Gewald Reaction Research Articles

Elaboration of newly synthesized tetrahydrobenzo[b]thiophene derivatives and exploring their antioxidant evaluation, molecular docking, and DFT studies

Herein, 2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (1) was synthesized in excellent yield through gewald reaction in multi components one pot reaction. Compound 1 was utilized as a building block to synthesize a new group of tetrahydro benzo[b] thiophene congeners. The chemical structure of all the novel tetrahydro benzo[b]thiophene derivatives were elucidated through the melting point, elemental analysis, FT-IR, 1H-NMR, and mass spectroscopy. Furthermore, the total antioxidant capacity (TAC) of all the newly synthesized heterocyclic derivatives was evaluated according to the phosphomolybdenum method using ascorbic acid as standard. The findings revealed that compounds 1, 16, and 17 demonstrated significant antioxidant potency comparable to that of ascorbic acid. This suggests the potential of these heterocycles as promising candidates for antioxidant drugs in the treatment of oxidative stress-related diseases. Finally, molecular docking was conducted to study the binding affinity for the most potent antioxidant compounds 1, 16, 17 and ascorbic acid inside the interactions of compounds 1, 16, and 17 with the Keap1 (Kelch-like ECH-associated protein 1) protein (PDB: 7C5E), compared to the co-crystallized ligand triethylene glycol (PGE) and ascorbic acid as a reference drug for antioxidants. DFT calculations and global descriptors were calculated for the most potent compounds to correlate the relation between chemical structure and reactivity.

Exploring Thiophene Derivatives: Synthesis Strategies and Biological Significance

Objectives: Thiophene is one of the most important heterocyclic scaffolds with notable pharmacological properties. Thiophene and its derivatives are of particular interest among sulphurcontaining heterocycles because of their similarities to numerous natural and synthetic compounds with identified potential. The purpose of this study is to extensively analyse the synthetic pathways adopted for synthesising thiophene derivatives and investigate their various biological functions. Methods: A comprehensive review of the existing literature was conducted to collect data pertaining to the methods that are employed for the synthesis of thiophene derivatives. A comprehensive search was carried out through relevant databases, including work published in 2024. A variety of synthesis procedures were identified and arranged, encompassing both traditional approaches like the Gewald reaction and contemporary ones like microwave-assisted synthesis and green synthesis. In addition, a comprehensive compilation of in vitro and in vivo studies was conducted to investigate the biological effects of 50 distinct thiophene derivatives. The primary focus of the studies was on various activities such as anti-cancer, anti-inflammatory, antiprotozoal, antibacterial, antioxidant, and antiviral functions. Results: Diverse methodologies have been employed in the synthesis of thiophene derivatives, encompassing both conventional and modern methods. Furthermore, the biological potential of thiophene derivatives was investigated, demonstrating a broad range of actions. Key structural elements necessary for biological activity were clarified by investigations of the structure-activity relationship. Conclusion: The biological potential and flexible synthesis pathways of thiophene derivatives make them attractive candidates for use in medicinal and pharmaceutical chemistry. Understanding the different synthesis methods and biological actions of thiophene derivatives may assist rational design and create novel treatments for a variety of conditions. The potential for these compounds to be further explored and optimised is considerable for the next drug development initiatives.

Mechanisms of the Gewald Synthesis of 2-Aminothiophenes from Elemental Sulfur.

The Gewald reaction is a well-established one-pot method to access 2-aminothiophenes from carbonyl compounds, activated acetonitriles, and elemental sulfur. To elucidate the reaction's poorly understood mechanism, with regard to the decomposition of sulfur and polysulfide intermediates, we have performed a comprehensive computational study using density functional theory (DFT) calculations at the M06-2X (or ωB97X-D)/aug-cc-pV(T + d)Z/SMD(C2H5OH) level of theory. The results show that the reaction is initiated by a Knoevenagel-Cope condensation, followed by opening of the elemental sulfur, leading to polysulfide formation. The polysulfide intermediates can interconvert and decompose using various mechanisms including unimolecular cyclization, nucleophilic degradation, and scrambling. Protonation of the polysulfides changes their electrophilic behavior and provides a kinetically favorable pathway for their decomposition. This protonation-induced intermolecular degradation is feasible for polysulfides of all lengths, but unimolecular decomposition is kinetically favored for long polysulfides (≥6 sulfur atoms). None of the pathways provide any thermodynamic benefit due to the lack of resonance-stabilized leaving group, and a complex equilibrium of polysulfides of all lengths is expected in solution. Cyclization of the monosulfide with aromatization to the thiophene product is the only driving force behind the reaction, funneling all of the various intermediates into the observed product in a thermodynamically controlled process.

