Indolizine Derivatives Research Articles

(5+1)−1] Cyclization of Nitroepoxides to Pyridinium 1,4‐Zwitterionic Thiolates for the Synthesis of Indolizine Derivatives

AbstractThe synthesis of indolizine derivatives was achieved through the reaction of pyridinium 1,4‐zwitterionic thiolates with a diverse array of 2‐methyl‐2‐nitro‐3‐aryloxiranes. Subsequent investigations unveiled a synthetic route to indolizines via a stepwise [(5+1)−1] pathway, with unstable pyridothiazines serving as transient intermediates. DFT calculations elucidated that this transformation entails sequential annulation, deacylation, desulfurization, and oxidation steps.

The synthesis of 2-amino-3-carboxamideindolizines with using pyridinium salt and C-nucleophiles–derivatives acetonitrile

This study reports the synthesis of a pyridinium salt achieved by heating 2-chloropyridine with 2-bromoacetamide in the absence of solvent. The synthesized salt exhibits a high reactivity towards nucleophilic substitution reactions with C-nucleophiles derived from acetonitrile. Furthermore, the resulting N-carboxamide-2(1H)pyridines are efficiently transformed into 2-amino-3-carboxamideindolizines via a cyclisation process, leading to a high yield of the desired product. These findings highlight the potential of this synthetic route for the production of valuable indolizine derivatives.

Larvicidal activity, molecular docking, and molecular dynamics studies of 7-(trifluoromethyl)indolizine derivatives against Anopheles arabiensis.

A novel series of 7-(trifluoromethyl)indolizine derivatives (4a-4n) was synthesized using a 1,3-Dipolar cycloaddition reaction. Structure elucidation of the synthesized compounds was done using various spectroscopic techniques. Compounds were assessed for their larvicidal activity against Anopheles arabiensis. Exposure of Anopheles arabiensis larvae to a series of 7-(trifluoromethyl)indolizine at 4µg/mL for 24 and 48h resulted in moderate to high larval mortality rates. Among them, compounds 4b, 4a, 4g, and 4m exhibited the most promising larvicidal activities, with mortality rates of 94.4%, 93.3%, 80.00%, and 85.6%, respectively, compared to controls, Acetone and Temephos. The structural activity relationship analysis of the evaluated compounds revealed that substitution with halogens or electron-withdrawing groups (CN, F, Cl, Br) at the para position of the benzoyl group is crucial for achieving promising larvicidal activity. Molecular docking studies were carried out involving six potential larvicidal target proteins to predict how the tested compounds might work. Compounds 4a and 4b showed strong binding to the Mosquito Juvenile Hormone-Binding Protein (5V13). Molecular dynamics (MD) simulations confirmed the stability of the protein-ligand complexes over the simulation period, reinforcing the reliability of the docking results. Compounds 4a and 4b also exhibited favourable ADMET profiles, showing high oral bioavailability, good permeability, moderate distribution, low plasma protein binding, sufficient metabolic stability, efficient renal clearance and low toxicity. Given the crucial role of Juvenile Hormone in regulating gene expression and developmental pathways through receptor interactions, compounds 4a and 4b show promise as inhibitors of this protein. Inhibiting this process could hinder larval growth and reproduction, presenting a promising approach for early-stage mosquito larvicidal activity. Therefore, compounds 4a and 4b represent lead candidates for further optimization and the development of new larvicidal agents.

Optimal donor groups for novel organic dye “3-(5-(4-(diphenylamino)styryl)thiophen-2-yl)-2-cyanoacrylic acid” in the context of N‑type dye-sensitized solar cells: A theoretical investigation

Theoretical modeling using DFT and TDDFT methods explored optimal donor groups for the organic dye “3-(5-(4-(Diphenylamino)styryl)thiophen-2-yl)-2-cyanoacrylic Acid”. Seven different moieties and their derivatives mostly used as donors as obtained from the literature (methylamine, benzene, fluorene, carbazole, phenylaniline, indolizine and pyrrolizine) were investigated, and our calculations highlighted indolizine and pyrrolizine derivatives as the most effective donors among those studied. The strong push pull effect of such derivatives of indolizine and pyrrolizine groups played a role in enhancing the efficiency of the dye sensitizers.

Single-Pot Reaction of Novel Fused Indolizine Derivatives.

