1,3-Dipolar cycloaddition reactions of isatin-derived azomethine ylides for the synthesis of spirooxindole and indole-derived scaffolds: recent developments.

The unique therapeutic and biological characteristics of spirooxindole have led to the presentation of numerous reactions for the synthesis of spirooxindoles through 1,3-Dipolar cycloaddition of highly reactive isatin-derived azomethine ylides with activated olefins as the main tool for the formation of spirocyclic oxindoles during the last 4 years. Therefore, there is a need to highlight the recent developments in this area, along with the representative synthetic methods and relevant reaction mechanisms from 2018 to 2021. The representative synthetic methodologies were listed in four sections based on the procedure to form the azomethine ylide species including isatins and amino acids, isatin-derived α-(trifluoromethyl)imine, isatins and benzylamines, and from isatin-derived cyclic imine 1,3-dipoles.

Catalyst-free synthesis of highly functionalized triazole hexahydroquinoline carbohydrazide scaffolds via four-component cyclocondensation reaction.

A new class of multi-functional triazole hexahydroquinoline carbohydrazide named 2-amino-7,7-dimethyl-5-oxo-4-phenyl-1-(4H-1,2,4-triazol-3-yl)-1,4,5,6,7,8-hexahydroquinoline-3-carbohydrazide has been synthesized by a novel multi-component process involving the reaction of dimedone, 3-amino-1,2,4-triazole, various benzaldehyde with cyanoacetohydrazide under mild conditions in the stoichiometric melt and chloroform in sequence. The simple one-pot process, straight product isolation without applying tedious purification procedures, progression of the reaction without using any catalyst, the application of diverse aldehydes causing a high molecular diversity, the existence of several nitrogen atoms in the product structure, and the possibility of creating multiple hydrogen bonding in the final compound are attractive specifications of the present strategy.

Synthesis of diverse spiro-imidazo pyridine-indene derivatives via acid-promoted annulation reaction of bindone and heterocyclic ketene aminals.

A new multi-component reaction for the synthesis of novel and diverse spiro-imidazo pyridine-indene derivatives named spiro[imidazo[1,2-a]indeno[2,1-e]pyridine-5,1'-indene and indenylidene-1H-spiro[imidazo[1,2-a]pyridine-7,1'-indene was successfully developed by the reaction between heterocyclic ketene aminals (generated from 1,1-bis(methylthio)-2-nitro ethylene and diamine) and [1,2'-biindenylidene]-1',3,3'-trione (bindone) (in situ generated from self-condensation of 1,3-indandion) by using malononitrile as a promoter or as one of the precursors respectively in the presence of p-TSA as the acid catalyst in EtOH as reaction medium under reflux conditions. Depending on whether the reaction is single-step or two-step, malononitrile can act as a promoter or reactant. The convenient one-pot operation, straightforward isolation without using additional purification methods, and the use of a variety of diamines and cysteamine hydrochloride causing a variety of structural products are attractive aspects of the present approach. The synthesized bindone and final product contains active methylene and this active site can be involved in further reactions to synthesize more complex heterocycles.

Recent developments in green approaches for sustainable synthesis of indole-derived scaffolds.

An important issue to discover biological structures is the design of sustainable, safe, clean, cost-effective, excellent efficient synthetic reactions, and minimal energy consumption to provide structural diversity compounds with interesting biological properties. Among five-membered nitrogen-containing heterocyclic compounds, indole-containing scaffolds are heterocyclic structures found in abundance in natural products and various synthetic compounds, which have received remarkable attention in recent years due to their therapeutic and pharmaceutical properties and valuable role in the process of drug discovery. Indoles can be synthesized by various procedures although most of these procedures have their own restrictions and drawbacks such as performing the reaction in a toxic solvent, need of transition-metal catalysts, and amount of waste solvents. Due to the medicinal importance of indole and the need for green methods of drug synthesis, this review highlights the latest green synthetic methods leading to the formation of indole-containing compounds focusing on the past 4 years with typical examples. This review is divided into two sections: green solvents and green techniques that lead to the synthesis of indole-derived scaffolds.

A one-pot synthesis of piperidinium spirooxindoline-pyridineolates and indole-substituted pyridones in aqueous or ethanol medium.

Piperidinium spirooxindoline-pyridineolate has been prepared via one-pot multicomponent reaction of isatin, malononitrile, cyanoacetohydrazide, and piperidine in water or ethanol medium at room temperature. In addition, the synthesis of two indole-substituted 2-pyridones from indole-3-carbaldehyde, malononitrile, and cyanoacetohydrazide in the presence of piperidine is described.

Strategies for synthesis of 1,2,4-triazole-containing scaffolds using 3-amino-1,2,4-triazole.

1,2,4-Triazole-containing scaffolds are unique heterocyclic compounds present in an array of pharmaceuticals and biologically important compounds used in the drug-discovery studies against cancer cells, microbes, and various types of disease in the human body. This review article summarizes the pharmacological significance of the 1,2,4-triazole-containing scaffolds and highlights the latest strategies for the synthesis of these privileged scaffolds using 3-amino-1,2,4-triazole. This review stimulates further research to find new and efficient methodologies for accessing new 1,2,4-triazole-containing scaffolds which would be very useful for the discover of new drug candidates.

