Synthesis Of Novel Pyrrolo Research Articles

Design and synthesis of novel pyrrolo[2,3-d]pyrimidine derivatives as potent JAK3 and SYK dual inhibitors

Janus kinase (JAK) and spleen tyrosine kinase (SYK) are two crucial tyrosine kinases implicated in the immune modulation and represent launched therapeutic targets for immunological disorders. Nevertheless, the monotherapy targeting a single kinase encounters challenges related to drug resistance and inadequate efficacy. In this case, the exploration of inhibitors targeting both JAK and SYK has emerged as a promising therapeutic strategy. In this study, a series of novel pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized to selectively inhibit both JAK3 and SYK. The lead compound, 6e, demonstrated an IC50 value of 2.14 μM against JAK3 and 7.10 μM against SYK, while exhibiting negligible activity against GSK3β (IC50 > 50 μM), providing a hit scaffold for the development of selective JAK/SYK dual inhibitors.

Synthesis of novel pyrrolo[1,2-a]quinoline derivatives as a new class of anti-inflammatory and antimicrobial agents: An approach to single crystal X-ray structure, Hirshfeld surface analysis and DFT studies

We report the synthesis and characterisation of pyrrolo[1,2-a]quinoline derivatives 3a-c. The synthesised compounds were characterised by FTIR, 1H NMR, 13C NMR, and mass spectrometry. The single crystal diffraction analysis revealed 3a crystallizes in monoclinic system with the space group P21/. Hirshfeld surfaces and two-dimensional (2D) fingerprint plots are employed to quantitatively characterize the influence of non-covalent interactions within the crystal lattice of 3a. The molecule geometry was optimised employing B3LYP/6-311++G(d,p) theoretical approach, and comparison was studied between the optimized structural parameters, including bond lengths, bond angles, and dihedral angles, and their corresponding experimental values. The compound's molecular structure, HOMO-LUMO, and molecular electrostatic potential (MEP) surface were calculated using the density functional theory (DFT) Becke-3-Lee Yang Parr (B3LYP) technique with the 6-311++G(d,p) basis set in the ground state. The synthesized derivatives undergo meticulous in-vitro evaluations for anti-inflammatory and antimicrobial potential. The Compound 3a has shown remarkable antibacterial efficacy against S. aureus and E. coli, alongside potent antifungal performance against A. niger and C. albicans. Whereas, the compound 3b has shown substantial anti-inflammatory activity compared to Ibuprofen.

Tunable reactivity of triphosgene-triethylamine: A study on the synthesis of pyrrole-based tricyclics

Abstract The synthesis of novel pyrrolo[1,2-c][1,3]benzodiazepine and pyrrolo[3,2-c]- [1]benzazepine ring systems from (2-aminophenyl)(1H-pyrrol-2-yl)methanone and 2-[(1H-pyrrol-2-yl)methyl]aniline is presented, utilizing triphosgene as carbonylation-cyclization reagent for the formation of the 7-membered heterocycle. A study of the reaction shows that small changes in the reaction conditions affect dramatically the course of the reaction. Acidity as well as aqueous workup play significant roles in the reaction outcome, directing product formation and revealing important aspects of triphosgene mediated cyclizations.

Design and synthesis of novel pyrrolo[2,3-b]pyridine derivatives targeting V600EBRAF

Several pyrrolo[2,3-b]pyridine-based B-RAF inhibitors are well known and some of them are currently FDA approved as anticancer agents. Based on the structure of these FDA approved V600EB-RAF inhibitors, two series of pyrrolo[2,3-b]pyridine scaffold were designed and synthesized in attempt to develop new potent V600EB-RAF inhibitors. The 38 synthesized compounds were biologically evaluated for their V600EB-RAF inhibitory effect at single dose (10 μM). Compounds with high percent inhibition were tested to determine their IC50 over V600EB-RAF. Compounds 34e and 35 showed the highest inhibitory effect with IC50 values of 0.085 µM and 0.080 µM, respectively. Headed for excessive biological evaluation, the synthesized derivatives were tested over sixty diverse human cancer cell lines. Only compound 35 emerged as a potent cytotoxic agent against different panel of human cancer cell lines.

Tandem heterocyclization of 2‐(azolyl‐(azinyl‐))anilines as an efficient method for preparation of substituted pyrrolo[1,2‐a]azolo‐(azino‐)[c]quinazolines

AbstractThe synthesis of novel pyrrolo[1,2‐a]azolo‐(azino‐)[c]quinazolines by tandem reaction of 2‐(azolyl‐(azinyl‐))anilines with oxocarboxylic acids was described in this article. The mechanism of obtained compounds formation was proposed, and the intermediate of the heterocyclization has been isolated and characterized. The IR‐, 1H and 13C NMR‐, chromato‐mass spectra of synthesized compounds were studied for estimation of their structure and spectral patterns features. The molecular structure of the obtained compounds was additionally proved by X‐ray diffraction method.