An unprecedented fused hexacyclic indolizine derivative generated by a single-pot reaction has been developed. This model overcomes the use of catalysts, inefficient atom economy, low yields, and limitations of lengthy steps. Density functional theory calculations reveal the reaction mechanism in which the oxygen molecule plays a crucial role in trapping the penultimate zwitterionic or biradical intermediate to generate the observed products.

Synthesis and structural elucidation of novel quaternary pyridinium salt and indolizine derivatives as an anti-tubercular agent: In Silico and In Vitro screening

The in vitro anti-mycobacterial activity of a novel series of diversely substituted quaternary pyridinium salts (3a-m) and indolizines (5a-h) were assessed against H37Rv strain of Mycobacterium tuberculosis (M.tb). The series of intermediate 1-(2-oxo-2-phenylethyl)-4-(piperidin-1-yl)pyridin-1-ium bromide, which contains a heterocyclic ring molecule, has been prepared by reacting with 4-(piperidin-1-yl)pyridine and phenacyl bromide at room temperature. The final ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues were prepared by using pyridin-1-ium bromide with electron-deficient acetylene, undergoing 1, 3-dipolar cycloaddition at the ambient temperature using anhydrous potassium carbonate and N, N-dimethylformamide as a solvent. All the newly synthesized compounds were characterized by spectroscopic techniques such as 1H and 13C NMR, and HRMS. All the synthesized intermediates and final compounds were evaluated for their anti-tubercular activities against H37Rv (ATCC 27294) strain. All the compounds exhibited anti-tubercular activities in the range of 12.5–50 µM. In vitro screening of all derivatives concluded that among all the screened candidates 3k emerged as an active hit with MIC 12.5 µM, 3l and 3m with MIC 25 µM.

Evaluation of Pyrazolyl-Indolizine Derivatives as Antimicrobial Agents: Synthesis, In vitro, In silico ADMET and Molecular Docking Studies.

Herein, we report analogues of s-indacene by the synthesis of novel indolizine derivatives. Using chloroform as an appropriate solvent, sixteen derivatives of pyrazolyl-indolizine (4--19) were prepared by the reaction of 3-(dimethylamino)-1-(1H-pyrrol-2-yl)prop-2-en-1-one (1) with hydrazonoyl chloride derivatives (2) in the presence of triethylamine in good to excellent yields. We used NMR spectra, IR, mass spectrometry, as well as elemental analyses to prove the chemical structures and the purity of the synthesized compounds 4-19. Among all tested compounds 5, 9, 13 and 19 had a potent antimicrobial efficiency against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aerginousea, Sallmonella typhemerium, and Candida albicans. Furthermore, a significant increase in lipid peroxidation (LPO) toward the Gram-negative bacteria, Pseudomonas aeruginosa when treated with compound 9 was observed, while compound 13 remarkably increased the cell membrane oxidation of Salmonella typhimurium. Additionally, we utilized docking studies and in silico methods to evaluate the drug-likeness, physicochemical properties, and ADMET profiles of the compounds. The results of the molecular docking simulation revealed that the synthesized compounds displayed decreased binding energy when interacting with the active sites of important enzymes, including Sterol 14-demethylase of C. albicans, Dihydropteroate synthase of S. aureus, LasR of P. aeruginosa, Glucosamine-6-phosphate synthase of S. typhimurium, and Gyrase B of B. subtilis.

Identification of potent indolizine derivatives against Mycobacterial tuberculosis: In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies

In the current study, two sets of compounds: (E)-1-(2-(4-substitutedphenyl)-2-oxoethyl)-4-((hydroxyimino)methyl)pyridinium derivatives (3a-3e); and (E)-3-(substitutedbenzoyl)-7-((hydroxyimino)methyl)-2-substitutedindolizine-1-carboxylate derivatives (5a-5j), were synthesized and biologically evaluated against two strains of Mycobacterial tuberculosis (ATCC 25177) and multi-drug resistant (MDR) strains. Further, they were also tested in vitro against the mycobacterial InhA enzyme. The in vitro results showed excellent inhibitory activities against both MTB strains and compounds 5a-5j were found to be more potent, and their MIC values ranged from 5 to 16 μg/mL and 16–64 μg/mL against the M. tuberculosis (ATCC 25177) and MDR-TB strains, respectively. Compound 5h with phenyl and 4-fluorobenzoyl groups attached to the 2- and 3-position of the indolizine core was found to be the most active against both strains with MIC values of 5 μg/mL and 16 μg/mL, respectively. On the other hand, the two sets of compounds showed weak to moderate inhibition of InhA enzyme activity that ranged from 5 to 17 % and 10–52 %, respectively, with compound 5f containing 4-fluoro benzoyl group attached to the 3-position of the indolizine core being the most active (52 % inhibition of InhA). Unfortunately, there was no clear correlation between the InhA inhibitory activity and MIC values of the tested compounds, indicating the probability that they might have different modes of action other than InhA inhibition.Therefore, a computational investigation was conducted by employing molecular docking to identify their putative drug target(s) and, consequently, understand their mechanism of action. A panel of 20 essential mycobacterial enzymes was investigated, of which β-ketoacyl acyl carrier protein synthase I (KasA) and pyridoxal-5′-phosphate (PLP)-dependent aminotransferase (BioA) enzymes were revealed as putative targets for compounds 3a-3e and 5a-5j, respectively. Moreover, in silico ADMET predictions showed adequate properties for these compounds, making them promising leads worthy of further optimization.

