Series Of Pyrrole Derivatives Research Articles

Development of an efficient biocatalytic three-component reaction for synthesizing pyrrole derivatives

Multi-component reactions (MCRs) enable the development of efficient and atom-economic methods for synthesizing pyrrole derivatives. However, the current MCRs methods for synthesizing pyrrole derivatives in the enzymatic process have been unexploited. Herein, we developed a one-pot three-component enzymatic promiscuous catalytic system with green, efficient, and atom-economic to construct pyrrole derivatives. In this system, amines and 1,3-dicarbonyl compounds formed enamines with subsequent Michael addition with nitroolefins catalyzed by trypsin. A series of pyrrole derivatives were successfully obtained with moderate to good yield (up to 92 %). In addition, molecular simulations were conducted to gain insight into the source of differing tolerance of aromatic amides and fatty amines and the intrinsic effect of solvents in this system. This enzymatic catalytic one-pot three-component system has excellent functional tolerance, simple operation, and application potential for industrial production demonstrated by the gram scale experiment.

Rational Design of a Low-Data Regime of Pyrrole Antioxidants for Radical Scavenging Activities Using Quantum Chemical Descriptors and QSAR with the GA-MLR and ANN Concepts

A series of pyrrole derivatives and their antioxidant scavenging activities toward the superoxide anion (O2•-), hydroxyl radical (•OH), and 1,1-diphenyl-2-picryl-hydrazyl (DPPH•) served as the training data sets of a quantitative structure-activity relationship (QSAR) study. The steric and electronic descriptors obtained from quantum chemical calculations were related to the three O2•-, •OH, and DPPH• scavenging activities using the genetic algorithm combined with multiple linear regression (GA-MLR) and artificial neural networks (ANNs). The GA-MLR models resulted in good statistical values; the coefficient of determination (R2) of the training set was greater than 0.8, and the root mean square error (RMSE) of the test set was in the range of 0.3 to 0.6. The main molecular descriptors that play an important role in the three types of antioxidant activities are the bond length, HOMO energy, polarizability, and AlogP. In the QSAR-ANN models, a good R2 value above 0.9 was obtained, and the RMSE of the test set falls in a similar range to that of the GA-MLR models. Therefore, both the QSAR GA-MLR and QSAR-ANN models were used to predict the newly designed pyrrole derivatives, which were developed based on their starting reagents in the synthetic process.

New Pyrrole Derivatives as Promising Biological Agents: Design, Synthesis, Characterization, In Silico, and Cytotoxicity Evaluation.

The current study describes the synthesis, physicochemical characterization and cytotoxicity evaluation of a new series of pyrrole derivatives in order to identify new bioactive molecules. The new pyrroles were obtained by reaction of benzimidazolium bromide derivatives with asymmetrical acetylenes in 1,2-epoxybutane under reflux through the Huisgen [3 + 2] cycloaddition of several ylide intermediates to the corresponding dipolarophiles. The intermediates salts were obtained from corresponding benzimidazole with bromoacetonitrile. The structures of the newly synthesized compounds were confirmed by elemental analysis, spectral techniques (i.e., IR, 1H-NMR and 13C-NMR) and single-crystal X-ray analysis. The cytotoxicity of the synthesized compounds was evaluated on plant cells (i.e., Triticum aestivum L.) and animal cells using aquatic crustaceans (i.e., Artemia franciscana Kellogg and Daphnia magna Straus). The potential antitumor activity of several of the pyrrole derivatives was studied by performing in vitro cytotoxicity assays on human adenocarcinoma-derived cell lines (i.e., LoVo (colon), MCF-7 (breast), and SK-OV-3 (ovary)) and normal human umbilical vein endothelial cells (HUVECs). The obtained results of the cytotoxicity assessment indicated that the tested compounds had nontoxic activity on Triticum aestivum L., while on Artemia franciscana Kellogg nauplii, only compounds 2c and 4c had moderate toxicity. On Daphnia magna, 4b and 4c showed high toxicity; 2a, 2b, and 2c moderate to high toxicity; only 4a and 4d were nontoxic. The compound-mediated cytotoxicity assays showed that several pyrrole compounds demonstrated dose- and time-dependent cytotoxic activity against all tested tumor cell lines, the highest antitumor properties being achieved by 4a and its homologue 4d, especially against LoVo colon cells.

Synthesis and Biological Activity Evaluation of 2-Cyanopyrrole Derivatives as Potential Tyrosinase Inhibitors.

