Fused 1,5-Naphthyridines: Synthetic Tools and Applications

Heterocyclic compounds are an important class of compounds in the field of pharmaceutical and synthetic organic chemistry. The Schiff bases contain azomethine linkages which are obtained by the condensation of aldehyde/ketone with amines. Among the various types of Schiff bases, the chalcone-based Schiff bases play a vital role in the treatment of various ailments and various applications, which can be synthesized by using different types of chalcones as the starting materials. These types of compounds were synthesized by using various techniques like conventional means of synthesis, microwave-assisted reaction, heterocyclic catalyst-mediated synthesis and also by means of trituration. The chalcone or bis-chalcone-based Schiff bases and their derivatives contain -C=N linkage which exhibits various activities including antimicrobial, anticancer, antioxidant, antidiabetic and immunosuppressant activities. Beyond these activities, these types of Schiff bases are also used in various chemical industries and fluorescent sensors, which also play a major role in the field of synthetic organic chemistry and coordination chemistry as intermediates. This review discusses the numerous synthetic strategies along with their applications in the field of medicine. Thus, this review will be helpful in developing more effective drug-like scaffolds for use in future drug design. Keywords: Schiff bases, Chalcone-based Schiff bases, Antimicrobial, Anticancer, Antioxidant, Biological Applications

The potential for anaerobic biodegradation of 12 heterocyclic model compounds was studied. Nine of the model compounds were biotransformed in aquifer slurries under sulfate-reducing or methanogenic conditions. The nitrogen and oxygen heterocyclic compounds were more susceptible to anaerobic biodegradation than those compounds containing a sulfur heteroatom. Carboxy-substituted compounds were anaerobically metabolized more readily than unsubstituted or methylated analogues. In methanogenic incubations, 47 to 84% of the expected amount of carbon in pyridine, 4-picoline, nicotinic acid and 2-thiophene carboxylic acid was recovered as methane. In contrast, only small amounts of methane were detected in aquifer slurries amended with compounds containing an oxygen heteroatom, even though a decrease in the parent substrate concentration occurred. Pyridine, 2-picoline and 4-picoline were biotransformed within three months under sulfate-reducing conditions. However, longer incubation times were required for the degradation of these substrates in methanogenic aquifer slurries. A literature survey reveals the widespread contamination of ground waters with heterocyclic compounds from waste management practice and fossil-fuel-related industries.

Artur Silva's research group has a long history in the field of medicinal chemistry. The development of new synthetic methods for oxygen (mostly polyphenols, e.g., 2- and 3-styrylchromones, xanthones, flavones) and nitrogen (e.g., pyrazoles, triazoles, acridones, 4-quinolones) heterocyclic compounds in order to be assessed as antioxidant, anti-inflammatory, antidiabetic, and anticancer agents has been the main core work of our research interests. Additionally, the synthesis of steroid-type compounds as anti-Alzheimer drugs as well as of several chromophores as important dyes for cellular imaging broadened our research scope. In this review article, we intend to provide an enlightened appraisal of all the bioactive compounds and their biological properties that were synthesized and studied by our research group in the last two decades.

A survey of the literature reveals that both coumarin and the 1,2,3-triazole nucleus have important and well-recognized biological and pharmaceutical activities. Furthermore, these fused scaffolds have demonstrated biological significance, making the design and development of coumarin-1,2,3-triazole hybrids a topic of great interest in the field of synthetic organic chemistry and medicinal chemistry. The wide-ranging applications of coumarin and triazole have stimulated interest among researchers to develop various methodologies for synthesizing new molecules incorporating these moieties. Consequently, numerous research and review articles have been published on the subject. In this review, we present some research conducted over the past five years on bioactive coumarin-1,2,3-triazole hybrids, with an emphasis on the synthesis of these compounds and their biological applications in the treatment of infectious diseases, cancer, and Alzheimer’s disease.