Recent Strategies in the Synthesis of Spiroindole and Spirooxindole Scaffolds.

Spiroindole and spirooxindole scaffolds are very important spiro-heterocyclic compounds in drug design processes. Significant attention has been directed at obtaining molecules based on spiroindole and spirooxindole derivatives that have bioactivity against cancer cells, microbes, and different types of disease affecting the human body. Due to their inherent three-dimensional nature and ability to project functionalities in all three dimensions, they have become biological targets. Considering reports on spiroindole and spirooxindole-containing scaffolds in the past decades, introducing novel synthetic procedures has been an active research field of organic chemistry for well over a century and will be useful in creating new therapeutic agents. This review summarizes the pharmacological significance of spiroindole and spirooxindole scaffolds and highlights the latest strategies for their synthesis, focusing particularly on the past 2 years with typical examples. The spiroindole and spirooxindoles in this review are divided by the type and ring size of the spirocycle that is fused to indole or oxindole. Summarizing these procedures will be very beneficial for discovering novel therapeutic candidate molecules.

A three-component cyclocondensation reaction for the synthesis of new triazolo[1,5-a]pyrimidine scaffolds using 3-aminotriazole, aldehydes and ketene N,S-acetal.

This study describes the use of 3-aminotriazole, different aldehydes and N-methyl-1-(methylthio)-2-nitroethenamine as a ketene N,S-acetal in a three-component condensation for the synthesis of a novel library of triazolo[1,5-a]pyrimidine scaffolds. The presence of trichloroacetic acid as a Brønsted-Lowry acidic promoter in acetonitrile or water solvent and room temperature condition resulting novel triazolo[1,5-a]pyrimidine systems named N-methyl-6-nitro-5-aryl-3,5-dihydro-[1, 2, 4]triazolo[1,5-a]pyrimidine-7-amine. The structure of products and direction of the N-cyclization could be confirmed using spectral data. The effect of various solvents on the progress of process was investigated in the paper. The presence of five nitrogen heteroatoms, the use of various aldehydes affording a range of skeletally distinct triazolo[1,5-a]pyrimidine-based heterocycles, the potency to create numerous hydrogen bonds in the product structure, and direction of cyclization are attractive features of this reaction.

Novel synthesis of oxoacetamides via reaction of salicylaldehyde and isocyanide under mild reaction condition.

A convenient procedure for the formation of oxoacetamides derivatives is reported via the reaction of salicylaldehyde and alkyl isocyanide in a simple process without the use of any catalyst or metal promoters in DCM at room temperature. The structure of all obtained derivatives were determined by elemental and spectral analyses. In this reaction, 1,3-dioxine-4,4-dicarboxamide was obtained as minor product. This process offers considerable advantages such as the simplicity of reaction, regioselectivity, and the use of commercially available materials.

Synthesis of new functionalized thiazolo pyridine-fused and thiazolo pyridopyrimidine-fused spirooxindoles via one-pot reactions.

A sequential multi-component reaction of the nitroketene dithioacetals, cysteamine hydrochloride, isatin and different CH-acids is described. This efficient method provides new functionalized thiazolo pyridine-fused spirooxindoles and thiazolo pyridopyrimidine-fused spirooxindoles in good yields. In the case of using isatin derivatives (5-bromoisatin and 5-chloroisatin), the reaction was carried out by using nano-SiO2 (20 mol%) as an effective heterogeneous Lewis acid promoter. This type of reaction provides a range of skeletally different polycyclic spiro thiazole-based heterocyclic structures and represents attractive advantages including straightforward one-pot operation under the catalyst-free condition and simple workup procedures without using tedious purification procedure.

Multi-stimuli responsive nanogel/hydrogel nanocomposites based on κ-carrageenan for prolonged release of levodopa as model drug.

This study describes the development of a novel biocompatible nanogel/hydrogel nanocomposite system for long-term delivery of bioactive molecules. To this aim, the nanogels were synthesized via radical polymerization of poly(N-isopropylacrylamide). The nanogels were introduced during the formation of a hydrogel network to produce nanogel/hydrogel soft nanocomposites, while the biocompatible hydrogel was based on poly (acrylic acid) grafted onto κ-carrageenan polysaccharide with entrapped magnetic iron oxide nanoparticles as crosslinker. In these systems, by using stimuli-responsive functional polymers in both gels (nanogels and hydrogels), pH, thermal and magnetic-responsive properties can be brought to final soft nanocomposites. The obtained soft nanocomposite was characterized by Fourier transform infrared spectrum (FT-IR), thermogravimetric (TG) analysis, and scanning electron microscopy (SEM). This biopolymer based nanogel/hydrogel used as a prolonged releasing drug carrier for levodopa (L-DOPA) as a main drug for treating Parkinson's symptoms. The in vitro release of L-DOPA was investigated at different pHs. pH-dependent release of the active drug can be sustained for >11 days from this soft nanocomposite. The results demonstrated a sustained release model that can be extended for other drugs.

