Current Organic Chemistry - Online First

Nickel-metallaphotoredox catalysis has emerged as a groundbreaking approach in organic synthesis research over the last decade. It integrates the accessibility of the redox states of inexpensive, earth-abundant nickel to capture carbon-centred radicals with the ability of photoredox catalysts (PCs) to mediate single-electron transfer (SET) or energy transfer (ET) for efficient, selective, and sustainable transformations. Advances in catalyst design, reaction optimization, and mechanistic understanding have unlocked a wide range of cross-coupling protocols, enabling previously inaccessible or less efficient C-C bond formations. This progress opens new possibilities for innovative applications in pharmaceuticals, materials science, and beyond. This mini-review focuses on advancements in the last three years in the formation of challenging C(sp³)-C(sp³) and C(sp³)-C(sp²) bonds, both in two-component and three-component systems, featuring a broad substrate scope, with chemo-, regio-, and stereo-selectivity under mild conditions. Although mechanistic studies have been conducted for some systems, and kinetic isotope effects have been probed for others, detailed investigations using computational methods to understand the molecular interactions are lacking or sometimes fail to indicate a general trend of the catalytic mechanism. The discovery of novel approaches to open-shell radical species, which dictate reactivity and selectivity, will be of utmost importance in developing new reactions. These advances will enrich all areas of chemical sciences and create numerous opportunities for interdisciplinary research.

Many parasitic diseases elicit significant immune responses, although these responses can sometimes be excessive or dysregulated, contributing to immunopathology. Moreover, the emergence of parasite clones and gene mutations has led to clinical resistance to widely used antiparasitic drugs, resulting in treatment failures and reduced drug efficacy. Consequently, there is an urgent need for new and alternative antiprotozoal therapies, including the enhancement of existing drug structures. Triazole-based compounds, known for their excellent pharmacological profiles, have shown promise in treating a variety of parasitic infections. The combination of triazoles with other nitrogen/oxygen/sulfur-based heterocyclic compounds presents a promising strategy for the effective clinical management of parasitic diseases. This review highlights recent advancements in the development of triazole hybrids and their structure-activity relationships, providing valuable insights for the design of more potent antiparasitic drugs.

Chisocheton is a genus of woody trees in the family Meliaceae. Due to the appearance of numerous bioactive compounds, it was widely used in traditional medicines. The current research aims to provide an extensive overview of phytochemical and pharmacological values. To find the English references, a thorough search of numerous electronic data sources, such as Web of Science, PubMed, Google Scholar, and Science Direct, was conducted. The “Sci-Finder” was used to confirm chemical structures and references. Documents that have been cited date back to the 1970s. The best keywords for the collection of articles are “Chisocheton”, “phytochemistry”, and “pharmacology”. Phytochemical investigations of Chisocheton extracts led to the separation of more than 270 secondary metabolites. They included limonoids, triterpenoids, sesquiterpenoids, phytosterols, chirol-inositols, flavonoids, and others. Various compounds were new in the literature. Chisocheton constituents possessed various pharmacological activities, including cytotoxicity, anti-inflammatory, antioxidative, antidiabetic, anti-obesity, antibacterial, antimalarial, tyrosinase inhibitory, mosquito larvicidal, and neuroprotective activities. Some compounds are better than standard agents in biological experiments. Apoptosis is the main pathway of Chisocheton anticancer compounds, whereas cytokine inhibition may be attributed to their anti-inflammatory actions. The studied genus Chisocheton is a good source of limonoids, terpenoids, and phytosterols with various pharmacological potentials.

Triazine compounds have become crucial entities in the pharmaceutical field due to their remarkable structural diversity and wide range of biological activities. This review explores their prominent role in drug discovery and development, focusing on their efficacy as potent anticancer, antiviral, antimicrobial, and antioxidant agents. Recent advances in synthetic methodologies using various starting materials, such as nitrile, biguanide, bromoester, arylamine, and cyanide chloride, are reviewed, along with their implications for improved pharmacological properties, including anticancer, antibacterial, antioxidant, anti-inflammatory, and antimicrobial effects. In addition, the structure-activity relationship of triazine derivatives is explored, offering insight into the key structural features that contribute to their therapeutic potential. This relationship plays an essential role in optimizing their efficacy as therapeutic agents, helping to guide the development of more effective drugs with improved pharmacological profiles.