Recently, quinoline has become an essential heterocyclic compound due to its versatile applications in the fields of industrial and synthetic organic chemistry. It is a vital scaffold for leads in drug discovery and plays a major role in the field of medicinal chemistry. Nowadays there are plenty of articles reporting syntheses of the main scaffold and its functionalization for biological and pharmaceutical activities. So far, a wide range of synthesis protocols have been reported in the literature for the construction of this scaffold. For example, Gould–Jacob, Friedländer, Pfitzinger, Skraup, Doebner–von Miller and Conrad–Limpach are well-known classical synthesis protocols used up to now for the construction of the principal quinoline scaffold. Transition metal catalysed reactions, metal-free ionic liquid mediated reactions, ultrasound irradiation reactions and green reaction protocols are also useful for the construction and functionalization of this compound. The main part of this review focuses on and highlights the above-mentioned synthesis procedures and findings to tackle the drawbacks of the syntheses and side effects on the environment. Furthermore, various selected quinolines and derivatives with potential biological and pharmaceutical activities will be presented.

Bacterial samples were collected from three marine beaches in coastal Newfoundland, Canada, and enriched by growth on 1-methylnaphthalene. The most prominent bacterial cell type for each consortium was isolated in a serial dilutions test, and a substrate utilization profile was obtained for each using the Biolog MicroStation System. Each bacterial community was tested for its ability to co-metabolize sulfur heterocycles (benzothiophene: BT, 3-methylbenzothiophene: 3-MBT, and dibenzothiphene: DBT), a nitrogen heterocycle (carbazole: CARB), and an oxygen heterocycle (dibenzofuran: DBF). Co-metabolism of the starting material was determined using gas chromatography-mass spectroscopy (GC-MS), and formation of products was investigated by GC-MS and Fourier transform infrared (FTIR) spectroscopy. Bacterial growth was monitored turbidimetrically to determine the dry weight (microgram) of cells/ml. The 2-ringed heterocycles were co-metabolized faster and to a greater extent than the 3-ringed compounds. Co-metabolism of BT was not statistically different from that for 3-MBT and, likewise, a comparison of the 3-ringed heterocycles showed no significant differences in degradation rates. Statistical examination showed that no one culture demonstrated a significantly greater ability to co-metabolize the heterocycles studied. This study represents the first comprehensive investigation of the ability of local bacteria to co-metabolize a range of aromatic compounds and provides a preliminary understanding of their fate in sediments should contamination by these compounds occur.

Conjugated dienes have occupied a pivotal position in the field of synthetic organic chemistry and medicinal chemistry. They act as important synthons for the synthesis of various biologically important molecules and therefore, gain tremendous attention worldwide. A wide range of synthetic routes to access these versatile molecules have been developed in the past decades. Transition metal-catalyzed cross-dehydrogenative coupling (CDC) has emerged as one of the utmost front-line research areas in current synthetic organic chemistry due to its high atom economy, efficiency, and viability. In this review, an up-to-date summary including scope, limitations, mechanistic studies, stereoselectivities, and synthetic applications of transition metal-catalyzed double Cvinyl-H bond activation for the synthesis of conjugated dienes has been reported since 2013. The literature reports mentioned in this review have been classified into three different categories, i.e. (a) Cvinyl-Cvinyl bond formation via oxidative homo-coupling of terminal alkenes; (b) Cvinyl-Cvinyl bond formation via non-directed oxidative cross-coupling of linear/cyclic alkenes and terminal/internal alkenes, and (c) Cvinyl-Cvinyl bond formation via oxidative cross-coupling of directing group bearing alkenes and terminal/internal alkenes. Overall, this review aims to provide a concise overview of the current status of the considerable development in this field and is expected to stimulate further innovation and research in the future.