Synthesis of novel π-extended 2,5-disubstituted indolizines and their absorption and fluorescence properties

We report herein the synthesis of novel π-extended fluorescent 2-aryl-indolizines bearing substituents such as chalcone, styrene and imine groups at the C-5 position of the indolizine. Absorption and fluorescence properties of these 2,5-substituted indolizines were significantly affected by the substitution pattern at the C-5 position, as evidenced by absorption spectra, Stokes shifts and fluorescence measurements. Among the indolizine derivatives, those containing chalcone exhibited a highly notable red shift in their maximum wavelength of fluorescence (λem= 650 nm) compared to those containing imine (λem= 487 nm) or olefin (λem= 543 nm), accompanied by relatively large Stokes shifts (71-171 nm / 2955–6761 cm−1) and fluorescence quantum-yield values from 0.002 to 0.296. All synthesized indolizines demonstrated colorful in solution, while the imine- and olefin-substituted indolizines exhibited fluorescence both in solution and the solid state. The chalcone derivatives showcased the capability to regulate its fluorescence modulation. Although the presence of the carbonyl group extensively suppressed this effect, it was significantly restored upon reduction to the hydroxyl group, demonstrating a promisor “off-on” fluorescent sensors for monitoring oxidative processes within biological systems.

Rh(III)-Catalyzed C-H Activation/Annulation for the Construction of Quinolizinones and Indolizines.

A catalytic-condition-controlled synthesis strategy was reported to build quinolizinone and indolizine derivatives from the easily available enamide and triazole substrates with high regioselectivity and good functional group tolerance. More especially, this transformation has successfully fulfilled a C-H bond activation of terminal olefin from enamides followed by a [3 + 3] and a [2 + 3] cyclization cascade under different catalytic conditions, respectively, to provide two kinds of potentially biologically active heterocyclic scaffolds with a ring-junction nitrogen atom. Mechanistically, the methoxyamine formyl group serves as either a traceless directing group (DG) or an oxidizing DG via the C-N and C-C cleavage in this protocol.

Synthesis, characterization, and anti-inflammatory properties of novel ethyl 3-benzoyl-7-(trifluoromethyl)indolizine-1-carboxylate derivatives: In silico and invitro analysis.

Series of 7-(Trifluoromethyl) substituted indolizine 4a-g was synthesized using the one-pot method. Spectroscopic techniques such as IR, 1H-NMR, 13C-NMR, and HRMS were used for the structure confirmation of newly synthesized compounds. These 4a-g compounds were tested for their anti-inflammatory activity. In this study, we identified novel indolizine derivative compounds 4a-g selectively targeting COX-2 enzyme, tumor necrosis factor-α (TNF-α) and, interleukin-6 (IL-6). The in silico docking studies of 4a-g showed that these compounds have a higher affinity for COX-2 enzyme, TNF- α, and IL-6. In silico ADME profile analysis predicts that these compounds have good gastrointestinal tract and blood-brain barrier absorption. Invitro studies showed that compound 4d significantly reduces the level of COX-2 enzymes as compared to indomethacin. Compounds 4e, 4f, and 4a were also found to significantly reduce the level of TNF-α, while compounds 4f, 4g, and 4d, showed a reduction in the level of IL-6 when compared to indomethacin. Compounds 4a, 4d, and 4f also reduces nitric oxide (NO) level, compared to indomethacin. Overall, the current study illustrates significant anti-inflammatory activities of these novel 7-(Trifluoromethyl) substituted indolizine derivatives.

