigenetic machinery. Recently, various novel inhibitors for epigenetic regulation have been introduced which promise a great therapeutic benefit. Inhibitors for the bromo- and extra-terminal domain (BET) family were of particular interest after inhibitors had shown a strong antiproliferative effect. More recently, the focus has increasingly shifted to bromodomains (BDs) outside the BET family. Based on previously developed inhibitors, we have optimized a small series of 4-acyl pyrroles, which we further analyzed by ITC, X-ray crystallography, selectivity studies, the NCI60 cell-panel, and GI50 determinations for several cancer cell lines. The inhibitors address both, BET and BRD7/9 BDs, with very high affinity and show a strong antiproliferative effect on various cancer cell lines that could not be observed for BD family selective inhibitors. Furthermore, a synergistic effect on breast cancer (MCF-7) and melanoma (SK-MEL-5) was proven.

Construction of pyrrole- and indole-fused CF3-piperazine derivatives

A series of pyrrole- and indole-fused trifluoromethyl-functionalized piperazine derivatives were constructed in moderate to good yields with excellent chemoselectivities via a Pictet-Spengler reaction under mild and operationally simple conditions. The synthetic utility of this protocol was further extended by the facile preparation of indole-fused CF3-1,4-diazocane and enantioenriched CF3-piperazines via a vinylogous Pictet-Spengler reaction and an asymmetric Pictet-Spengler reaction, respectively.

Design, synthesis and antifungal activities of novel pyrrole- and pyrazole-substituted coumarin derivatives.

We synthesized a series of novel pyrrole- and pyrazole-substituted coumarin derivatives and evaluated their antifungal activity against six phytopathogenic fungi invitro. The primary assay results demonstrated that some designed compounds displayed potent activities. Among them, compounds 5g, 6a, 6b, 6c, 6d and 6h exhibited more effective control than Osthole against Cucumber anthrax and Alternaria leaf spot. Furthermore, compound 5g displayed stronger antifungal activity against Rhizoctorzia solani (EC50 = 15.4µg/mL) than positive control Osthole (EC50 = 67.2µg/mL).

Pyrrolizidine Alkaloid Secondary Pyrrolic Metabolites Construct Multiple Activation Pathways Leading to DNA Adduct Formation and Potential Liver Tumor Initiation.

Pyrrolizidine alkaloids (PAs) and their N-oxide derivatives are hepatotoxic, genotoxic, and carcinogenic phytochemicals. PAs induce liver tumors through a general genotoxic mechanism mediated by a set of four (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5 H-pyrrolizine (DHP)-derived DNA adducts. To date, the primary pyrrolic metabolites dehydro-PAs, their hydrolyzed metabolite DHP, and two secondary pyrrolic metabolites 7-glutathione-DHP (7-GS-DHP) and 7-cysteine-DHP are the known metabolites that can generate these DHP-DNA adducts in vivo and/or in PA-treated cells. Secondary pyrrolic metabolites are formed from the reaction of dehydro-PAs with glutathione, amino acids, and proteins. In this investigation, we determined whether or not more secondary pyrrolic metabolites can bind to calf thymus DNA and to cellular DNA in HepG2 cells resulting in the formation of DHP-DNA adducts using a series of secondary pyrrolic metabolites (including 7-methoxy-DHP, 9-ethoxy-DHP, 9-valine-DHP, 7-GS-DHP, 7-cysteine-DHP, and 7,9-diglutathione-DHP) and synthetic pyrroles for study. We found that (i) many secondary pyrrolic metabolites are DNA reactive and can form DHP-DNA adducts and (ii) multiple activation pathways are involved in producing DHP-DNA adducts associated with PA-induced liver tumor initiation. These results suggest that secondary pyrrolic metabolites play a vital role in the initiation of PA-induced liver tumors.

Estimating the energy of intramolecular bifurcated (three-centered) hydrogen bond by X-ray, IR and 1H NMR spectroscopy, and QTAIM calculations

The structure of a series of the 2-substituted pyrroles containing the intramolecular NH⋯OC hydrogen bond and the 2,5-disubstituted pyrroles having the three-centered intramolecular CO⋯H(N)⋯OC hydrogen bond was studied by X-ray, IR, NMR spectroscopy, and quantum chemical calculations, including calculations in terms of Quantum Theory of Atoms in Molecules (QTAIM). The X-ray diffraction data show that the intramolecular rH … O and RN … O distances increase upon conversion from a two-centered hydrogen bond to a three-centered hydrogen bond, indicating a weakening of the last interaction. The topological parameters of the hydrogen bond obtained from the QTAIM calculations (electron density ρBCP and potential energy density V at the critical point of the hydrogen bond) made it possible to quantify the hydrogen bond energy in the studied compounds. The energy of intramolecular NH⋯OC hydrogen bond in the 2-substituted pyrroles is in the range from 5.5 to 6.0 kcal mol−1 (moderate hydrogen bond), whereas the energy of the components of the three-centered intramolecular CO⋯H(N)⋯OC hydrogen bond in the 2,5-disubstituted pyrroles is reduced to 2.5–3.5 kcal mol−1 (weak hydrogen bond). For weak components of the three-centered hydrogen bond, the principle of the additivity of effects on the spectral parameters influenced by the hydrogen bond (change in the vibration frequency of the NH bond, ΔνN‒H, and the chemical shift of bridge proton, ΔδNH) was proposed. For this reason, the ½ΔνN-H and ½ΔδNH values also were used for estimating the energy of the two-centered components of the three-centered CO⋯H(N)⋯OC hydrogen bond. These estimates are in good agreement with those obtained from the ρBCP and V parameters. Consequently, the ½ΔνN-H and ½ΔδNH parameters can be used as an energy descriptor for two-centered components in the case of a symmetric intramolecular three-centered hydrogen bond.

