Synthetic Medicinal Chemistry Research Articles

Diversified applications and synthesis of hydroxamic acids

Owing to the ability to form coordination complexes with several metal ions, hydroxamic acids have been widely used in the fields of medicinal chemistry, mineral flotation, metal–organic frameworks (MOFs), remediation of metal contamination and more. Since three hydroxamic acid-based histone deacetylase (HDAC) inhibitors were approved by the US Food and Drug Administration (FDA) for the treatment of haematologic malignancies, such functional groups have acquired even more attention in synthetic medicinal chemistry. However, application of hydroxamic acids for ore beneficiation is a unique area and has attracted the attention of few researchers. In order to provide insights for chemists in drug development, chelating mineral collector selection, remediation of metal pollution and preparation of MOFs, we summarize the applications of hydroxamic acids in the above-mentioned fields, and then introduce some related synthesis strategies including microwave synthesis, use of continuous flow reactors, solid-phase synthesis and enzymatic synthesis as supplements to classical synthetic methods.

Collective Synthesis of Furanocoumarin Natural Products Through a Radical‐mediated Construction of Furanocoumarin Skeletons

AbstractFuranocoumarins are attractive targets in the synthetic organic and medicinal chemistry field because of their structural diversity and interesting biological properties. Herein, we describe the synthesis of furanocoumarin natural products from common furanocoumarin skeletons. A key step was a novel intramolecular radical cyclization onto nitrile to synthesize angular and linear franocoumarins, which was optimized by reacting iodocoumarin derivatives in the presence of (Me3Si)3SiH and oxygen. These compounds served as intermediates in the syntheses of vaginidiol, vaginidin, oroselol, multivittan D, gaudichaudine, oreoselone, peucedanin, and smyrindiol, successfully demonstrating the versatility of the intermediates and utility of the radical cyclization method for accessing furanocoumarin natural products.

Unraveling the Potential of Cyclic N‐Sulfonyl Ketimines in the MCR Universe

Cyclic N‐sulfonyl ketimines constitute an accessible class of lead‐like heterocycles with a vast application in both synthetic organic and medicinal chemistry. In this context, we harness the capabilities of these heterocycles in four different isocyanide‐based multicomponent reactions. Our goal was to create libraries of compounds with functional groups and vectors that are compatible for structural elaboration and optimization of their physical properties. We synthesized 15 unprecedented compounds with high diversity and complexity, whereas we have obtained four single crystal structures of each scaffold, unraveling their geometrical features and potential employment in drug discovery.

Synthesis of Azo-Substituted Bicyclo[1.1.1]pentanes (BCPs) via Base-Promoted Halogen Atom Transfer.

Because of the three-dimensional bioisosteric feature, bicyclo[1.1.1]pentylamines (BCPAs) are valuable scaffolds in synthetic chemistry and medicinal chemistry. Here, we report a Halogen Atom Transfer (XAT) mediated radical C-N coupling between C3-iodo-BCPs and diazonium salts in the presence of base. Similarly, a multicomponent reaction (MCR) enables the simultaneous construction of the C-C bond and C-N bond simultaneously. Versatile roles of diazonium salts were also explored.

Cell Therapies and Gene Therapy for Diabetes: Current Progress.

The epidemic of diabetes continues to be an increasing problem, and there is a need for new therapeutic strategies. There are several promising drugs and molecules in synthetic medicinal chemistry that are developing for diabetes. In addition to this approach, extensive studies with gene and cell therapies are being conducted. Gene therapy is an existing approach in treating several diseases, such as cancer, autoimmune diseases, heart disease and diabetes. Several reports have also suggested that stem cells have the differentiation capability to functional pancreatic beta cell development in vitro and in vivo, with the utility to treat diabetes and prevent the progression of diabetes-related complications. In this current review, we have focused on the different types of cell therapies and vector-based gene therapy in treating or preventing diabetes.

Synthetic Update on Antimicrobial Potential of Novel Pyrazole Derivatives: A Review

Abstract: Heterocyclic compounds containing nitrogen and their derivatives have been a rich source of medicines. Pyrazole, a five-membered ring structure, offers a variety of functionalities as well as stereo-chemical complexity. Studies conducted over the past 10 years revealed that an increasing amount of research has been performed on different pyrazole derivatives and their physiological and pharmacological activities. The objective of these studies is to uncover the full potential of pyrazole derivatives by elucidating the many druglike properties and their link between the structure and mode of action. Here, we discuss different ways of synthesizing pyrazole derivatives. Due to recent advances in synthetic medicinal chemistry, this class of compounds can be readily developed and becomes a viable target for the discovery of novel drugs.