Exploring novel HIV-1 reverse transcriptase inhibitors with drug-resistant mutants: A double mutant surprise.

HIV-1 reverse transcriptase (RT) remains a key target for HIV drug development. As successful management of the disease requires lifelong treatment, the emergence of resistance mutations is inevitable, making development of new RT inhibitors, which remain effective against resistant variants crucial. To this end, previous computationally guided drug design efforts have resulted in catechol diether compounds, which inhibit wildtype RT with picomolar affinities and appear to be promising preclinical candidates. To confirm that these compounds remain potent against Y181C, a widespread mutation conferring resistance to first generation inhibitors, they were screened against the HIV-1 N119 clinical isolate, reported as a Y181C single mutant. In comparison to a molecular clone with the same mutation, N119 appears less susceptible to inhibition by our preclinical candidate compounds. A more detailed sequencing effort determined that N119 was misidentified and carries V106A in combination with Y181C. While both indolizine and naphthalene substituted catechol diethers are potent against the classical Y181C single mutant, the addition of V106A confers more resistance against the indolizine derivatives than the naphthalene derivatives. Crystal structures presented in this study highlight key features of the naphthyl group, which allow these compounds to remain potent in the double mutant, including stronger interactions with F227 and less reliance on V106 for stabilization of the ethoxy-uracil ring, which makes critical hydrogen bonds with other residues in the binding pocket.

Corrosion Inhibition of Benzyl Quinoline Chloride Derivative-Based Formulation for Acidizing Process

Summary Due to the severe and rapid corrosion of metallic equipment by strong acids at high temperatures, a high concentration of acidizing corrosion inhibitors (ACIs) is required during acidizing processes. There is always a need to develop more effective and environmentally friendly ACIs than current products. In this work, a highly effective ACI obtained from a novel main component and its synergistic effect with paraformaldehyde (PFA) and potassium iodide (KI) is presented. The ACI was prepared from the crude product of benzyl quinolinium chloride derivative (BQD) synthesized from benzyl chloride and quinoline in a simple way. The new ACI formulation, named “synergistic indolizine derivative mixture” (SIDM), which consists of BQD, PFA, and KI, showed superior corrosion inhibition effectiveness (IE) and temperature stability compared with commercially available ACI. More importantly, the SIDM formulation eliminates the need for commonly used highly toxic synergists (e.g., propargyl alcohol and As2O3). In a 20 wt% hydrochloric acid (HCl) solution, the addition of 0.5 wt% SIDM mitigates the corrosion rate of N80 steel down to less than 0.00564 lbm·ft−2 at 194°F, while the corrosion rate at 320 °F is 0.0546 lbm·ft−2·when 4.0 wt% SIDM is added.

Green “one-pot” fluorescent bis-indolizine synthesis with whole-cell plant biocatalysis

Abstract An efficient one-pot route leading to bis-indolizine symmetric compounds has been developed via a new approach from the dipyridinium heterocyclic compound, reactive halogenated derivative, and activated alkyne through biocatalysis. A set of local plants was evaluated for its catalytic potential in “one-pot” biocatalysis of these valuable fluorescent compound synthesis reactions. Most of these biocatalysts containing enzymes from the oxidoreductase class (peroxidase: 0.56–1.08 mmol purpurogallin‧g−1 fresh weight‧min−1, polyphenol oxidase (PPO) : 27.19–48.95 PPO units‧mg tissue−1, CAT: 3.27–21.71 µmol O2‧g−1 fresh weight‧min−1), were used as green catalysts in the multi-component cycloaddition reaction, in an aqueous buffer solution, for the production of bis-indolizine compounds in moderate to excellent yields (45–85%). The horseradish root (Armoracia rusticana) has been selected as the most promising biocatalyst source among the evaluated plants, and the obtained yields were greater than in the conventional synthesis method. The structures of indolizine derivatives were confirmed by nuclear magnetic resonance spectra, elemental analyses, as well as Fourier transform-infrared spectra. The cytotoxicity of the latter obtained indolizine compounds on the growth of the model microorganism, Saccharomyces cerevisiae MIUG 3.6 yeast strain, was also evaluated. Various parameters (number of generations, growth rate, generation time, dry matter yield, the degree of the budding yeast cells, and the degree of yeast autolysis, fermentation intensity), which describe the yeast growth, suggest that the nutrient broth supplemented with different concentrations of bis-indolizine compounds (10 and 1 µM) had no toxic effect on the yeast strain growth, under submerged cultivation conditions.