Alarming data on the neglected tropical disease leishmaniasis, especially for global visceral cases, have motivated the development of novel drugs to overcome the emergence of resistance. In this context, quinoline derivatives, especially quinoline-4-carboxylic acids, have shown promising antileishmanial activity. More recently, acetanilide linked quinoline derivatives revealed selective antileishmanial activity. Now, we are motivated to investigate the influence of the substituent group on antileishmanial and toxicity properties of sixteen 2-acetanilide 2-arylquinoline-4-carboxylates. To this end, the precursors, 2-arylquinoline-4-carboxylic acids, prepared from isatin through the Pfitzinger reaction, and 2-chloroacetanilides were used in an alkylation reaction to obtain the final products (5e-t) in yields of 40-88%. Next, 2-acetanilide 2-arylquinoline-4-carboxylates (5e-t) had their in silico/vitro activity evaluated against Leishmania infantum promastigotes. From the MolPredictX program, all compounds were predicted to be active, and only four halogenated compounds (5k, 5n, 5o, 5r) were active by in vitro assays, with the best result for the compound 5n (R/R’ = Br/Cl), IC50 = 17.08 ± 1.09 µM. From the pkCSM program, these compounds were predicted as non-mutagenic, hepatotoxic, and highly cytotoxic on Flathead Minnows. On the other hand, compounds showed moderate ecotoxicity on Artemia salina, with IC50 = 256-297 µg.mL^-1. Finally, in contrast of Amphotericin B which caused relevant erythrocyte lysis starting from 50 μM, none of the compounds showed hemolytic activity. Furthermore, compounds were more selective against L. infantum promastigotes than against human erythrocytes, with a selectivity index (HC50/IC50) > 15.63, which demonstrates a promising therapeutic window for 2-acetanilide 2-arylquinoline-4-carboxylates.

The alarming rise in life-threatening infections caused by Gram-positive and Gram-negative bacteria has become a significant global health concern, urging the scientific community to explore new therapeutic solutions. Among heterocyclic compounds, the quinoline nucleus has emerged as a versatile scaffold with diverse pharmacological properties. Naturally occurring quinoline-based compounds provide a foundation for designing novel semi-synthetic and synthetic derivatives with broad-spectrum antibacterial activity. Quinoline-fused derivatives have shown potent anticancer effects by targeting critical enzymes and proteins, including topoisomerase I, telomerase, farnesyl transferase, Src tyrosine kinase, and protein kinase CK-II. Additionally, these compounds exhibit antitubercular, anticonvulsant, analgesic, and anti-inflammatory activities. Their potential as cardiovascular agents, acting as calcium-channel blockers and cAMP phosphodiesterase III inhibitors, further highlights their pharmacological significance. The fusion of quinoline with other heterocyclic systems such as indoles, pyridines, triazoles, imidazoles, and pyrazoles presents a promising strategy for drug discovery. Such combinations leverage the individual activities of each moiety, producing synergistic effects and enhancing therapeutic potential. These advances underscore the need for continued exploration of quinoline derivatives to identify novel lead compounds with improved efficacy and broadened activity spectra. This paradigm not only offers a pathway to address pressing antimicrobial resistance but also opens new opportunities for synthetic chemistry and the development of multifunctional therapeutic agents.

Quinoxaline and indoline-2,3-dione, as heterocyclic scaffolds, provide significant features as crucial components for material science and the construction of new pharmacological drugs. Several interesting biological and technical characteristics have been established by their combination in indolo[2,3-b]quinoxaline (IQs) moieties. The synthesis, therapeutic chemistry, and technical application of indolo[2,3-b]quinoxalin ring systems (IQs) have been the focus of numerous studies of research in recent years. This review presents the synthesis of these derivatives by the condensation of aryl-1,2-diamines with indoline-2,3-diones (isatins) in boiling acetic acid or through microwave-assisted approaches. Additionally, the review highlights the usage of IQs in several electronic applications, including organic transistors, deep-red OLEDs, electron-transporting layers, chemical sensors, and emitting layers. These synthetic approaches and technical usage of IQs enable the efficient building of these scaffolds, accelerating further discovery and examination of their medicinal and technical potential.

Indane-1,3-dione is a reactive cyclic β-diketone that could be employed for preparing various molecular systems of potential biological applications. Among these, 4-azafluorenones (also known as indeno[1,2-b]pyridines) represent one of the most promising classes of carbocyclic systems. Indeno-fused pyridines possess a wide range of medicinal properties, including anti-proliferative activity and DNA topoisomerase Iα/Iiα inhibitory activity. In this review, we presented all reports from 2000 to 2024 that cover the synthesis of indeno[1,2-b]pyridines and diindeno[1,2-b:2',1'-e]pyridines starting from indane-1,3-dione. The review is classified according to the type of reaction conditions that were applied. Additionally, the reports that are related to the new trends in preparing indenopyridines are indexed in separate sections, including the use of ionic liquids, heterogeneous catalysts, and microwave- and ultrasonic-assisted synthetic routes. Some complex synthetic routes are explained by plausible mechanisms.