Pharmacophore-based, rationale design, and efficient synthesis of novel tetrahydrobenzo[b]thiophene candidates as potential dual Topo I/II inhibitors and DNA intercalators.

A series of tetrahydrobenzo[b]thiophene derivatives was designed and synthesized as dual topoisomerase (Topo) I/II inhibitors implicating potential DNA intercalation. Ethyl-2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carboxylate (1) was prepared by modification of the Gewald reaction procedure using a Fe2O3 nanocatalyst and then it was used as a building block for the synthesis of tetrahydrobenzo[b]thiophene candidates (2-14). Interestingly, compound 14 showed the best cytotoxic potential against hepatocellular, colorectal, and breast cancer cell lines (IC50 = 7.79, 8.10, and 3.53 µM), respectively, surpassing doxorubicin at breast cancer (IC50 = 4.17 µM). Meanwhile, the Topo I and II inhibition assay displayed that compound 3 could exhibit the best inhibitory potential among the investigated candidates (IC50 = 25.26 and 10.01 nM), respectively, in comparison to camptothecin (IC50 = 28.34 nM) and doxorubicin (IC50 = 11.01 nM), as reference standards. In addition, the DNA intercalation assay showed that compound 14 could display the best binding affinity with an IC50 value of 77.82 µM in comparison to doxorubicin (IC50 = 58.03 µM). Furthermore, cell cycle and apoptosis analyses described that compound 3 prompts the G1 phase arrest in michigan cancer foundation-7 cancer cells and increases the apoptosis ratio by 29.31% with respect to untreated cells (2.25%). Additionally, the conducted molecular docking assured the promising binding of the investigated members toward Topo I and II with potential DNA intercalation. Accordingly, the synthesized compounds could be treated as promising anticancer candidates for future optimization.

Synthesis, Biological Evaluation, and Docking Study of a New Series of Thiophene Derivatives Based on 3‐Oxobutanamidothiophene as an Anticancer Agent

AbstractHerein, the constructing synthon 3‐oxobutanamidothiophene derivatives 2 a and 2 b were synthesized and utilized for building a wide variety of pyran, thiazole, pyrazole or pyrimidine ring heterocyclic compounds that can be used as anticancer medications. 3‐Oxobutanamidothiophene derivatives 2 a,b were coupled with 4‐substitutedphenyl diazonium chloride to produce the corresponding hydrazones derivatives 3 a–f. Various thiophene‐pyran derivatives 4 a,b were synthesized through the treatment of thiophene components 2 a,b with different arylidene‐malononitrile. 2‐Aminothiophene derivatives 5 were prepared via Gewald's reaction between 2 a,b, elemental sulfur, and various activated nitrile derivatives. The 3‐oxobutanamidothiophene derivatives 2 a,b were reacted with PhNCS and the potassium salt intermediates 6 a,b with ethyl bromoacetate to pick up the corresponding thiophene‐thiazolidin‐4‐one derivatives 7. Treatment of the conforming thiocarbamoyl compounds 8 a,b, which undergo heating with three types of α‐halogenated reagents to afford the corresponding substitutedthiophene‐3‐carboxamides 9 a,b. Condensation of keteneN,S‐acetals 10 a,b with hydrazines furnished the thiophene‐pyrazole‐4‐carboxamide hybrids 11 a,b, while condensation with urea and/or thiourea afforded the corresponding thiophene‐pyrimidine‐5‐carboxamides 12 a,b. The recently synthesized thiophene compounds were characterized there in vitro anticancer properties against HepG2 (hepatocellular carcinoma) and MDA‐MB‐231 (breast cancer) were evaluated. Molecular docking was also performed to predict the binding modes of synthesized derivatives with the good anticancer results designed as potential inhibitors for a specific target.

