Synthesis of α,α‐Difluoromethylene Alkynes by Palladium‐Catalyzed gem‐Difluoropropargylation of Aryl and Alkenyl Boron Reagents

gem‐Difluoropropargyl bromides are versatile intermediates in organic synthesis, but have rarely been employed in transition‐metal‐catalyzed cross‐coupling reactions. The first palladium‐catalyzed gem‐difluoropropargylation of organoboron reagents with gem‐difluoropropargyl bromides is now reported. The reaction proceeds under mild reaction conditions with high regioselectivity; it features a broad substrate scope and excellent functional‐group compatibility and thus provides an attractive approach for the synthesis of complex fluorinated molecules, in particular for drug discovery and development.     

A practical synthesis of nitrocefin

Nitrocefin is a key reagent for high and low throughput assays of the activities of penicillin-binding proteins (PBPs) and beta-lactamases, the former used for discovery of antibiotics and the latter for inhibitors of resistance determinants for beta-lactam antibiotics. This compound is commercially available but is prohibitively expensive because of the circuitous routes to its synthesis. We describe herein a three-step synthesis of nitrocefin that gives an overall yield of 44%. This is a practical route to the synthesis of this key reagent for drug discovery.     

Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

Natural products have historically been a major source of antibiotics and therefore novel scaffolds are constantly of interest. The lipoxazolidinone family of marine natural products, with an unusual 4‐oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow‐up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogues to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4‐oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.     

Molecular Imprinting of Cyclodextrin Supramolecular Hydrogels Improves Drug Loading and Delivery

Cyclodextrin‐based controlled delivery materials have previously been developed for controlled release of different therapeutic drugs. In this study, a supramolecular hydrogel made from cyclodextrin‐based macromonomers is subjected to molecular imprinting to investigate the impact on release kinetics and drug loading, when compared with non‐imprinted, or alternately imprinted hydrogels. Mild synthesis conditions are used to molecularly imprint three antibiotics—novobiocin, rifampicin, and vancomycin—and to test two different hydrogel chemistries. The release profile and drug loading of the molecularly imprinted hydrogels are characterized using ultraviolet spectroscopy over a period of 35 days and compared to non‐imprinted, and alternately imprinted hydrogels. While only modest differences are observed in the release rate of the antibiotics tested, a substantial difference is observed in the total drug‐loading amount possible for hydrogels releasing drugs which has been templated by those drugs. Hydrogels releasing drugs which are templated by other drugs do not show improved release or loading. Analysis by FTIR does not show substantial incorporation of drug into the polymer. Lastly, bioactivity assays confirmed long‐term stability and release of incorporated antibiotics.     

One‐Step Synthesis of 1‐(4,5‐Diphenylpyrimidin‐2‐yl)thiourea

A simple and straightforward methodology toward the synthesis of novel 1‐(4,5‐diphenylpyrimidin‐2‐yl)thiourea has been developed by a one‐step reaction of isoflavones with amidinothiourea. A series of 16 new compounds was synthesized. All compounds were characterized by FT‐IR, NMR, and elemental analysis. The structure of a typical compound was established by X‐ray diffraction. A variety of substrates can participate in the process with good yields and high purities, making this methodology suitable for library synthesis in drug discovery.     

Discovery by serendipity: a new context for an old riddle

In the last years there has been a great improvement in the development of computational methods for combinatorial chemistry applied to drug discovery. This approach to drug discovery is sometimes called a “rational way” to manage a well known phenomenon in chemistry: serendipity discoveries. Traditionally, serendipity discoveries are understood as accidental findings made when the discoverer is in quest for something else. This ‘traditional’ pattern of serendipity appears to be a good characterization of discoveries where “luck” plays a key role. In this sense, some initial failures in combinatorial chemistry are frequently attributed to a naïf appropriation of a “serendipity model” for discovery (a “serendipity mistake”). In this paper we try to evaluate this statement by criticizing its foundations. It will be suggested that the notion of serendipity has different aspects and that the criticism to the first attempts could be understood as a “serendipity mistake.” We will suggest that “serendipity” strategies, a kind of blind search, can be seen sometimes as a “genuine part” of scientific practice. A discussion will ensue about how this characterization can give us a better understanding of some aspects of serendipity discoveries.     