The use of micelles enables the resolution of a number of problems associated with the aggregation and reduction in photocatalytic activity of porphyrins. The formation of transport systems is impossible without information on the localization of porphyrins containing hydrophilic and hydrophobic parts in highly organized systems, such as liposomes or model systems–micelles. To solve the above issues, 5,10,15,20-tetra(3ʹ,4ʹ-dihydroxyphenyl)porphin (Por(OH)8), 5-(3ʹ,4ʹ-dihydroxyphenyl)-10,15,20-triphenylporphin (Por(OH)2), and 5-(3ʹ,4ʹ-dihydroxyphenyl)-10,15,20-tri(pyridinium-3ʹ-yl)porphine (PorN (OH)2) were synthesized, and their state was studied in aqueous media in the presence of an anionic surfactant in the premicellar region. It was found that the porphyrins are sedimentation-stable in the premicellar region, while in the micellar region, Por(OH)2 and PorN(OH)2 are localized inside SDS micelles. However, the peripheral substituents of PorN(OH)2 are oriented toward the “head” of the surfactant. Por(OH)8 is the worst isolated from water molecules of all the studied porphyrins, and can be located both on the surface and inside the micelle, orienting the OH groups toward the surface of the micelle, or the channels inside it. The results obtained can be used to design transport systems for the delivery of hydroxy-substituted porphyrin photosensitizers.

Phenyltrichlorosilane is an important organosilicon compound, and its synthesis technology is a key research focus in the field of organosilicon chemistry. This article introduces the three main techniques for synthesizing phenyltrichlorosilane: the Grignard reagent method, the direct method, and the vapor phase condensation method, along with their respective advantages and disadvantages. It demonstrates that the vapor phase condensation method has become the dominant process due to its simple reaction apparatus and the feasibility of achieving continuous production. However, this method faces significant challenges, including low yield and the formation of carbon deposits within production pipelines. The process conditions of the vapor phase condensation method are summarized, including the reaction conditions of chlorobenzene and trichlorosilane at 540-680°C, which achieves a product yield of up to 65%. This study provides an in-depth analysis of the decomposition mechanism of trichlorosilane and chlorobenzene under high-temperature vapor-phase conditions, emphasizing the synthesis mechanism of phenyltrichlorosilane and analyzing the role of free radical initiators and their impact on enhancing the yield of phenyltrichlorosilane. Future research should focus on the development of new catalysts and initiators, process optimization, and the expansion of phenyltrichlorosilane's application fields.

Thiocrown ethers, thiocalixarenes, and thiocyclodextrins, as important host macrocycles, have been synthesized as crown ether, calixarene, and cyclodextrin derivatives, respectively. They have shown special properties compared with their prototypes. Hemicucurbiturils, as a subset of cucurbiturils, are yet to have their thio-derivatives. In this article, methods for the synthesis of hybrid thiohemicucurbiturils were proposed, and several hybrid thiohemicucurbiturils were formed. The mono ethylene thiourea-substituted hemicucurbituril was formed by simply mixing ethylene thiourea and ethylene urea with formaldehyde in an HCl aqueous solution. The synthesis of more ethylene thioureas-substituted hemicucurbituril by acid-catalyzed conversion of an ethylene thiourea-substituted hemicucurbituril has been presented, which differs from the traditional method for synthesizing hemicucurbituril derivatives. These methods provide alternatives for the synthesis of novel hybrid hemicucurbiturils with more complex structures.

Heterocyclic rings containing heteroatoms at the 1,4-position and fused to a benzene ring are essential in medicinal chemistry due to their wide range of therapeutic and biological properties. Among them, 1,4-benzoxazine derivatives are distinguished by their heterocyclic structure, characterized by the fusion of a benzene ring with an oxazine ring with oxygen and nitrogen atoms in 1,4-positions. The latter heterocyclic motif gives these compounds great versatility, improving their chemical stability and promoting specific interactions with various biological targets. These compounds possess various pharmacological properties, including antifungal, antistrophic, antihypertensive, anti-Parkinson, anti-Alzheimer, anti-Huntington, antibacterial, and antirheumatic activities. Various synthetic methods have been developed to obtain 1,4-benzoxazine derivatives. These methods typically involve the condensation of 2-aminophenol with α(β)-dicarbonyl and α-halocarbonyl compounds, alkyl 2-halomalonates, and diethyl fumarate. This review focuses on synthetic approaches and methods used to synthesize 1,4-benzoxazine derivatives. It examines a range of proven pharmacological applications of these derivatives described in the literature from 1960 to 2024. The aim is to provide valuable insights for medicinal and organic chemistry researchers, offering guidance on developing and designing novel 1,4-benzoxazine derivatives.

In this study, a series of 2-amino-4-(substituted phenyl)-5,6,7,8-tetrahydroquinoline -3-carbonitrile derivatives (IVa-j) was synthesized using a one-pot process. The titled compounds were successfully synthesized by employing aromatic aldehydes with satisfactory yields. Docking studies were directed to explore the DNA-binding interactions of the synthesized compounds. These studies involved docking the compounds with B-DNA (PDB ID: 1BNA) to investigate the preferred binding sites, interaction modes, and binding affinities.