In order to find potential inhibitors of tyrosinase, two series of pyrrole derivatives A (1–17) and B (1–8) were synthesized and screened for their inhibitory activities on tyrosinase. Most of the 2-cyanopyrrole derivatives exhibited effective inhibitory activities. In particular, A12 exhibited the strongest inhibitory activities, with the IC50 values of 0.97 μM, which is ∼30 times stronger than the reference inhibitor kojic acid (IC50: 28.72 μM). The inhibitory mechanism analysis results revealed that A12 was a reversible and mixed-type inhibitor. Molecular docking experiments clarified the interaction between A12 with tyrosinase. Furthermore, A12 (100 μM) presented effective inhibitory effect on tyrosinase in B16 melanoma cells with inhibition of 33.48%, which was equivalent to that of Kojic acid (39.81%). Accordingly, compound A12 may serve as the lead structure for the further design of potent tyrosinase inhibitors. Molecular docking studies confirmed the interaction between the compound and tyrosinase.

Synthesis, Characterization and Biological Evaluation of Some Pyrrole Derivatives as Potential Antimicrobial Agents

Novel series of pyrrole derivatives were synthesized with an approach to develop more potent and less side effects having antimicrobial activity. An efficient synthesis of different novel 2-methyl-7(4-nitrophenyl)-5,6-diphenyl-3,7-dihydro-4H-pyrrolo-[2,3-d]pyridine-4-one derivatives by the Paal-knorr Condensation. Benzoin with primary aromatic amines refluxing in ethanol resulted the formation of α-aminoketone intermediates, which were condensed, without isolation, with malononitrile to yield the various 2-amino-4,5-diphenyl-1-substituted-1H-pyrrole-3-carbonitriles (Ia-e). Pyrrole (Ia-e) further reacted with acid such as acetic acid to yield compound (IIa-e). The synthesized compounds were confirmed through spectral characterization using IR, Mass and 1H NMR. Result indicated that these compounds showed promising antimicrobial activity by comparing to standard drugs.

The Fe(iii)-catalyzed decarboxylative cycloaddition of β-ketoacids and 2H-azirines for the synthesis of pyrrole derivatives

An Fe(iii)-catalyzed Mannich/decarboxylative ring expansion reaction to generate pyrrole derivatives has been achieved using Fe(OTf)3 as the catalyst. A series of pyrrole derivatives was obtained in moderate to excellent yields.

Novel Bifunctional Mesoporous Catalysts Based on Preyssler Heteropolyacids for Green Pyrrole Derivative Synthesis

In this paper, we report the synthesis of Preyssler heteropolyacids supported on mesoporous alumina in order to obtain materials with acid–base properties. A series of pyrrole derivatives were synthesized using a suitable procedure under solvent-free conditions. Using the alumina-supported material, more complex pyrrole derivatives can be obtained through a tandem one-pot process that involves the formation of 2-amino-3-cyano 4-H-chromenes by a multicomponent reaction and their subsequent conversion to pyrrole using a Paal–Knorr reaction.

Design, synthesis and biological evaluation of novel pyrrole derivatives as potential ClpP1P2 inhibitor against Mycobacterium tuberculosis

In an effort to discover novel inhibitors of M. tuberculosis Caseinolytic proteases (ClpP1P2), a combination strategy of virtual high-throughput screening and in vitro assay was employed and a new pyrrole compound, 1-(2-chloro-6-fluorobenzyl)-2, 5-dimethyl-4-((phenethylamino)methyl)-1H-pyrrole-3-carboxylate was found to display inhibitory effects against H37Ra with an MIC value of 77 µM. In order for discovery of more potent anti-tubercular agents that inhibit ClpP1P2 peptidase in M. tuberculosis, a series of pyrrole derivatives were designed and synthesized based on this hit compound. The synthesized compounds were evaluated forin vitrostudies against ClpP1P2 peptidase and anti-tubercular activities were also evaluated. The most promising compounds 2-(4-bromophenyl)-N-((1-(2-chloro-6-fluorophenyl)-2, 5-dimethyl-1H- pyrrolyl)methyl)ethan-1-aminehydrochloride 7d, ethyl 4-(((4-bromophenethyl) amino) methyl)-2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13i, ethyl 1-(4-chlorophenyl)-4-(((2-fluorophenethyl)amino)methyl)-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13n exhibited favorable anti-mycobacterial activity with MIC value at 5 µM against Mtb H37Ra, respectively.

Synthesis and Anti-cancer Activity of 3-substituted Benzoyl-4-substituted Phenyl-1H-pyrrole Derivatives.