Thiophene-based lipids for mRNA delivery to pulmonary and retinal tissues

Lipid nanoparticles (LNPs) largely rely on ionizable lipids to yield successful nucleic acid delivery via electrostatic disruption of the endosomal membrane. Here, we report the identification and evaluation of ionizable lipids containing a thiophene moiety (Thio-lipids). The Thio-lipids can be readily synthesized via the Gewald reaction, allowing for modular lipid design with functional constituents at various positions of the thiophene ring. Through the rational design of ionizable lipid structure, we prepared 47 Thio-lipids and identified some structural criteria required in Thio-lipids for efficient mRNA (messenger RNA) encapsulation and delivery in vitro and in vivo. Notably, none of the tested lipids have a pH-response profile like traditional ionizable lipids, potentially due to the electron delocalization in the thiophene core. Placement of the tails and localization of the ionizable headgroup in the thiophene core can endow the nanoparticles with the capability to reach various tissues. Using high-throughput formulation and barcoding techniques, we optimized the formulations to select two top lipids-20b and 29d-and investigated their biodistribution in mice. Lipid 20b enabled LNPs to transfect the liver and spleen, and 29d LNP transfected the lung and spleen. Unexpectedly, LNP with lipid 20b was especially potent in mRNA delivery to the retina with no acute toxicity, leading to the successful delivery to the photoreceptors and retinal pigment epithelium in non-human primates.

Recent advancement in the synthesis of quinoline derivatives via multicomponent reactions.

The synthesis of quinoline derivatives through multicomponent reactions (MCRs) has emerged as an efficient and versatile strategy in organic synthesis. MCRs offer the advantage of constructing complex molecular architectures in a single step, utilising multiple starting materials in a convergent manner. This review provides an overview of recent advancements in the field of quinoline synthesis via MCRs. Various MCRs, such as the Povarov reaction, the Gewald reaction, and the Ugi reaction have been successfully employed for the synthesis of diverse quinoline scaffolds. These methodologies not only showcase high atom economy but also allow the incorporation of structural diversity into the final products. The versatility of MCRs enables the introduction of functional groups and substitution patterns tailored to specific applications. This review highlights the significance of quinoline derivatives in medicinal chemistry, materials science, and other interdisciplinary areas. The continuous innovation and development of novel MCR-based approaches for quinoline synthesis hold great promise for the rapid and efficient generation of valuable compounds with a wide range of biological and physicochemical properties.

Catalytic and anti-cancer properties of platinum, gold, silver, and bimetallic Au-Ag nanoparticles synthesized by Bacillus sp. bacteria

Metallic nanoparticles play a significant role in the catalysis of chemical processes, besides, bimetallic nanoparticles with abundant active sites can reduce metallic nanoparticles toxicity in addition to increasing their catalytic performances. In this work, the platinum, gold, and silver nanoparticles are bio-synthesized using a native bacterium (GFCr-4). Also, the Au-Ag and Au@Ag bimetallic nanoparticles with alloy and core-shell structures, respectively, are biologically synthesized. To improve the synthesis, the effects of various factors like pH, temperature, electron donor, and ionic liquids were investigated. The as-synthesized nanoparticles were characterized with different techniques. The microscope images and dynamic light scattering (DLS) analysis confirm the uniform distribution of as-synthesized nanoparticles with average sizes of 25, 30, 47, 77, and 86 nm obtained for Ag, Au, Pt, Au-Ag alloy, and Au@Ag core-shell, respectively. The catalytic performances of as-synthesized nanoparticles were investigated. The Au-Ag alloy nanoparticles exhibit better catalytic performance than the as-synthesized metallic Au nanoparticles, according to the Gewald reaction. According to the photocatalytic study, the yield can be increased by up to 92% by using PtNPs in the presence of a green LED. Additionally, for the first time, PtNPs were utilized as an effective catalyst in a peroxyoxalate chemiluminescence (POCL) system in the presence of nuclear fast red (NFR) as a novel fluorophore. In addition, the results of the MTT (3-[4,5-dimethylthiazol-2-yl]−2,5 diphenyl tetrazolium bromide) assay revealed that the synthesized eco-friendly nanoparticles have a low effect on the lethality of 3T3 normal cells whereas MCF-7 cancer cells were inhibited up to 77.3% after treatment by PtNPs nanoparticles.