Oxygen and nitrogen heterocycles are well-known classes of compounds due to their excellent biological activity. Halogenated compounds are very useful synthetic intermediates and can function as suitable building blocks for pharmaceutical products. Thus, halocyclisation reactions to deliver fluorine and iodine into oxygen and nitrogen heterocycles have been investigated using electrophilic reagents N-fluorobenzensulfonimide and iodine with alkyne-containing tertiary alcohol substrates and alkyne-containing amides.Chapter 2 describes the synthesis and characterisation of a series of alkyne-containing tertiary alcohol substrates that have been targeted as starting materials to allow an investigation of iodocyclisation/fluorocyclisation reactions in order to generate cyclised products. Complications caused by protocyclisation reactions to give undesired dihydroisobenzofuran products have been overcome by using the different reaction sequences. In Chapter 3, a new fluorocyclisation methodology for Ag-catalysed electrophilic fluorination of alkynes to give monofluorinated or difluorinated dihydroisobenzofuran products has been designed, including avenues for regiospecific control to expand both the utility and substrate scope of the reaction. Chapter 4 shows divergent behaviour in the iodocyclisation reactions of the same alkyne substrates in different solvents where different regioselectivity for the (E)/(Z) 5-exo-dig product has been demonstrated. This regioselectivity depends on the functional groups present and the reaction conditions. Finally, Chapter 5 describes the synthesis of terminal alkynes containing benzyl or aryl amides which have been prepared in excellent yields. The amide groups have been used as internal nucleophiles for iodocyclisation reactions using the methods outlined in Chapter 4. It was found that the aryl amide (5.62e) gave oxygen-heterocyclic product mixtures in both CH2Cl2 and MeCN solvents. However, the benzyl amides (5.62a,b) gave oxygen-heterocycles in MeCN and nitrogen-heterocycles in DCM. It is presumed that the relative nucleophilicities of the oxygen and nitrogen centres in these amides are influenced by both the electronic influence of the N-substituent and interactions with the solvent.

Uhle’s ketone and its derivatives are highly versatile intermediates for the synthesis of a variety of 3,4-fused tricyclic indole frameworks, i.e. indole alkaloids of the ergot family, that are found in various bioactive natural products and pharmaceuticals. Therefore, the development of a convenient preparative method for this structural motif as well as its opportune/useful derivatization have been the subject of longstanding interest in the fields of synthetic organic chemistry and medicinal chemistry. Herein, we summarize recent and less recent methods for the preparation of Uhle’s ketone and its derivatives as well as its main reactivity towards the synthesis of bioactive substances. Regarding the preparation, it can be roughly classified into two categories: (a) using 4-unfunctionalized and 4-functionalized indole derivatives as starting materials to construct a fused six-member ring, and (b) constructing the indole ring through intramolecular cycloaddition. Principally, the reactivity of the cyclic Uhle’s ketone shown here is derived from the classical electrophilicity of the carbonyl carbon or the acidity of the α-hydrogen and, though less intensively investigated, chemical reactions that induce ring expansion to form novel ring skeletons.1 Introduction2 Synthesis2.1 Disconnection A: Cyclization Reaction of the Opportune 3,4-Disubstituted Indole2.2 Disconnection B: Intramolecular Friedel–Crafts Cyclization2.3 Disconnection B: Intramolecular Cyclization via Metal–Halogen Exchange2.4 Disconnection C: Intramolecular Diels–Alder Furan Cycloaddition2.5 Disconnection D: Intramolecular Dearomatizing [3 + 2] Annulation3 Reactivity3.1 Use of Uhle’s Ketone for Lysergic Acid3.2 Use of Uhle’s Ketone for Rearranged Clavines3.3 Use of Uhle’s Ketone for Medicinal Chemistry4 Conclusion and Outlook

Abstract3,4‐Fused tricyclic indole frameworks are found in various bioactive natural products and pharmaceuticals. The development of an efficient synthetic method for this structural motif has therefore attracted attention in the field of synthetic organic chemistry and medicinal chemistry. Herein, we summarize recent advances in the synthesis of 3,4‐fused tricyclic indoles. This class of synthetic methods can be roughly classified into two categories: methods using functionalized indole derivatives as starting materials to construct a fused medium‐sized ring (Types A–D: Category I), and methods of constructing a 3,4‐fused tricyclic indole skeleton via indole ring formation (Types E–G: Category II). In this focus review, synthetic methods for 3,4‐fused tricyclic indoles classified as Category II methods are highlighted, following a brief overview of the Category I methods.

