Indole-based Heterocycles Research Articles

The Biological and Pharmacological Potentials of Indole-based Heterocycles

Abstract: An important bioactive heterocycle having several uses in medicinal chemistry, synthetic organic chemistry, material chemistry, and natural product is indole along with its analogues. Many bioactive indole-based heterocycles have important antibacterial, anti-inflammatory, analgesic, antiviral, antimalarial, chemotherapeutic, antifungal, and anti-TB effects, as well as antioxidant capabilities. Several well-known medications, including tadalafil, rizatriptan, sumatriptan, and fluvastatin are indole- based potential bioactive compounds. Based on the existing and latest evidence, researchers have focused on developing indole-based compounds with novel biological and pharmacological properties for decades. Owing to useful bioactivities, we have described many bioactive indoles and their synthetic methods in this review article.

Facile Synthesis and Antioxidant Activity Screening of Some Novel 3-Substituted Indole Derivatives

The 2-cyano-3-(indol-3-yl)acryloyl chloride, a building block synthon prepared in good yield, was utilized for the synthesis of various indolylacrylamide and indole-based heterocycles. Thus, the aforementioned acid chloride was allowed to react with various oxygen, sulfur, and nitrogen nucleophiles, in addition to mono- and bidentate nucleophiles. The pyrazolidine derivatives were produced on interactions with phenylhydrazine and 2-cyanoethanohydrazide. The antioxidant activity of the synthesized compounds was assessed using the phosphomolybdenum technique and ascorbic acid as a standard. The findings displayed that indolyl-based azine, pyrazolidine, cyanoacetamide, and benzodiazepine derivatives were the most active antioxidants.

Montmorillonite clay-based heterogenous catalyst for the synthesis of nitrogen heterocycle organic moieties: a review.

The use of montmorillonite clay as solid catalyst has grabbed much attention in the liquid phase reactions for organic synthesis. In recent years, there has been a lot of interest in organic synthesis using montmorillonite-based composites, especially in the synthesis of heterogeneous nanoparticles. Due to the robust and green nature of montmorillonite-based nanocatalysts, it has been widely used in N-heterocyclic reactions. In this review, we have concentrated on the reports pertaining the use of montmorillonite-based nanocatalyst in the synthesis of N-heterocycles, a category of organic compounds with excellent biological properties. This manuscript is arranged by the types of N-containing heterocycles synthesized using montmorillonite-based composite as catalysts including polycyclic spirooxindoles, heterocyclic propargylamine, indole-based heterocycles, quinoline and its derivatives, six-membered N-heterocyclic-based compounds and five-membered N-heterocyclic-based compounds. Special attention was given to the structural stability under experimental parameters of the montmorillonite-based composite with the incidence of metal leaching and reusability. Finally, along with recent developments, new findings in heterogeneous montmorillonite (Mt)-based catalysis have also been addressed.

Design, Synthesis, Biological Evaluation, 2D-QSAR Modeling, and Molecular Docking Studies of Novel 1H-3-Indolyl Derivatives as Significant Antioxidants.

Novel candidates of 3-(4-(thiophen-2-yl)-pyridin/pyran/pyrimidin/pyrazol-2-yl)-1H-indole derivatives (2–12) were designed by pairing the pyridine/pyrane/pyrimidine/pyrazole heterocycles with indole and thiophene to investigate their potential activities as (2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) inhibitors. The purpose of these derivatives’ modification is to create high-efficiency antioxidants, especially against ABTS, as a result of the efficiency of this set of key heterocycles in the inhibition of ROS. Herein, 2D QSAR modeling was performed to recommend the most promising members for further in vitro investigations. Furthermore, the pharmacological assay for antioxidant activity evaluation of the yielded indole-based heterocycles was tested against ABTS (2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid); by utilizing ascorbic acid as the standard. Candidate 10 showed higher antioxidant activity (IC50 = 28.23 μg/mL) than ascorbic acid itself which achieved (IC50 = 30.03 μg/mL). Moreover, molecular docking studies were performed for the newly designed and synthesized drug candidates to propose their mechanism of action as promising cytochrome c peroxidase inhibitors compared to ascorbic acid as a reference standard. Our findings could be promising in the medicinal chemistry scope for further optimization of the newly designed and synthesized compounds regarding the introduced structure-activity relationship study (SAR) in order to get a superior antioxidant lead compound in the near future.

Construction of Unusual Indole-Based Heterocycles from Tetrahydro-1H-pyridazino[3,4-b]indoles.

Herein, we report the successful syntheses of scarcely represented indole-based heterocycles which have a structural connection with biologically active natural-like molecules. The selective oxidation of indoline nucleus to indole, hydrolysis of ester and carbamoyl residues followed by decarboxylation with concomitant aromatization of the pyridazine ring starting from tetrahydro-1H-pyridazino[3,4-b]indole derivatives lead to fused indole-pyridazine compounds. On the other hand, non-fused indole-pyrazol-5-one scaffolds are easily prepared by subjecting the same C2,C3-fused indoline tetrahydropyridazines to treatment with trifluoroacetic acid (TFA). These methods feature mild conditions, easy operation, high yields in most cases avoiding the chromatographic purification, and broad substrate scope. Interestingly, the formation of indole linked pyrazol-5-one system serves as a good example of the application of the umpolung strategy in the synthesis of C3-alkylated indoles.

Palladium-Catalyzed, Enantioselective (3 + 2)-Cycloannulation of β-Keto Esters with Alkylidene 2H-Indoles toward Complex Indole-Based Heterocycles.