Late‐Stage Functionalization of Biologically Active Heterocycles Through Photoredox Catalysis

The direct C? H functionalization of heterocycles has become an increasingly valuable tool in modern drug discovery. However, the introduction of small alkyl groups, such as methyl, by this method has not been realized in the context of complex molecule synthesis since existing methods rely on the use of strong oxidants and elevated temperatures to generate the requisite radical species. Herein, we report the use of stable organic peroxides activated by visible‐light photoredox catalysis to achieve the direct methyl‐, ethyl‐, and cyclopropylation of a variety of biologically active heterocycles. The simple protocol, mild reaction conditions, and unique tolerability of this method make it an important tool for drug discovery.     

Antibiotics: a new hope

Antibiotic resistance is one of the most significant challenges to the health care sector in the 21st century. A myriad of resistance mechanisms have emerged over the past decades and are widely disseminated worldwide through bacterial populations. At the same time there have been ever fewer new antibiotics brought to market, and the pharmaceutical industry increasingly sees antibiotics as a poor investment. Paradoxically, we are in a Golden Age of understanding how antibiotics work and where resistance comes from. This knowledge is fueling a renaissance of interest and innovation in antibiotic discovery, synthesis, and mechanism that is poised to inform drug discovery to address pressing clinical needs.     

Inhibitory mechanisms of antibiotics targeting elongation factor Tu

Since the pioneering discovery of the inhibitory effects of kirromycin on bacterial elongation factor Tu (EF-Tu) more than 25 years ago [1], a great wealth of biological data has accumulated concerning protein biosynthesis inhibitors specific for EF-Tu. With the subsequent discovery of over two dozen naturally occurring EF-Tu inhibitors belonging to four different subclasses, EF-Tu has blossomed into an appealing antimicrobial target for rational drug discovery efforts. Very recently, independent crystal structure determinations of EF-Tu in complex with two potent antibiotics, aurodox and GE2270A, have provided structural explanations for the mode of action of these two compounds, and have set the foundation for the design of inhibitors with higher bioavailability, broader spectra, and greater efficacy.     

One‐step synthesis of 2,4,5‐trisubstituted pyrimidines

A simple and straightforward methodology towards the synthesis of 2,4,5‐trisubstituted pyrimidines has been developed by one‐step reaction of isoflavones with thiourea or guanidine. Ten 2‐mercapto‐4,5‐diphenylpyrimidines and eight 2‐amino‐4,5‐diphenylpyrimidines were reported. All of them were characterized by FT‐IR, NMR, and elemental analysis. A variety of substrates can participate in the process with good yields and high purities, making this methodology suitable for library synthesis in drug discovery. J. Heterocyclic Chem., (2011).     

Designed Spiroketal Protein Modulation

Spiroketals are structural motifs found in many biologically active natural products, which has stimulated considerable efforts toward their synthesis and interest in their use as drug lead compounds. Despite this, the use of spiroketals, and especially bisbenzanulated spiroketals, in a structure‐based drug discovery setting has not been convincingly demonstrated. Herein, we report the rational design of a bisbenzannulated spiroketal that potently binds to the retinoid X receptor (RXR) thereby inducing partial co‐activator recruitment. We solved the crystal structure of the spiroketal–hRXRα–TIF2 ternary complex, and identified a canonical allosteric mechanism as a possible explanation for the partial agonist behavior of our spiroketal. Our co‐crystal structure, the first of a designed spiroketal–protein complex, suggests that spiroketals can be designed to selectively target other nuclear receptor subtypes.     

Different synthetic routes to 4-(1H-benzo[d]imidazol-2-yl)aniline

The benzimidazole nucleus is an important pharmacophore in drug discovery, being a good bioisostere of naturally occurring nucleotides. This heterocycle may represent a type of privileged substructure which can interact with proteins and enzymes; it has, hence, been extensively utilized as a drug scaffold in medicinal chemistry. The connection between wide ranging biological activity and compounds containing the benzimidazole nucleus is known, and well documented in the literature. Benzimidazole derivatives have a multitude of interesting pharmacological activity, including antiviral, antitumor, antihypertensive, proton pump inhibitory, anthelmintic, antimicrobial, and anti-inflammatory activity. Accordingly, a brief survey is given below covering the synthesis of 2-phenybenzimidazole derivatives and their biological importance.     