: Pyrimidobenzothiazoles and its derivatives are important structural scaffolds in the field of synthetic organic chemistry and medicinal chemistry. The review is focused on one pot multicomponent approaches for generating pyrimidobenzothiazoles and its derivatives along with their interesting biological profile over the last ten years. Several eco-benign and cost effective approaches such as nano catalyst, ionic liquid, metal, solid acid, catalyst free, solvent free, etc. for its synthesis have been discussed in this review. Different synthetic strategies of pyrimidobenzothiazole derivatives have been compiled and discussed using 2-aminobenzothiazole, 1,3 diketones, substituted aldehydes, alkynoic acid, bis-methyl thiomethylene malononitrile, Baylis Hillman acetates, etc.

Development of efficient chiral catalyst continues to be an important challenge in the fields of synthetic organic chemistry and medicinal chemistry. Although metal-based Lewis acid catalysts had been extensively studied for the activation of carbonyl group and imine, chiral Brønsted acid has emerged in the beginning of 21st century. We synthesized chiral phosphoric acid, derived from (R)-BINOL, and demonstrated its catalytic activity in the Mannich-type reaction as a chiral Brønsted acid in 2004. Chiral phosphoric acid functioned as bifunctional catalyst bearing both basic site and Brønsted acidic site. The 3,3’-substituents play an important role. Since then, chiral phosphoric acid catalysis has become a popular research area, and its utility has been remarkably expanded. In this article, we will describe the development of chiral phosphoric acid and recent progress of the chiral phosphoric acid catalysis from our research group, in particular following topics; 1) transfer hydrogenation reaction of ketimines by use of benzothiazoline as a hydrogen donor, and oxidative kinetic resolution of indolines, 2) Friedel-Crafts alkylation reaction of indoles, and 3) enantioselective synthesis of chiral biaryls by bromination and transfer hydrogenation. In addition, several tips for using chiral phosphoric acid are also described.

This review will primarily focus on recent methods employed for the synthesis of a diverse array of chalcones with broad-ranging biological activities, with a particular emphasis on the past five years. The utilization of aromatic methyl ketones and their derivatives as starting materials for the synthesis of various heterocyclic compounds, such as chalcones, pyrazolines, dioxolanes, aminothiazoles, and more, holds significant importance in the field of synthetic organic chemistry. The synthesized heterocyclic compounds can serve as valuable subjects for testing to assess their biological activity.

The literature survey reveals that the individual coumarin and heterocyclic molecules have biological and pharmaceutical activities. Moreover, integrated coumarinfused heterocyclic compounds have shown interesting biological and physiochemical properties and thus, designing and development of coumarin-fused heterocyclic molecules are of great interest in the field of synthetic organic chemistry. Several coumarin-fused heterocyclic molecules have been synthesized by using different strategies such as multistep method, one-pot multi-component protocol, coupling and condensation method. The wide applications of integrated coumarin-fused heterocyclic molecules stimulated interest among researchers to develop different methodologies for the synthesis of novel fused molecules. As a consequence, several research articles, papers and review articles have been published in the literature. In this review article, we have presented various methods for the synthesis of different class of coumarin-fused heterocyclic molecules and their applications in chemical, optical, pharmaceutical and other useful applications.

A growing number of researchers in the field of medicinal chemistry are focused on nitrogenous heterocyclic compounds. Benzimidazole scaffolds appear often in this group of heterocyclic compounds. Benzimidazole derivatives are important chemotherapeutic drugs because of their isostructural pharmacophore of naturally occurring active biomolecules. Many benzimidazole derivatives have been produced in the recent few decades, and many of these compounds have shown high bioactivity against a wide range of diseases and have bioavailability, safety, and stability profiles that are among the best in the industry. Here, we've included data on the antihypertensive properties of benzimidazole derivatives that have appeared in recent studies (2010–2022), along with a structure-activity link for each. Human studies are underway for a number of intriguing therapeutic candidates, and some of them will be authorized for use in clinical settings. In order to gather the information on proposed topic all the scientific search engines and publisher sites were used such as Google scholar, Science direct, Bentham science, PubChem, PubMed, Tayler and Francis, Hindawi, Springer nature, and ACS websites. The present review provides a detailed insight of benzimidazole derivatives reported as antihypertensive agents.