Truly Catalytic Gewald Synthesis of 2-Aminothiophenes Using Piperidinium Borate (Pip Borate), a Conjugate Acid–Base Pair

AbstractThe Gewald reaction has been well-known for more than half a century as an excellent method to provide bioactive 2-aminothiophene heterocycles from the reaction of carbonyl compounds, α-cyanoacetates, and elemental sulfur, in the presence of amines, in stoichiometric amounts. This work describes the use of salts of boric acid as conjugate acid-base pairs in a truly catalytic amount for the cyclocondensation of ketones with active methylenes such as malononitrile, ethyl cyanoacetate, and benzoyl acetonitrile with sulfur to give 2-aminothiophenes via the Gewald reaction. The present protocol is also applied for synthesizing Tinoridine, an anti-peroxidative NSAID, with excellent yield. Additionally, the catalyst has great recyclability and reusability.

Synthesis of biologically active xanthene, chromene, thiazole, thiophene, pyrazole, and isoxazole derivatives from camphor

ABSTRACT. Xanthene, chromene, thiazole, thiophene, pyrazole, and isoxazole derivatives were synthesized from camphor-D monoterpene using multi-component reactions. Camphor has anti-bacterial, anti-fungal and anti-inflammatory properties. It is also used to mitigate pain, treat skin diseases, and improve respiratory functions. In this research, we focus on the effectiveness of the produced compounds from the biologically active camphor. The produced compounds were formed according to various reactions such as a Knoevenagel condensation, Michael adduct, Gewald reaction, a nucleophilic attack, substitution, addition, elimination and cyclization reactions. Furthermore, the novel produced compounds have been tested towards the six cancer cell lines namely A549, MKN-45, U87MG, HT-29, H460 and SMMC-772. Compounds 5, 11, 15b, 16, 25b and 27b displayed the highest inhibitions compounds toward the mentioned cancer cell lines. In addition, compounds 3, 13, 15a, 22a, 27a and 28 showed moderate inhibitory effects against the cancer cell lines.
 KEY WORDS: Camphor, Xanthenes, Pyrimidine, Heterocyclic, Anti-cancer
 Bull. Chem. Soc. Ethiop. 2023, 37(6), 1539-1552. DOI: https://dx.doi.org/10.4314/bcse.v37i6.18

Synthesis of Pyridine Clubbed Tetrahydrobenzo[b]thiophene Azo Dye Analogues Using the Gewald Reaction: Catalytic Optimization, Antibacterial, and Dye Investigation

Synthesis of Pyridine Clubbed Tetrahydrobenzo[b]thiophene Azo Dye Analogues Using the Gewald Reaction: Catalytic Optimization, Antibacterial, and Dye Investigation

An efficient synthesis of 2-aminothiophenes via the Gewald reaction catalyzed by enzymes in ionic liquids

A green and efficient alkali protease lipase-ionic liquids system has been developed to catalyze the Gewald reaction between 2,5-dihydroxy-1,4-dithiane and different substituted activated nitriles. A series of 3-substituted 2-aminothiophenes were synthesized with moderate to good yields (67.8–97.4%) at 50 °C. Notable, a good recycling experiment was observed that the catalytic system was cycled 10 times without any loss in yield. Combined with the recycling results, the stability of the lipase-ionic liquids system and the practicability of the protocol were proved.

Discovery of tetrasubstituted thiophenes as Cisd2 activators: A potential novel therapeutic option in nonalcoholic fatty liver disease

Down-regulation of Cisd2 in the liver has been implicated in the development of nonalcoholic fatty liver disease (NAFLD) and increasing the level of Cisd2 is therefore a potential therapeutic approach to this group of diseases. Herein, we describe the design, synthesis, and biological evaluation of a series of Cisd2 activators, all thiophene analogs, based on a hit obtained using two-stage screening and prepared via either the Gewald reaction or by intramolecular aldol-type condensation of an N,S-acetal. Metabolic stability studies of the resulting potent Cisd2 activators suggest that thiophenes 4q and 6 are suitable for in vivo studies. The results from studies on 4q-treated and 6-treated Cisd2hKO-het mice, which carry a heterozygous hepatocyte-specific Cisd2 knockout, confirm that (1) there is a correlation between Cisd2 levels and NAFLD and (2) these compounds have the ability to prevent, without detectable toxicity, the development and progression of NAFLD.