Cancer is considered a major public health problem worldwide. The aim of this paper is to design and synthesis of novel anticancer agents with potent anticancer activity and minimum side effects. A series of pyrrole derivatives were synthesized, their anti-cancer activity against nine cancer cell lines and two non-cancer cell lines were evaluated by MTT assay, and their cell cycle progression were determined by flow cytometry analysis. The study of the structure-activity relationships revealed that the introduction of the electron-donation groups at the 4th position of the pyrrole ring increased the anti-cancer activity. Among the synthesized compounds, specially the compounds bearing 3,4-dimethoxy phenyl at the 4th position of the pyrrole ring showed potent anti-cancer activity, cpd 19 was the most potent against MGC 80-3, HCT-116 and CHO cell lines (IC50s = 1.0－1.7 μM), cpd 21 was the most potent against HepG2, DU145 and CT-26 cell lines (IC50s = 0.5－0.9 μM), and cpd 15 was the most potent against A549 (IC50 = 3.6 μM). Moreover, these potent compounds showed weak cytotoxicity against HUVEC and NIH/3T3. Thus, the cpds 15, 19 and 21 show potential anti-cancer for further investigation. Furthermore, the flow cytometry analysis revealed that cpd 21 arrested the CT-26 cells at S phase, and induced the cell apoptosis. Thus, these compounds with the potent anticancer activity and low toxicity have potential for the development of new anticancer chemotherapy agents.

Synthesis and Cytotoxicity Evaluation of New 3‐substituted 4‐(4‐methyloxy phenyl)‐1H‐Pyrrole Derivatives

A new series of 3‐substituted 4‐(4‐methyloxy phenyl)‐1H‐pyrrole derivatives were synthesized and biologically evaluated for potential anticancer activity. Fifteen targeted compounds showed high selectivity toward normal cells and cancer cells: that is, all targeted compounds had no obvious cytotoxicity toward normal human cells (HUVEC and NIH/3T3), but some compounds exhibited broad‐spectrum proliferation inhibitory activity against the screened cancer cell lines. Among these pyrrole derivatives, compounds 3b and 3o showed potent anticancer activity against the MG‐63 cell line, with IC50 values of 14.9 and 12.7 μM, respectively. Other pyrrole derivatives also showed promising proliferation inhibitory activity, including compound 3d against A375 (IC50 = 18.6 μM), compound 3f and 3j against MGC80‐3 (IC50 = 19.9 μM), and compound 3o against MGC80‐3 (IC50 = 11.9 μM). Because the developed pyrrole derivatives showed strong anticancer activity and high selectivity, this new series of pyrrole derivatives could be considered as promising lead compounds for further development of potent and safe anticancer agents.

Synthesis and anti-tubercular evaluation of some pyrrole derivatives

Novel series of pyrrole derivatives were synthesized with an approach to reduce the growing anti-tubercular resistance and to develop more potent and less side effects having anti-tubercular, anti-inflammatory and anticancer activity. An efficient synthesis of different novel 2-amino-4,5-diphenyl-1-substituted-1H-pyrrole-3-carbonitrilesderivatives by the Paal- Knorr Condensation of benzoin with primary aromatic amines in refluxing ethanol resulted in the formation of ?-amino ketone intermediates, which were condensed without isolation, with malononitrile to yield the various 2-amino-4,5-diphenylpyrrole-3-carbonitriles ( 1a-d ). Pyrroles 1a-d reacted with different reagents such as acetic anhydride, sodium azide, hydroxyl amine hydrochloride to yield compound (1a1-1d1). The synthesized compounds were confirmed through spectral characterization using IR, 1H NMR and Mass. The Pyrrole derivatives examined for their in vitro anti-tubercular testing using Nitrate Reductase Assay. Activity of the synthesized compounds was carried out against H37RV bacteria. Result indicated that these compounds showed promising anti-tubercular activity in comparison to rifamycin (the standard anti-tubercular drug).

Synthesis, characterization, biological activity, and 3D-QSAR studies on some novel class of pyrrole derivatives as antitubercular agents

A new series of pyrrole derivatives have been designed, synthesized, and their structures have been elucidated along with the evaluation of antitubercular activity against Mycobacterium tuberculosis H37Rv using the microplate alamar blue assay method and antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumoniae, and Escherichia coli by broth micro-dilution assay method. Structural activity relationships and 3D-QSAR analysis have been carried out by Topomer Comparative Molecular Field Analysis (CoMFA). Training set of 42 and test set of 8 active compounds were used to develop the method that showed cross-validated correlation coefficient (q 2) of 0.815, standard error of prediction of 0.36, non-cross-validated correlation coefficient (r 2) of 0.973, and standard error of estimate of 0.14 with six components. Synthesis; spectral and 3D-QSAR studies; and antibacterial, antitubercular, and cytotoxic activities of a novel series of pyrrole derivatives are described.

