Current Organic Chemistry - Online First

The increasing threat of antimicrobial resistance (AMR) has driven the need for novel antibacterial agents. Conjugating antibiotics with siderophores may expand their spectrum of activity or enhance their efficacy against AMR strains. In this study, we developed a synthetic route for azithromycin derivatives bound with siderophore moieties containing one or two 2,3-dihydroxybenzamide residues, yielding two series of hybrid molecules (5a-b, 6a-b, 7a-b, and 8a-b, 9a-b, 10a-b). Derivatives 5a, 6a-b, and 7a-b, which bear a single siderophore fragment, exhibited MIC values comparable to those of azithromycin against the majority of tested pathogens. Notably, compounds 7a-b demonstrated increased activity under iron-deficient conditions against Gram-negative Pseudomonas aeruginosa and Escherichia coli strains. In contrast, azotochelin-containing conjugates (9a-b and 10a-b) were found to be completely inactive. Although the introduction of a siderophore did not significantly enhance the potency of macrolides in this study, further optimization of the conjugation strategy, linker structure, or chelating moieties may lead to more effective siderophore-macrolide antibiotics.

The Biginelli Reaction stands out as a highly versatile one-pot cyclocondensation process that effectively combines β-keto esters, urea, and aromatic aldehydes in the presence of a catalyst. This powerful reaction yields various 3,4-dihydro-2(H)-pyrimidinones (DHPMs), known for their significant pharmacological applications in synthetic and natural forms. In recent years, this reaction has been expertly refined to improve efficiency and reduce environmental impact. By employing a range of catalysts and green solvents, such as water, researchers achieve high yields of DHPMs in an environmentally friendly manner. In this review, we have thoroughly explored the literature on Biginelli reactions carried out under aqueous conditions, utilizing various reaction promoters, including catalysts, polymers, and enzymes, all in an eco-conscious way. The article encompasses the advantages of the use of ‘in water’ synthesis in various facets and highlights a sustainable pathway for the Biginelli reaction, facilitating the efficient synthesis of bioactive compounds while prioritizing environmental preservation.

Plants can produce a wide range of bioactive compounds. High concentrations of phytochemicals prevent the accumulation of free radical damage in fruits and vegetables. Flavonoids a group of natural products with different phenolic structures are found in fruits, vegetables, grains, bark, roots, stems, flowers, tea, and wine. These natural products are known for their health benefits, and thus efforts are being made to isolate these flavonoids. Flavonoids are now recognised as important components of many nutraceutical, medical, pharmaceutical, and cosmetic products. This is attributed to their antioxidant, anti-inflammatory, anti-mutagenic, and anti-cancer properties and their ability to alter the activity of important cellular enzymes. Information about how flavonoids work is still not fully understood. However, it has been widely known that plant-derived derivatives have had many biological activities for centuries. Current flavonoid research and development trends include the isolation, identification, characterisation, and activity of flavonoids and their potential health benefits. Bioinformatics information is also used to estimate economic potential and productivity. This article discusses current research, mechanisms of action, functions, and uses of flavonoids, predictions of flavonoids as potential anti-inflammatory agents, and future recommendations. Due to the antioxidant, anti-proliferative, anti-tumour, anti-microbial, estrogenic, acetylcholinesterase, and anti-inflammatory activities of flavonoids they are also used as therapeutics in cancer, cardiovascular diseases, neurodegenerative diseases, and other diseases. It also covers the mechanism of action of flavonoids, which highlights the role of flavonoids as kinase inhibitors and their effect on membrane-bound receptors. Tyrosinase is involved in several human pigmentation-related diseases, among which hyperpigmentation can be treated by using flavonoid-based drugs as tyrosinase inhibitors. This review will provide researchers in the discipline of medicinal chemistry with the opportunity to develop options, improve quality, and use various flavonoid derivatives and their conjugates as therapeutics and in the treatment of various diseases.

MurB is an enzyme that is crucial to the survival of bacterial strains. Recently, considerable interest has been generated in developing new antibacterial agents that effectively inhibit MurB. We synthesized herein new thiazolone-based Schiff bases derived from salicylaldehydes in good yields. The appropriate thiosemicarbazones were prepared and then reacted with a variety of hydrazonyl chlorides in dioxane. The reaction was mediated using an equimolar amount of triethylamine. The new Schiff bases were tested against six different ATCC bacterial strains with the reference ciprofloxacin. Generally, Schiff bases 2a-2f linked to 5-((4-chlorophenyl)thio)methyl units outperformed their analogues 1a-1f linked to 5-(phenylthio)methyl units fourfold. The best activity was obtained from Schiff base 2f linked to the 5-(2-(4-methoxyphenyl)hydrazineyl)thiazol-4(5H)-one unit. Product 2f had more effective antibacterial activity than ciprofloxacin, with MIC/MBC of 1.8/3.7 µM against S. aureus and E. faecalis. It also exhibited good activity against S. mutans and K. pneumoniae, with MIC/MBC values of 3.7/7.4 µM. Moreover, 2e exhibited the second-highest activity against all tested strains, with MIC/MBC values of 3.8/7.6 µM for S. aureus and E. faecalis, and 7.6/15.3 µM for S. mutans and K. pneumoniae. Schiff bases with potential antibacterial activity were further screened for their MurB inhibitory activity. Furthermore, 2e and 2f displayed the best inhibitory activity against MurB with IC50 of 5.0 and 4.6 µM, respectively.