Synthetic Strategies for the Construction of Indolizines and Indolizine‐fused Compounds: Thienoindolizines and Indolizinoindoles

AbstractThis paper provides a review on various methodologies developed for the synthesis of different indolizine derivatives and an overview of their application. These include thienoindolizine and indolizino[8,7‐b]indole derivatives. The indolizine nucleus occurs as privileged scaffold of many natural and synthetic molecules with significant biological activity. Fused‐indolizines such as thienoindolizines and indolizinoindole derivatives are of great interest, due to their antitumor, antimicrobial and enzyme inhibitor activity. Because of their widespread use in chemical, medicinal, biological, and materials science research, indolizines and their fused derivatives are attractive synthetic targets in the search for efficient methods for their construction.

Synthesis of Propargylamine and Indolazine Derivatives via Three‐Component Reaction Catalyzed by CuOx/CeO2 Materials

AbstractIn this paper, nanorod CeO2 supports were prepared by hydrothermal method using Ce(NO3)3 ⋅ 6H2O as raw material. CuOx/CeO2‐r materials were prepared by calcination using Cu salt‐loaded CeO2‐r supports as raw materials. The three‐component coupling reaction of phenylacetylene, amine and aldehyde was successfully catalyzed by CuOx/CeO2‐r material as a non‐homogeneous catalyst, which showed good catalytic activity. Furthermore, a series of indolizine derivatives can be obtained in higher isolated yields by replacing benzaldehyde with pyridinecarbaldehyde and catalyzing the three‐component synthesis with the same CuOx/CeO2‐r material. The synthesis mechanisms of propargylamine and indolizine were discussed. It is worth noting that the CuOx/CeO2‐r material system is provided for two three‐component reactions, and has the advantages of less catalyst dosage, short reaction time, simple post‐treatment, and a wide range of substrates.

Cu(II)‐Catalyzed [3+2]‐Annulation of 2‐Pyridinyl‐substituted p‐Quinone Methides with Enaminones: Access to Functionalized Indolizine Derivatives

AbstractThis article describes an effective and atom‐economical protocol to access a wide range of synthetically important functionalized indolizine derivatives. This transformation basically takes place through a Cu(II) catalyzed formal [3+2] annulation of 2‐pyridinyl substituted p‐quinone methides with enaminones. This method displayed a good functional group tolerance and, was found to be effective for most of the enaminones and p‐QMs, and the corresponding indolizines were obtained in moderate to good yields.

B(C6F5)3‐Catalyzed Aza‐Friedel–Crafts Reaction of Indolizines with 2‐Aryl‐3H‐indol‐3‐ones

AbstractA Friedel–Crafts reaction of indolizines with 2‐aryl‐3H‐indol‐3‐ones catalyzed by B(C6F5)3 is described. This protocol gives access to indolizine derivatives that are valuable building blocks in synthetic and pharmaceutical chemistry. The reaction proceeds under mild conditions, affording various C2‐quaternary indolin‐3‐ones based on indolizine with high yields and regioselectivities. Moreover, the synthetic transformations of the target products were realized by N‐methylation and trifluoromethane sulfonation.

Catalyst‐free oxidative [3+2]‐annulation of (2‐nitroethene‐1,1‐diyl)bis(methylsulfane) and pyridinium ylides: Efficient synthesis of (methylsulfanyl)indolizines heterocycles

AbstractA facile and efficient protocol has been developed for the synthesis of (methylsulfanyl)indolizine derivatives via oxidative [3+2]‐annulation of bis(methylthio)‐2‐nitroethylen(BMTNE) and pyridinium ylides under K2CO3. The target products could be obtained in moderate to good yields.

Acetic Acid‐Catalyzed 1,6‐Addition of Indolizine to para‐Quinone Methides

AbstractThis article describes the development of a metal and additive‐free protocol that utilizes acetic acid (AcOH) as a catalyst for the C3‐alkylation of indolizines using para‐Quinone Methides (p‐QMs) as an alkylation agent. The metal and additive free method offers an easy route to various substituted indolizine derivatives with good functional group tolerance and delivering acceptable good yields (up to 93%). A gram‐scale synthesis and further product derivatization show the synthetic potential of this technique. The significance of these findings for medicinal chemistry makes this easy and green approach relevant to both medicinal and synthetic organic chemists, given the crucial role of indolizine in the pharmaceutical industry.