Synthesis and evaluation of anti-tumor activity of novel triazolo[1,5-a] pyrimidine on cancer cells by induction of cellular apoptosis and inhibition of epithelial-to-mesenchymal transition process.

Cancer is a leading cause of human death worldwide. One of the greatest challenges in cancer therapy is the discovery and design of novel products with potential anti-tumor activities. In this study, a new protocol involves three-component condensation of the 3-amino-1,2,4-triazole as a 1,3-binucleophile, versatile aldehydes and N-methyl-1-(methylthio)-2-nitroethenamine as an enamine analogous in the presence of trichloroacetic acid as a Brønsted-Lowry acidic promoter leads to new functionalized N-alkyl-6-nitro-3,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine in moderate to good yields. The presence of five nitrogen heteroatoms in the product structure has gathered immense attention among chemists and biologists due to their biological values. Therefore, we evaluated the anti-tumor activity of our synthetic compounds on different cancer cells including human malignant melanoma cells (A375), prostate cancer cells (PC3 cells, LNCaP cells) and normal cells HDF (human dermal fibroblast). Notably, we found that compound 4b that contains a nitro group has the best anti-tumor activity on three different cancer cells. By using DAPI staining, we showed cancer cells death. Apoptosis induction was shown using quantitative real time PCR (qRT-PCR) by evaluating of Bax and Bcl2 mRNA levels. Finally, we demonstrated that 4b has epithelial-to-mesenchymal transition (EMT) inhibition effect on cancer cells (by induction of E-cadherin and reduction of vimentin mRNA expression levels as two potential EMT markers). So, 4b could be an anti-cancer promising drug. Although, in vivo experiments will be required to evaluate possible side effects.

Synthesis of new pyrimidine-containing compounds: 5-(2-(alkylamino)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione derivatives.

In this study, the one-pot reaction between primary amines, 1,1-bis-(methylthio)-2-nitroethene, ninhydrin, and barbituric acid as an enolizable C-H-activated compound provides a simple method for the preparation of 5-(2-(alkylamino)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione derivatives with potential synthetic and pharmacological interest. This reaction shows attractive characteristics, such as substrate availability, good yields, existence of numerous hydrogen-bonding possibilities in product, and its mild conditions in ethanol media.

Catalyst-free four-component domino synthetic approach toward versatile multicyclic spirooxindole pyran scaffolds.

A new versatile strategy involving a sequential four-component reaction of the nitroketene dithioacetals, alkylamine/benzylamine, isatin and various enolizable active methylene structures (pyrazolone, barbituric acid, 1,3-indandione and 2-hydroxy-1,4-naphthoquinone) as precursors under mild and catalyst-free conditions results in the synthesis of new functionalized spirooxindole pyrans named spiro[indoline-3,4'-pyrano[2,3-c]pyrazol], spiro[indoline-3,5'-pyrano[2,3-d]pyrimidine], spiro[indeno[1,2-b]pyran-4,3'-indoline] and spiro[benzo[g]chromene-4,3'-indoline] in moderate to good yields. The use of various active methylene compounds affords a range of skeletally distinct spirooxindole-based heterocycles with potential biological properties. The present strategy has many advantages, such as convenient one-pot operation, simple workup procedures and straightforward isolation without using tedious purification steps such as column chromatography, progress under catalyst-free condition and high molecular diversity.

Synthesis, characterization and energy transfer studies of fluorescent dye-labeled metal-chelating polymers anchoring pendant thiol groups for surface modification of quantum dots and investigation on their application for pH-responsive controlled release of doxorubicin.

We describe the synthesis of an end-functionalized fluorescent dye-labeled poly(N-(2-thiolethyl methacrylamide) as a metal chelating polymer with a very narrow size distribution and controllable molecular weights by reversible addition-fragmentation chain transfer polymerization. In following, we apply this water-soluble metal-chelating polymer for surface modification of cadmium telluride quantum dots (CdTe QDs) by ligand exchange method. The obtained poly(N-(2-thiolethyl methacrylamide)/CdTe QDs hybrid was fully characterized using Fourier transform infrared spectroscopy (FT-IR), thermo-gravimetric analysis (TG) and transmission electron microscopy (TEM). The size of the prepared hybrid was estimated around 3.2 nm by TEM. Furthermore, we used this hybrid for improving the release performance of doxorubicin hydrochloride as a chemotherapeutic model drug. The in vitro release of doxorubicin was studied in pH 5.4 and 7.4, which release curves were nicely fitted by the Korsemeyer-Peppas equation and the release followed by non-Fickian diffusion or anomalous diffusion in pH 5.4. The synthesized fluorescent dye-labeled hybrid can be used as a donor-acceptor pair for fluorescence resonance energy transfer (FRET) experiments, so the energy transfer behavior between fluorescent dye as a donor and CdTe QDs as an acceptor were interrogated using Förster/fluorescence resonance energy transfer model, which the distance was found to be 3.95 nm. This present work has potential for both diagnostic and therapeutic aspects for cancer patients.