A cooperative approach toward biologically important N-fused polycyclic indoles with synthetically challenging tetracyclic [6-5-5-6] and [6-5-5-5] core structures has been developed. The concept is based on a highly stereoselective (3 + 2)-cycloannulation of chiral metal enolates with a reactive vinylogous iminium ion, both generated in situ via dual activation with a single chiral Pd catalyst (5 mol %). Densely functionalized pyrrolo[1,2-a]indoles with three contiguous chiral centers were constructed with high stereoselectivities (>95:5 d.r. and up to >99% ee) and excellent yields (up to 99%). ESI-MS studies and additional control experiments provided a clear mechanistic picture of the cycloannulation event. The products were readily transformed into an array of valuable, indole-based, highly complex heterocycles.

New Quinoline-Based Heterocycles as Anticancer Agents Targeting Bcl-2.

The Bcl-2 protein has been studied as an anticancer drug target in recent years, due to its gatekeeper role in resisting programmed cancer cell death (apoptosis), and the design of BH3 domain mimetics has led to the clinical approval of Venetoclax (ABT-199) for the treatment of chronic lymphocytic leukaemia. In this work we extend our previous studies on the discovery of indole-based heterocycles as Bcl-2 inhibitors, to the identification of quinolin-4-yl based oxadiazole and triazole analogues. Target compounds were readily synthesized via a common aryl-substituted quinolin-4-carbonyl-N-arylhydrazine-1-carbothioamide (5a–b) intermediate, through simple variation of the basic cyclisation conditions. Some of the quinoline-based oxadiazole analogues (e.g. compound 6i) were found to exhibit sub-micromolar anti-proliferative activity in Bcl-2-expressing cancer cell lines, and sub-micromolar IC50 activity within a Bcl2-Bim peptide ELISA assay. The Bcl-2 targeted anticancer activity of 6i was further rationalised via computational molecular modelling, offering possibilities to extend this work into the design of further potent and selective Bcl-2 inhibitory heteroaromatics with therapeutic potential.

Medicinal applications of (benz)imidazole‐ and indole‐based macrocycles

Macrocyclic chemistry is one of the emerging research areas in the chemical science. Macrocyclic compounds continue to attract significant attention due to their numerous possible applications particularly in the areas like biology, catalysis and industry. This review article summarizes the developments and advances in synthesis and medicinal applications of macrocyclic compounds derived from (benz)imidazole- and indole-based heterocycles. Important medicinal applications of (benz)imidazole- and indole-based macrocycles include antimicrobial and anticancer activities. The representative lead compounds in each series of macromolecules have been discussed. All these initial lead breakthroughs help validate the great potential of (benz)imidazole- and indole-based macrocyclic compounds as a class of effective medicinal agents.

Solvent-controlled bifurcated cascade process for the selective preparation of dihydrocarbazoles or dihydropyridoindoles.

A solvent-controlled cascade process has been identified for the dual purpose of the preparation of either dihydrocarbazoles or dihydropyridoindoles from identical N-aryl-α,β-unsaturated nitrones and electron-deficient allene starting materials. These reactions proceed smoothly under mild metal-free conditions affording a range of two types of skeletally distinct indole-based heterocycles in high yield and diastereoselectivity. These transformations demonstrate the use of a bifurcated cascade process that hinges on the ring-opening event of a benzazepine intermediate for the synthesis of skeletally diverse heterocyclic products and rapid access to biologically-significant, indole-based structures.

Bronsted acid-catalyzed rapid enol-ether formation of 2-hydroxyindole-3-carboxaldehydes

A one-step Bronsted acid-catalyzed synthetic methodology leading to 3-(alkoxymethylene)indolin-2-ones was developed starting from easily accessible 2-hydroxyindole-3-carboxaldehydes. The procedure simply involves a treatment of differently substituted 2-hydroxyindole-3-carboxaldehydes with various alcohols (primary/secondary/tertiary/allyl/propargyl/benzyl) in the presence of a catalytic amount of Bronsted acids such as [Formula: see text]-toluenesulfonic acid and trifluroacetic acid. A series of 19 indolin-2-one-based enol-ethers were synthesized in excellent yields, which implies the general character of our methodology. The enol-ethers produced could be used as a useful building block for the synthesis of indole-based heterocycles.

Rapid and selective access to three distinct sets of indole-based heterocycles from a single set of Ugi-adducts under microwave heating

Three distinct sets of indole-based heterocycles were rapidly and selectively synthesized from the same set of Ugi-adducts under microwave heating in a reaction-condition-controlled manner. Notably, an unprecedented metal-free intramolecular sp(3)-hybridized C-H arylation using only cesium carbonate was discovered.

Synthesis and Antiviral Activity of New Indole-Based Heterocycles

New 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine and 1,3-thiazole derivatives incorporating indole nucleus were prepared using 3-acetylindole as precursor and evaluated for their antiviral activity against herpes simplex type 1 (HSV-1).

A Practical Synthesis of Indole-Based Heterocycles Using an Amidoaluminum-Mediated Strategy

A large number of biologically active compounds consist of an indole scaffolding. Because of this, chemists are continually searching for more efficient means through which to successfully synthesize the required alkaloids. In our recent effort to synthesize indole-based p38 inhibitors and gramines, we found that a series of indole-based indole-3-carboxamides could be efficiently synthesized from various indole-3-carboxylates using an amidoaluminum-mediated strategy. The treatment of ethyl indole-3-carboxylates bearing a range of substitution patterns on the indole ring with various amidoaluminum complexes, led to the corresponding 1H-in- dole-3-carboxamides in yields up to 75%. Reduction by diisobutylaluminum hydride afforded the corresponding gramines in 63―85% yield. This is the first reported example of amidoalumi- num complexes of type Al 2 (CH 3 ) 4 (NR 2 ) 2 promoting facile amidation of relatively inert indole esters. This particularly promising approach has resulted in the first strategy for generating medicinally important alkaloids of this type.