T3P® facilitated one pot multicomponent reaction comprising unique intra-molecular rearrangement

Present work describes the T3P® mediated one pot four component reaction between 2-aminoacetamide, methylene-active carbonyl compounds, S8 and isothiocyantes in synthesizing 1-(3-cyanothiophen-2-yl)-3-phenylureas. The strategy developed here comprises Gewald reaction followed by the T3P intervened unique intra-molecular rearrangement. The novel and eco-friendly route achieved here is operationally facile and offers versatile 1-(3-cyanothiophen-2-yl)-3-phenylureas, which are expected to show good biological activities.

Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents.

A series of eleven 4-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines were designed and synthesized and their biological activities were evaluated. Synthesis involved the Gewald reaction to synthesize ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate ring, and SNAr reactions. Compound 4 was 1.6- and ~7-fold more potent than the lead compound 1 in cell proliferation and microtubule depolymerization assays, respectively. Compounds 4, 5 and 7 showed the most potent antiproliferative effects (IC50 values < 40 nM), while compounds 6, 8, 10, 12 and 13 had lower antiproliferative potencies (IC50 values of 53–125 nM). Additionally, compounds 4–8, 10 and 12–13 circumvented Pgp and βIII-tubulin mediated drug resistance, mechanisms that diminish the clinical efficacy of paclitaxel (PTX). In the NCI-60 cell line panel, compound 4 exhibited an average GI50 of ~10 nM in the 40 most sensitive cell lines. Compound 4 demonstrated statistically significant antitumor effects in a murine MDA-MB-435 xenograft model.

Cs-containing hierarchical zeolites as catalysts for Gewald reaction

Catalytic activity of Cs-ion-exchange form of aluminosilicate zeolites with MOR and BEA topology with the morphology of aggregated nanosheets, nanorods, or close to spherical nanoparticles was evaluated in Gewald reaction using cyclic ketones, malonodinitrile and sulphur. It was shown that morphology and zeolite topology significantly influenced on amount of Cs- incorporated into ion-exchange positions of hierarchical zeolites and consequently its catalytic activity in Gevald reaction including cyclic ketones, especially for BEA zeolites.

Base-Catalyzed Three-Component Reaction of α-Cyanoacetates with Chalcones and Elemental Sulfur: Access to 2-Aminothiophenes Unobtainable via the Gewald Reaction

Although the Gewald reaction was well-known for more than half a century as an excellent method providing bioactive 2-aminothiophenes from reactions of α-cyanoacetates and carbonyl compounds and elemental sulfur, its application to dibenzoylmethanes as the carbonyl substrates was, however, unknown and experimentally proven unsuccessful. We propose here a convenient approach to such a series of compounds by a DABCO-catalyzed, one-pot, two-step, three-component reaction of α-cyanoacetate with chalcones and elemental sulfur. This catalytic strategy is highlighted by its excellent atom/step efficiency and high degree of structural diversification by simply choosing the suitable starting chalcones, which are unarguably much more readily available than dibenzoylmethanes.

Cytotoxic and apoptotic potential of some coumarin and 2-amino-3-carbonitrile selenophene derivatives in prostate cancer.

3-acetyl coumarin derivatives (1a-d) are formed as a result of condensation of salicylaldehyde derivatives and ethyl acetoacetate and were converted into coumarin-selenophene hybrid compounds (2a-d) in the basic medium by modified Gewald reaction in the presence of malononitrile and selenium. Products are characterized by nuclear magnetic resonance (NMR). The prepared compounds are screened for their anticancer activity against DU-145 cell line. In addition, selected target compounds are evaluated for apoptosis and oxidative stress on DU-145 (prostate carcinoma) cell lines.

Synthesis of novel 3-(1,2,4-oxadiazol-5-yl)thiophen-2-amine derivatives via gewald reaction

Novel substituted 3-(1,2,4-oxadiazol-5-yl)thiophen-2-amines were obtained by the multicomponent Gewald reaction of an activated nitrile with 1,2,4-oxadiazole moiety, a carbonyl component and elemental sulphur in the presence of morpholine as a catalyst. Keywords : 2-aminothiophenes, 1,2,4-oxadiazole, Gewald reaction, multicomponent reaction.

Microwave-Assisted Synthesis of 2-Aminothiophene Derivatives via Improved Gewald Reactions

Microwave-Assisted Synthesis of 2-Aminothiophene Derivatives via Improved Gewald Reactions