Design and synthesis of novel pyrrolo[2,3-a]carbazoles: 7-Chloro-2-oxo-3a-(2′-oxo-2′,3′-dihydro-1′H-indol-3′-yl)-2,3,3a,4,5,10-hexahydro-pyrrolo[3,2-a]carbazole-1-carbonitrile as an efficient anticancer agent

Highly efficient poly functionalized pyrrolo[3,2-a]carbazoles via ring contraction through rearrangement and intramolecular Michael addition reaction using one pot multicomponent reaction (MCR) is reported for the first time. Free radical scavenging and anticancer activities were determined by DPPH and MTT assays respectively. Of these, compound 8d exhibited most potent activity against HCT-15 human colon cancer cell lines with an IC50 value of 9.9 μM and low toxicity toward normal human red blood cells. The morphological changes were visualized using scanning electron microscopy (SEM) technique, intracellular ROS generation measured by spectrofluorometer and gene expression levels of caspase-3, caspase-9 and Bcl-2 were determined using Semi quantitates PCR analysis for the target compound. Further, the structure activity relationships were also carried out. The results of the present study revealed that among pyrrolo[3,2-a]carbazole compounds, 7-chloro-2-oxo-3a-(2′-oxo-2′,3′-dihydro-1′H-indol-3′-yl)-2,3,3a,4,5,10-hexahydro-pyrrolo[3,2-a]carbazole-1-carbonitrile could be exploited as an excellent anticancer agent against colon cancer cells.

One-pot synthesis of novel 1-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine derivatives via an Ugi-azide 4CR process.

A facile one-pot method has been developed for the synthesis of novel pyrrolo[2,1-a]pyrazine scaffolds. A variety of 1-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine derivatives were obtained in moderate to high yields in methanol using a one-pot four-component condensation of 1-(2-bromoethyl)-1H-pyrrole-2-carbaldehyde, amine, isocyanide and sodium azide at room temperature. These reactions presumably proceed via a domino imine formation, intramolecular annulation and Ugi-azide reaction. Unambiguous assignment of the molecular structures was carried out by single-crystal X-ray diffraction.

Efficient synthesis of novel pyrrolo[2,3-c]pyridone derivatives using the Ugi four-component reaction followed by condensation reaction

An efficient, cost effective and multicomponent method for the synthesis of new pyrrolo[2,3-c]pyridone derivatives.

Three-component reaction between substituted 2-(2-nitrovinyl)-phenols, acetylenedicarboxylate and amines: diversity-oriented synthesis of novel pyrrolo[3,4-c]coumarins

The diversity-oriented synthesis of pyrrolo[3,4-c]coumarins via FeCl3-promoted three component reaction between substituted 2-(2-nitrovinyl)phenols, acetylenedicarboxylate and amines has been developed.

A facile synthesis of novel pyrrolo[3,4-b]quinolin-1-one derivatives

A simple and concise construction of a series of new quinoline-based isoindolin-l-ones, namely N-substituted-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-ones, wherein the benzene moiety of isoindolin-l-one is replaced by a quinoline ring has been achieved via a two-step procedure, involving the one-step synthesis of ethyl 2-chloromethyl-quinoline-3-carboxylate followed by its one-pot reaction with various amines in a refluxing EtOH–AcOH (v/v, 10:1) solvent system. These newly synthesized compounds could be good candidates for the development of lead compounds for use in medicinal chemistry.

Design, synthesis and pharmacological evaluation of novel polycyclic heteroarene ethers as PDE10A inhibitors: Part II

We report the design and synthesis of novel pyrrolo[3,2-b]quinoline containing heteroarene ethers as PDE10A inhibitors with good to excellent potency, selectivity and metabolic stability. Further optimization of this primary series resulted in the identification of 1-methyl-3-(4-{[3-(pyridine-4-yl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-b]pyridine 13a with good hPDE10A potency (IC50: 6.3nM), excellent selectivity over other related PDEs and desirable physicochemical properties. The compound exhibited high peripheral and adequate brain levels upon oral dosing in rodents. The compound also showed excellent efficacy in multiple preclinical animal models related to psychiatric disorders, particularly schizophrenia.