Site‐Specific Deaminative Trifluoromethylation of Aliphatic Primary Amines**

AbstractThe introduction of trifluoromethyl groups into organic molecules is of paramount importance in modern synthetic chemistry and medicinal chemistry. While methods for constructing C(sp2)−CF3 bonds have been well established, the advancement of practical and comprehensive approaches for forming C(sp3)−CF3 bonds remains considerably restricted. In this work, we describe an efficient and site‐specific deaminative trifluoromethylation reaction of aliphatic primary amines to afford the corresponding alkyl trifluoromethyl compounds. The reaction proceeds at room temperature with readily accessible N‐anomeric amide (Levin's reagent) and bench‐stable bpyCu(CF3)3 (Grushin's reagent, bpy=2,2′‐bipyridine) under blue light. The protocol features mild reaction conditions, good functional group tolerance, and moderate to good yields. Remarkably, the method can be applied to the direct, late‐stage trifluoromethylation of natural products and bioactive molecules. Experimental mechanistic studies were conducted, and a radical mechanism is proposed, wherein the dual roles of Grushin's reagent have been elucidated.

Site-Specific Deaminative Trifluoromethylation of Aliphatic Primary Amines.

The introduction of trifluoromethyl groups into organic molecules is of paramount importance in modern synthetic chemistry and medicinal chemistry. While methods for constructing C(sp2 )-CF3 bonds have been well established, the advancement of practical and comprehensive approaches for forming C(sp3 )-CF3 bonds remains considerably restricted. In this work, we describe an efficient and site-specific deaminative trifluoromethylation reaction of aliphatic primary amines to afford the corresponding alkyl trifluoromethyl compounds. The reaction proceeds at room temperature with readily accessible N-anomeric amide (Levin's reagent) and bench-stable bpyCu(CF3 )3 (Grushin's reagent, bpy=2,2'-bipyridine) under blue light. The protocol features mild reaction conditions, good functional group tolerance, and moderate to good yields. Remarkably, the method can be applied to the direct, late-stage trifluoromethylation of natural products and bioactive molecules. Experimental mechanistic studies were conducted, and a radical mechanism is proposed, wherein the dual roles of Grushin's reagent have been elucidated.

Synthesis of Organofluorine Compounds with Acylsilanes†

Comprehensive SummaryOrganofluorine compounds are central in synthetic chemistry, medicinal chemistry and material chemistry. In this review, we summarize the investigations on the synthesis of organofluorine compounds with acylsilanes. For the non‐fluorinated acylsilanes, the in situ generation of difluoroenoxysilanes from the reactions of the acylsilanes with trifluoromethylation reagents is the major pathway, leading to the facile preparation of various α,α‐difluoroketones. For the fluoroalkylacylsilanes, apart from the in situ generation of difluoroenoxysilanes through anion Brook rearrangement, radical Brook rearrangement of the photoexcited acylsilanes and the selective control of reactivities of the biradicals pave the way for the synthesis of a variety of organofluorine compounds. In general, most of these reactions gave racemic products, and the asymmetric synthesis of organofluorine compounds with acylsilanes is still rare, which would be a future direction of this field. Key ScientistsIn 1957, the first acylsilane compound, triphenylsilyl phenyl ketone was reported by Brook group. In 1991, Portella and coworkers reported the reaction of non‐fluorinated acylsilanes and perfluoroorganometallic reagents without Brook rearrangement, resulting in the formation of alcohols as the products. In 1992, Xu and coworkers carried out the first investigation on fluoroalkylacylsilanes for the preparation of difluoroenoxysilanes through anion Brook rearrangement. In 1994, Portella group reported the synthesis of difluoroenoxysilanes with non‐fluorinated acylsilanes and Ruppert‐Prakash reagent. In 2009, Otaka and coworkers reported a NHC‐mediated intramolecular redox reaction to prepare (Z)‐fluoroalkene dipeptide isosteres (FADIs) from γ,γ‐difluoro‐α,β‐ enoylsilane. Until 2022, the application of radical Brook rearrangement of fluoroalkylacylsilanes for the generation of fluoroalkylsiloxycarbenes was achieved by Shen group, enabling the synthesis of fluoroalkylated cyclopropenols. In 2022, Shen and coworkers successfully achieved the trapping of biradical intermediates generated from fluorine‐containing acylsilanes, leading to the facile preparation of fused gem‐difluorooxetanes. In the same year, Shen group reported the first asymetric reactions of fluoroalkylacylsilanes to prepare enantiomerically enriched fluoroalkyl alcohols and difluoroenoxysilanes.

Organocatalytic enantioselective construction of Si-stereocenters: recent advances and perspectives.