Synthesis of fused pyrroles containing 4-hydroxycoumarins by regioselective metal-free multicomponent reactions.

The reaction of arylglyoxals, 4-hydroxycoumarin, and aromatic amines such as 7-amino-2-methylchromone, 6/7-aminoflavone, 7-amino-4-methylcoumarin, 1-amino-9-fluorenone, 1-aminoanthraquinone and aniline derivatives in acetic acid medium under microwave conditions provides the corresponding regioselective fused pyrroles having hydroxycoumarin and aryl substituents. Alternatively, we have developed another method using in situ arylglyoxals from acetophenone derivatives by I2/DMSO promoted C-H oxidation followed by one-pot three component cyclization reactions to provide similar fused pyrroles. Using both the methods a series of novel pyrroles fused with pharmacologically important chromone, flavone, coumarin, fluorenone, and anthraquinone moieties were synthesized under metal-free reaction conditions in good to very good yields within a short reaction time. The structures of the synthesized fused pyrroles have been unambiguously confirmed by spectroscopic techniques, mass analysis and single crystal XRD.

Synthesis and Evaluation of Cytotoxic Activity of Some Pyrroles and Fused Pyrroles.

Pyrrole derivatives represent a very interesting class as biologically active compounds. The objective of our study was to investigate the cytotoxic and apoptotic effects and antioxidant activity of the newly synthesized pyrrole derivatives. A series of novel pyrroles and fused pyrroles (tetrahydroindoles, pyrrolopyrimidines, pyrrolopyridines and pyrrolotriazines) were synthesized and characterized using IR, 1H NMR, 13C NMR, MS and elemental analysis techniques. The antiproliferative activity of our synthesized compounds and their modulatory effect apoptotic pathway were investigated. The effect on cellular proliferation and viability was monitored by resazurin assay. Apoptotic effect was evaluated by caspase glo 3/7 assay. Synthesized compounds are then tested for their anticancer activities against three different cell lines representing three different tumor types, namely; the HepG-2 (Human hepatocellular liver carcinoma cell line), the human MCF-7 cell line (breast cancer) and the pancreatic resistant Panc-1 cells. Compounds Ia-e, IIe, and IXc, d showed a promising anti-cancer activity on all tested cell lines. Antioxidant and wound healing invasion assays were examined for promising anticancer candidate compounds.

Design and Synthesis of Diverse Pyrrole‐2‐carboxamide Derivatives as a Potent Antibacterial Agents

A series of pyrrole–2–carboxamide derivatives (4a–j) were synthesized and evaluated for theirantibacterial activity. Among the tested compounds, the most effective were 4a, 4b, 4c, 4d, 4e, 4g and 4h with MIC value in the range of 1.05–12.01 μg/mL against Gram–positive and Gramnegativebacterial strains. Further, the synthesized compounds have been screened for their invitro antifungal activity. In the present study, design and expeditious synthesis of novel 1–(4–chlorobenzyl)–N–(4–methoxybenzyl)–1H–pyrrole–2–carboxamide hybrid molecules as promising antibacterial agents.

Proton acceptor abilities of heterocyclic compounds determined by stretching vibration bands of the N–H groups of associated molecules

Proton acceptor abilities of some heterocyclic compounds of the pyrrole series are determined by data on the self-association of molecules. It is demonstrated that a change in the vibrational frequency νас of the N–H group of associated molecules is observed in the transition from pyrrole to other compounds of this series. This change in the frequency is due to the inductive effect of the introduced structural fragments on the equilibrium electron configuration of the N–H group.

The Synthesis of Multisubstituted Pyrroles via a Copper-Catalyzed Tandem Three-Component Reaction.

An unprecedented nucleophilic addition/cyclization/aromatization cascade of basic chemicals, i.e., aromatic alkenes/alkynes, trimethylsilyl cyanide and N,N-disubstituted formamide, has been developed to give a series of multisubstituted pyrroles in moderate to good yields with high regioselectivities. This reaction not only reveals a new reaction mode for α-aminonitriles, but also provides a new and efficient cyclization pattern for the synthesis of multisubstituted pyrroles as well as their derivatives, which might facilitate related biological studies.