Synthesis of Pyrazole Derivatives Possessing Anticancer Activity: Current Status

Pyrazole is a versatile lead compound to design potent bioactive molecules for drug discovery and development, particularly in cancer therapy. The aim of this review is to present the most recent deeds in the field of synthetic route made for functionalized pyrazole derivatives active against cell proliferation disease. The review article covers the synthesis of 1H-pyrazole, synthesis of N-substituted pyrazoles, synthesis of pyrazolopyrazoles, and synthesis of pyrazoles fused with a naturally occurring moiety. Some of these reported compounds have passed the preclinical or initial-phase clinical trials for their anticancer activity.     

1‐Substituted 2‐Azaspiro[3.3]heptanes: Overlooked Motifs for Drug Discovery

The 2‐substituted piperidine core is found in drugs (18 FDA‐approved drugs), however, their spirocyclic analogues remain unknown. Described here is the synthesis of spirocyclic analogues for 2‐substituted piperidines and a demonstration of their validation in drug discovery.     

Development of a Terpenoid Alkaloid‐like Compound Library Based on the Humulene Skeleton

Many natural terpenoid alkaloid conjugates show biological activity because their structures contain both sp³‐rich terpenoid scaffolds and nitrogen‐containing alkaloid scaffolds. However, their biosynthesis utilizes a limited set of compounds as sources of the terpenoid moiety. The production of terpenoid alkaloids containing various types of terpenoid moiety may provide useful, chemically diverse compound libraries for drug discovery. Herein, we report the construction of a library of terpenoid alkaloid‐like compounds based on Lewis‐acid‐catalyzed transannulation of humulene diepoxide and subsequent sequential olefin metathesis. Cheminformatic analysis quantitatively showed that the synthesized terpenoid alkaloid‐like compound library has a high level of three‐dimensional‐shape diversity. Extensive pharmacological screening of the library has led to the identification of promising compounds for the development of antihypolipidemic drugs. Therefore, the synthesis of terpenoid alkaloid‐like compound libraries based on humulene is well suited to drug discovery. Synthesis of terpenoid alkaloid‐like compounds based on several natural terpenoids is an effective strategy for producing chemically diverse libraries.     

Asymmetric Synthesis of Pochonin E and F,Revision of Their Proposed Structure,and Their Conversion to Potent Hsp90 Inhibitors

A concise and modular synthesis of pochonin E and F, and their epimers at C‐6 established the correct stereochemistry of these two natural products. Several members of the pochonin family have been shown to bind the heat shock protein 90 (Hsp90), which has been the focus of intense drug discovery efforts. Pochonin E and F as well as their epimers were derivatized into the corresponding pochoximes and further modified at the C‐6 position. Molecular dynamics simulations, docking studies, and Hsp90 affinity measurements were performed to evaluate the impact of these modifications.     

Synthesis of Bisheteroarylalkanes by Heteroarylboration: Development and Application of a Pyridylidene–Copper Complex

The development of pyridylidene‐Cu‐complexes and their application in Cu/Pd‐catalyzed heteroarylboration of alkenylheteroarenes is reported. The significance of 1,1′‐heteroarylalkanes as building blocks for drug discovery, as well as the straightforward and modular sequence to prepare the pyridylidene‐Cu‐complexes, makes this catalyst and it applications attractive for chemical synthesis. Furthermore, chiral variants of the pyridylidene‐Cu‐complexes have been prepared and utilized in the enantioselective arylboration of E‐alkenes, further demonstrating the value and potential of this class of catalysts.     

General Enantioselective C−H Activation with Efficiently Tunable Cyclopentadienyl Ligands

Cyclopentadienyl (Cp) ligands enable efficient steering of various transition‐metal‐catalyzed transformations, in particular enantioselective C−H activation. Currently only few chiral Cp ligands are available. Therefore, a conceptually general approach to chiral Cp ligand discovery would be invaluable as it would enable the discovery of applicable Cp ligands and to efficiently and rapidly vary and tune their structures. Herein, we describe the three‐step gram‐scale synthesis of a structurally diverse and widely applicable chiral Cp ligand collection (JasCp ligands) with highly variable and adjustable structures. Their modular nature and their amenability to rapid structure variation enabled the efficient discovery of ligands for three enantioselective Rh^III‐catalyzed C−H activation reactions, including one unprecedented transformation. This novel approach should enable the discovery of efficient chiral Cp ligands for various further enantioselective transformations.     

多组分反应在合成含肽类药物开发中的应用

多组分反应可以快速大量的合成结构复杂的药物分子,因此现代药物开发与多组分反应的发展密切相关。本文总结了近年来国内外有关多组分反应研究的发展概况及其在含肽链类新药物开发中的应用研究进展。