A novel enzyme-catalyzed synthesis of N-substituted pyrrole derivatives

A novel method for the synthesis of substituted pyrroles catalyzed by α-amylase from hog pancreas via Paal-Knorr reaction was developed. A series of pyrrole derivatives were synthesized under mild conditions and the products were obtained with good to excellent yields (60-99 %). The impact of factors, such as solvents, enzyme amount, and temperature, on the reaction were investigated. This study reports an efficient route for the synthesis of N-substituted pyrrole derivatives.

Synthesis of new 4-(2,5-dimethylpyrrol-1-yl)/4-pyrrol-1-yl benzoic acid hydrazide analogs and some derived oxadiazole, triazole and pyrrole ring systems: a novel class of potential antibacterial, antifungal and antitubercular agents

A series of 4-(2,5-dimethylpyrrol-1-yl)/4-pyrrol-1-yl benzoic acid hydrazide analogs, some derived 1,3,4-oxadiazoles, 5-substituted-4-amino-1,2,4-triazolin-3-thione and 2,5-dimethyl pyrroles have been synthesized in good yields and structures of these compounds were established by IR, 1H NMR, 13C NMR, Mass spectral and elemental analysis. These compounds were evaluated for their preliminary in vitro antibacterial, antifungal and antitubercular activities against Mycobacterium tuberculosis H37Rv strain by broth dilution assay method. Twelve of these compounds displayed good antimicrobial activity, with a minimum inhibitory concentration (MIC) values 1–4 μg mL−1. Several compounds 4, 8d, 9, 12c–d and 12f–h exhibited good in vitro antitubercular activity with MIC values 1–2 μg mL−1. Further, some title compounds were also assessed for their cytotoxic activity (IC50) against mammalian Vero cell lines and A549 (lung adenocarcinoma) cell lines using MTT assay method. The results reveal that these compounds exhibit antitubercular activity at non-cytotoxic concentrations. Synthesis, spectral studies and antibacterial, antifungal and antitubercular activities of a novel series of pyrrole derivatives are described

A QSAR Study on a Series of Pyrrole Derivatives Acting as Lymphocyte- Specific Kinase (Lck) Inhibitors

A quantitative structure-activity relationship (QSAR) study has been made on a novel series of pyrrole derivatives acting as lymphocyte-specific kinase (Lck) inhibitors. The Lck inhibition activity of compounds is found to be significantly correlated with their molar volume (MV) and surface tension (ST) and the hydrophobic constant of one of their substituents. Both the molar properties MV and ST of the compounds are found to have the negative effect but the hydrophobic property of R(2)-substituen is found to have the positive effect. This leads to suggest that the bulky molecules and the those with high surface tension will not be advantageous to the Lck inhibition, rather their R(2)-substituent with hydrophobic property will be conducive to the activity.

Synthesis and anticonvulsant activity of some new series of pyrrole derivatives

A new series of compounds 3a–f were synthesized from condensation method. Newly synthesized compounds were established by IR, 1H NMR, 13C NMR, mass spectral and elemental analysis. Synthesized compounds 3a–f were screened for anticonvulsant activity. The compound 2,2′-({3-methyl-5-[2-phenylethenyl]-1H-pyrrole-2,4-diyl}dicarbonyl)dihydrazinecarbothioamide 3a showed significant activity compared with other compounds 3b–f against pentamethylene tetrazole-induced seizures.

Pyrrole derivatives as potent inhibitors of lymphocyte-specific kinase: Structure, synthesis, and SAR

We have described the synthesis, enzyme inhibitory activity, structure-activity relationships, and proposed binding mode of a novel series of pyrrole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC(50)s <10nM) for Lck kinase inhibition.

Antimycobacterial compounds. Optimization of the BM 212 structure, the lead compound for a new pyrrole derivative class

Our work on antitubercular agents led to the identification of BM 212 as a lead compound among a series of pyrrole derivatives with good in vitro activity against mycobacteria and candidae. Further studies led us to synthesize additional pyrroles bearing the thiomorpholinomethyl moiety and different aryl substituents at N1 and C5. Some of them revealed very active, prompting us to design the new pyrrole derivatives 5– 20 in the hope of increasing the activity and better understanding the influence of ortho halogens on the antimycobacterial activity. Microbiological data showed interesting in vitro activity toward Mycobacterium tuberculosis and atypical mycobacteria.

Antimycobacterial compounds. New pyrrole derivatives of BM212

We have identified BM212 as a lead compound among a series of pyrrole derivatives with good in vitro activity against mycobacteria and candidae. First studies led us to synthesize some pyrrole compounds in which the thiomorpholine fragment was present. Some compounds revealed very active and these findings prompted us to prepare new pyrrole derivatives 2– 15 in the hope of increasing the activity. The microbiological data showed interesting in vitro activity against Mycobacterium tuberculosis and atypical mycobacteria.