Nitrogen-containing heterocycles play a crucial role in medicinal chemistry and drug discovery, as several anticancer FDA-approved medicines are based on these compounds. Their structural and biological properties significantly impact their anticancer activity. Pyrazole and pyrimidine scaffolds show great anticancer potential. This review summarizes the synthesis and anticancer activity of several pyrazole and pyrimidine-based compounds, which exhibit great potential as cancer treatment candidates. The structural and biological characteristics of pyrazole and pyrimidine rings make them suitable scaffolds for designing novel anticancer agents. This review describes various synthetic routes for the preparation of pyrazole and pyrimidine derivatives, as well as their mechanisms of action in cancer therapy. These compounds exhibit potent cytotoxicity against breast, lung, and colon cancer cell lines. A detailed synthesis scheme shows how to incorporate pyrazole and pyrimidine scaffolds into medicinal compounds. Recent studies suggest that these derivatives exhibit substantial antitumor effects, supporting their development as targeted cancer therapies. Through the detailed description of synthesis, mechanisms of action, and anticancer activity, this review provides useful information on pyrazole and pyrimidine derivatives as potential future anticancer agents, highlighting their therapeutic potential in cancer treatment.

Triazine is a heterocyclic aromatic ring that is divided into three isomers by nitrogen atom positions. 2-Aza-2-desamino-5,8-dideazafolic acid and 2-azaadenosine are 1,2,3-triazine derivatives, whereas azaribine, tirapazamine, lamotrigine, and 6-azacytosine are 1,2,4-triazine derivatives. Natural antibiotics like fervenulin, reumycin, and toxoflavin have a triazine ring structure. Ammeline, aceto-guanide, acetoguanamine, cyanuric acid, and melamine all include 1,3,5-triazine isomer or s-triazine as a lead structure. Hexamethylmelamine (altretamine), atrazine, cycloguanil, and almitrine are examples of s-triazine-containing medications. Triazines are important in pharmaceutical chemistry because they exhibit a wide range of pharmacological actions, making them valuable for drug design and development. Some triazine analogs have recently been tested in clinical trials, which might lead to more powerful medications and have fewer adverse effects than currently available pharmaceuticals. This article discusses the biological significance and synthesis of several triazine derivatives derived from heterocyclic and Triazine-containing medicines.

Indole derivatives possess a wide range of biological activities, including antibacterial, anti-inflammatory, analgesic, and anticancer properties. The Nenitzescu reaction is a valuable approach for their synthesis; however, there are challenges, such as the limited availability of dinitro derivatives and complex workup procedures, which necessitate optimization and improvement in practical efficiency. The Nenitzescu reaction is a versatile method for synthesizing hydroxyindoles, particularly 5-hydroxyindoles. 5-Hydroxyindoles play a crucial role as fundamental components in a wide range of natural chemicals and pharmaceuticals. This reaction has the potential to be applied in the fields of medicinal chemistry and natural product synthesis. The selection of catalysts, solvents, and temperature is a crucial factor in maximizing yields. Scientists have examined different solvents, catalysts, and reaction conditions in order to improve the output and effectiveness of the Nenitzescu process. The objective of this study is to examine the requirements for producing 5-hydroxyindoles by the Nenitzescu reaction. The study investigates the influence of catalysts, solvents, and reaction temperatures on the yield of the reaction. The main emphasis is on the Nenitzescu reaction, with the objective of enhancing its practicality and environmental friendliness. Several trials using various solvents and catalysts are conducted. Nitromethane and acetic acid serve as effective solvents. The cyclization of hydroxy indoles is enhanced by zinc halides, specifically ZnCl2 or ZnI2.

This comprehensive review outlines the multifaceted applications of pyrazolines and benzimidazoles, encompassing their discovery, synthetic methodologies, patent landscape, and clinical trial outcomes, with a focus on pyrazoline-benzimidazole or pyrazole-benzimidazole derivatives. This review highlights the synthesis and biological evaluation of pyrazoline-bearing benzimidazoles obtained through the reaction of benzimidazoles with substituted pyrazolines/pyrazoles. The synthesized compounds demonstrated a broad spectrum of pharmacological activities, including antimicrobial, antibacterial, antitubercular, antimalarial, anthelmintic, antiproliferative, anticancer, antinociceptive, antihistaminic, antiulcer, etc. Research on pyrazoline and benzimidazole derivatives constitutes a dynamic field, expanding the research domain within pharmaceutical chemistry and offering potential therapeutic solutions for various diseases.

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.