An Efficient Synthesis of Pyrrolo[2,3,4-kl]acridin-1-one Derivatives Catalyzed by l-Proline

An efficient domino approach for the synthesis of novel pyrrolo[2,3,4-kl]acridin-1-one derivatives has been established. This reaction represents the first facile conversion of an isatin to a pyrrolo[2,3,4-kl]acridin-1-one via a C-N bond cleavage reaction without the need for a multistep reaction process.

Novel Synthesis of Pyrrolo [2,3-d] pyrimidines Bearing Sulfonamide Moieties as Potential Antitumor and Radioprotective Agents

A novel series of pyrrolo[2,3-d] pyrimidines bearing sulfonamide moieties have been synthesized and tested for their antitumor activity. Among them, compounds 4, 8b, Bd, 8g and 14 showed promising antitumor activity. Moreover, compound 8d exhibited radioprotective activity. The structures of the newly synthesized compounds were established by their elemental analyses and spectral data.

ChemInform Abstract: A Novel Synthesis of Pyrrolo[1,2‐d][1,4]diazocines from Tetrahydropyrrolo[1,2‐a]pyrazines Using Activated Alkynes in Pyrazine Ring Expansion.

A novel and efficient one-pot synthesis of pyrrolo[1,2-d][1,4]diazocines based on tandem transformation of tetrahydropyrazine ring was elaborated.

A novel synthesis of pyrrolo[1,2- d][1,4]diazocines from tetrahydropyrrolo[1,2- a]pyrazines using activated alkynes in pyrazine ring expansion

A novel and efficient one-pot synthesis of pyrrolo[1,2- d][1,4]diazocines based on tandem transformation of tetrahydropyrazine ring was elaborated.

Microwave-assisted multi-step synthesis of novel pyrrolo-[3,2- c]quinoline derivatives

A new approach for the synthesis of original substituted pyrrolo-[3,2- c]quinoline derivatives using microwave-assisted chemistry is described. The use of microwave activation in this synthesis resulted in high yielding and clean steps. The key step for introducing diversity is the amination or the Pd-catalyzed cross-coupling of an imidoyl chloride derivative, obtained in a straightforward manner and in good yield.

Synthesis of Novel Pyrrolo[3,4‐d]pyrazole‐dicarboxylic Acids and Evaluation of Their Interaction with Glutamate Receptors

Chiral pyrazoline amino acids (3aR,4S,6aR)-1a and (3aR,4S,6aR)-1b, and (3aS,6S,6aS)-2a and (3aS,6S,6aS)-2b, which are conformationally constrained analogues of glutamic and homoglutamic acid, respectively, were prepared via a strategy based on the 1,3-dipolar cycloaddition of a nitrile imine to methyl N-Boc-3,4-didehydro-(S)-prolinate. The new 'amino acids' were tested for activity at ionotropic glutamate receptors. Solely the derivative (3aR,4S,6aR)-1a, which is structurally related to the previously described 4,5-dihydroisoxazole analogue (S)-CIP-A, turned out to be a potent and selective agonist for the AMPA receptors. The biological activity is due to the interaction with the orthosteric glutamate binding site.

Molecular modeling study and synthesis of novel pyrrolo[2,3- d]pyrimidines and pyrrolotriazolopyrimidines of expected antitumor and radioprotective activities

Novel pyrrolo[2,3- d]pyrimidine derivatives 4a– e, 10, 14, 15, pyrazolopyrrolopyrimidine 13, pyrrolotriazolopyrimidine 5– 9, 17 and pyrrolopyrimidotriazine 18 are reported herein. The design of these compounds was based upon the molecular modeling simulation of the fitting values and conformational energy values of the best-fitted conformers to VEGFRTK inhibitor hypothesis. This hypothesis was generated from its corresponding lead compounds using CATALYST software. The structures of these compounds were confirmed by microanalyses, IR, 1H NMR, and mass spectral data. Compounds 6 and 15 showed interesting in vitro antitumor activity compared to doxorubicin as positive control. These results are nearly consistent with the molecular modeling studies. Docking studies were made on compound 15 to predict its binding mode. Moreover, compound 10 exhibited a significant radioprotective activity.

Novel Synthesis of Pyrrolo[2,3‐d]pyrimidines Bearing Sulfonamide Moieties as Potential Antitumor and Radioprotective Agents.

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Design and Synthesis of Novel Pyrrolo[2,1-c][1,4]benzodiazepine - Imidazole Containing Polyamide Conjugates

Article Design and Synthesis of Novel Pyrrolo[2,1-c][1,4]benzodiazepine - Imidazole Containing Polyamide Conjugates was published on February 1, 2002 in the journal Heterocyclic Communications (volume 8, issue 1).