Silicon-stereogenic chiral organosilanes have found increasing applications in synthetic chemistry, medicinal chemistry, and materials science. In this context, various asymmetric catalytic methods have been established for the diverse synthesis of silicon-stereogenic silanes. In particular, asymmetric organocatalysis is emerging as an important and complementary synthetic tool for the enantioselective construction of silicon-stereocenters, along with the rapid development of chiral-metal catalyzed protocols. Its advent provides a powerful platform to achieve functionalized silicon-stereogenic organosilanes with structural diversity, and should lead to great development in chiral organosilicon chemistry. In this Tutorial Review, we highlight these latest achievements from two aspects: desymmetrizations of prochiral tetraorganosilanes and dynamic kinetic asymmetric transformations of racemic organosilanes by employing five organocatalytic activation modes. The advantages, limitations and synthetic value of each protocol, as well as the synthetic opportunities still open for further exploration, are also discussed.

A General Photochemical Strategy for the Oximation of Activated Alkenes without a Catalyst

Oximes are crucial in several areas such as synthetic chemistry, medicinal chemistry, and materials science. In this context, we have developed a general photochemical approach for synthesizing diverse oximes without...

Synthetic Strategies for Quinoline Based Derivatives as Potential Bioactive Heterocycles.

Quinoline derivatives are an important class of heterocyclic compounds and possess various applications in synthetic organic chemistry, medicinal chemistry, material chemistry and natural product chemistry. This review article describes the different quinoline derivatives having antimalarial, analgesic, anti-inflammatory, antineoplastic, antibacterial, antifungal, antiviral, anthelmintic, antiprotozoal, cardiovascular, CNS and other useful bioactivities. We have delineated the general synthetic routes for the synthesis of many bioactive quinoline based heterocycles. In addition to this, we have also discussed the crucial synthetic routes as well as their mechanistic paths for the formation of bioactive quinoline derivatives. The study shows that substitution at the 4 and 8- position of quinoline is more crucial for bioactivity as compared to other positions.

Photocatalytic Alkynylation of Hydrosilanes via Hydrogen Atom Transfer.

Alkynylsilanes are significant structural units frequently used in synthetic chemistry, medicinal chemistry, functional materials, and life sciences. Herein, we report a method for using a hydrogen atom transfer (HAT) strategy in combination with visible-light-driven photocatalysis to achieve a direct coupling reaction between benzene sulfonyl acetylene and tertiary silanes, and a diverse alkynylation of hydrosilanes in the presence of reactive groups was achieved with this strategy. It is important to note that dihydroalkyl/aryl silanes are also suitable for the protocol of HAT photocatalytic of 4CzIPN and quinuclidine.

Recent Developments towards the Synthesis of Pyrimidopyrimidine and Purine Derivatives

AbstractFused pyrimidines scaffolds such as pyrimidopyrimidines, purines and xanthines are important structural motifs found in various natural products and drug molecules. They are used as anticancer, antiviral, antibacterial, antifungal, antioxidant, antitumor, anti‐diabetic, adenosine potentiating, and hepatoprotective agents. Due to their diverse biological applications, the synthesis of pyrimidopyrimidines, purines and xanthines has gained great importance among the researchers in recent years. Thus, the present study aims to review the synthetic methodologies published during the years 2000–2022 for the preparation of pyrimidopyrimidines, purines and xanthines nucleus. Mechanistic interpretation of some important cases has also been discussed. This survey will help researchers working in the fields of synthetic organic and medicinal chemistry to undertake and improve new approaches for the construction of titled compounds.

Catalytic N‐H Insertion Reactions with α‐Diazoacetates: An Efficient Method for Enantioselective Amino Acid Synthesis

AbstractAs the monomers of proteins, amino acids are critical in chemistry and biology, playing important roles in multiple fields such as synthetic chemistry, medicinal chemistry, and materials chemistry. Unlike proteinogenic amino acids, unnatural amino acids can be difficult to obtain from living organisms and generally are synthesized chemically. Recently, a method involving the asymmetric N−H bond carbene insertion reaction with α‐diazoacetates as the carbene precursor has shown high enantioselectivity and good functional group tolerance, allowing for the facile synthesis of natural and unnatural amino acids and the introduction of new concepts in catalysis.

A New, Convenient Way to Fully Substituted α,β-Unsaturated γ-Hydroxy Butyrolactams.

The synthesis of novel, highly functionalized 5-hydroxy 3-pyrrolin-2-ones via a two-step procedure involving an addition reaction between KCN and corresponding chalcones, followed by ring condensation of the obtained β-cyano ketones with het(aryl)aldehydes under basic conditions is described. This protocol enables the preparation of various 3,5-di-aryl/heteroaryl-4-benzyl substituted α,β-unsaturated γ-hydroxy butyrolactams, which are subjects of significant interest to synthetic organic and medicinal chemistry.

Transition‐Metal‐Free Radical Borylation Reactions

AbstractOrganoboron compounds are versatile synthons in synthetic chemistry, materials science, and medicinal chemistry. The preparation of them often requires either reactive organometallic reagents or transition metals. In recent years, transition‐metal‐free borylation methodologies using radical chemistry for C−B bond formation have attracted much attention and developed rapidly, which circumvents the use of preformed organometallic reagents. Various successful approaches from different radical precursors (such as carboxylic acids, amines and alcohols, which are abundant in nature) through either thermochemical, photochemical or electrochemical pathways have been developed. Therefore, in this review, we hope to provide an overview of recent advances in the discovery, development, and mechanistic study of transition‐metal‐free radical borylation processes.

An Investigation into the In Vitro Metabolic Stability of Aryl Sulfonyl Fluorides for their Application in Medicinal Chemistry and Radiochemistry.

Molecules that feature a sulfonyl fluoride (SO2F) moiety have been gaining increasing interest due to their unique reactivity and potential applications in synthetic chemistry, medicinal chemistry, and other biological uses. A particular interest is towards 18F-radiochemistry where sulfonyl fluorides can be used as a method to radiolabel biomolecules or can be used as radiofluoride relay reagents that facilitate radiolabeling of other molecules. The low metabolic stability of sulfonyl fluoride S-F bonds, however, presents an issue and limits the applicability of sulfonyl fluorides. The aim of this work was to increase understanding of what features contribute to the metabolic instability of the S-F bond in model aryl sulfonyl fluorides and identify approaches to increasing sulfonyl fluoride stability for 18F-radiochemistry and other medicinal, synthetic chemistry and biological applications. To undertake this, 14 model aryl sulfonyl fluorides compounds with varying functional groups and substitution patterns were investigated, and their stabilities were examined in various media, including phosphate-buffered saline and rat serum as a model for biological conditions. The results indicate that both electronic and steric factors affect the stability of the S-F bond, with the 2,4,6-trisubstituted model aryl sulfonyl fluorides examined displaying the highest in vitro metabolic stability.

A Detailed Review on C‐Fused Furan/3,4‐Fused Furan Analog and its Potential Applications

Abstractc‐fused furan and their derivatives are widely used as essential components of agrochemicals, bioregulators, dyes, essential skin and hair oils, cosmetics, flavouring agents, photosensitizers in industry and also show a broad range of biological activity. To the best of our knowledge, as of yet, no review has been published that covers the entire synthetic pathway leading to the formation of just c‐fused or 3, 4‐fused furans. In this review, we outline the various pathways for bicyclic, tricyclic, and polycyclic c‐fused furans, along with their detailed mechanisms, concrete examples, and biological activity. We have focused particularly on the synthetic route to medicine, natural products, and their analogues, such as c‐fused furanoditerpenes isospongiadiol, radermachol, a potential folk medicine ingredient, furo[3,4]quinolin‐4(5H)‐ones core, an inhibitor of lymphoma, bhimamycin B, hibiscone‐c core moiety of antibiotic lactonamycin, and analogue of natural product furanether A/ furanether B. Previous approaches and recent methods are described including metal‐free, transition metal, bio‐catalyst, and multi‐substrate approaches with mechanisms. The review covers the literature for more than six decades and presents an overview of the synthesis of different c‐fused furans and their utility in various disciplines such as synthetic chemistry, medicinal chemistry, and drug discovery.

Sulfonamides with Heterocyclic Periphery as Antiviral Agents.

Sulfonamides are the basic motifs for a whole generation of drugs from a large group of antibiotics. Currently, research in the field of the new sulfonamide synthesis has received a "second wind", due to the increase in the synthetic capabilities of organic chemistry and the study of their medical and biological properties of a wide spectrum of biological activity. New reagents and new reactions make it possible to significantly increase the number of compounds with a sulfonamide fragment in combination with other important pharmacophore groups, such as, for example, a wide class of N-containing heterocycles. The result of these synthetic possibilities is the extension of the activity spectrum-along with antibacterial activity, many of them exhibit other types of biological activity. Antiviral activity is also observed in a wide range of sulfonamide derivatives. This review provides examples of the synthesis of sulfonamide compounds with antiviral properties that can be used to develop drugs against coxsackievirus B, enteroviruses, encephalomyocarditis viruses, adenoviruses, human parainfluenza viruses, Ebola virus, Marburg virus, SARS-CoV-2, HIV and others. Since over the past three years, viral infections have become a special problem for public health throughout the world, the development of new broad-spectrum antiviral drugs is an extremely important task for synthetic organic and medicinal chemistry. Sulfonamides can be both sources of nitrogen for building a nitrogen-containing heterocyclic core and the side chain substituents of a biologically active substance. The formation of the sulfonamide group is often achieved by the reaction of the N-nucleophilic center in the substrate molecule with the corresponding sulfonylchloride. Another approach involves the use of sulfonamides as the reagents for building a nitrogen-containing framework.