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The integration of trifluoromethyl groups and three-dimensional quaternary carbon moieties into organic molecules has emerged as a prominent strategy in medicinal chemistry to augment drug efficacy. Although trifluoromethyl (hetero)aromatic amines and derivatives are prevalent frameworks in pharmaceuticals, the development of trifluoromethyl-embedded, intricately structured alkyl amine scaffolds for medicinal research remains a significant challenge. Herein, we present a metallaphotoredox multicomponent amination strategy employing 3,3,3-trifluoropropene, nitroarenes, tertiary alkylamines, and carboxylic acids. This synthetic pathway offers notable advantages, including the accessibility and cost-effectiveness of starting materials, high levels of chemo- and regioselectivity, and modularity. Furthermore, this approach enables the synthesis of a broad spectrum of aniline compounds featuring both trifluoromethyl group and distal quaternary carbon motifs along the aliphatic chains. The accelerated access to such elaborate N-trifluoroalkyl anilines likely involves three sequential radical-mediated coupling events, providing insightful implications for the retrosynthesis of potential compounds in organic synthesis and drug discovery. The trifluoromethyl group can confer advantageous properties to biologically relevant molecules, but methods for its incorporation into aliphatic carbons that are more embedded within the core of the structure are less available. Here, the authors present a multicomponent coupling to synthesize carbon skeletons with a branched trifluoromethyl group via iridium metallaphotoredox catalysis. [ABSTRACT FROM AUTHOR]

The reproducibility of chemical reactions, when obtaining protocols from literature or databases, is highly challenging for academicians, industry professionals and even now for the machine learning process. To synthesize the organic molecule under the photochemical condition, several years for the reaction optimization, highly skilled manpower, long reaction time etc. are needed, resulting in non-affordability and slow down the research and development. Herein, we have introduced the DigiChemTree backed with the artificial intelligence to auto-optimize the photochemical reaction parameter and synthesizing the on demand library of the molecules in fast manner. Newly, auto-generated digital code was further tested for the late stage functionalization of the various active pharmaceutical ingredient. Light-induced reactions of diazo compounds have become crucial in organic synthesis and drug discovery, however, optimization of reaction conditions is still very time-consuming. Here, the authors develop a DigiChemTree platform using artificial intelligence to auto-optimize the photochemical reaction parameters and rapidly synthesize an on-demand library of molecules. [ABSTRACT FROM AUTHOR]

Site‐selective amination of N‐heterocycles is an interesting topic in organic synthesis and drug discovery. We herein present a method for the vicarious‐type nucleophilic amination of azine N‐oxides and cyclic iminoamides using iminyl anions, readily generated from organic azides under basic conditions. The plausible reaction mechanism involving nucleophilic aromatic substitution by iminyl anions is elucidated by a series of mechanistic investigations. [ABSTRACT FROM AUTHOR]

Atropisomers have attracted a great deal of attention lately due to their numerous applications in organic synthesis and to their employment in drug discovery. However, the synthetic arsenal at our disposal with which to access them remains limited. The research described herein is two‐pronged; we both demonstrate the use of MCR chemistry as a synthetic strategy for the de novo synthesis of a class of atropisomers having high barriers to rotation with the simultaneous insertion of multiple chiral elements and we study these unprecedented molecular systems by employing a combination of crystallography, NMR and DFT calculations. By fully exploiting the synthetic capabilities of our chemistry, we have been able to monitor a range of different types of interaction, i. e. π‐π, CH–π, heteroatom‐π and CD–π, in order to conduct structure‐property studies. The results could be applied both to atroposelective synthesis and in drug discovery. [ABSTRACT FROM AUTHOR]

Sulfinamidines are promising aza‐SIV chiral building blocks in asymmetric synthesis and drug discovery. However, no report has documented their enantioselective synthesis. Here we present an enantioselective synthesis of sulfinamidines via electrophilic amination of sulfenamides using an enantiopure N−H oxaziridine. The resulting enantiomerically enriched primary sulfinamidines are configurationally stable at 90 °C in solution and show remarkable stability against organic acids and bases under non‐aqueous conditions. We also demonstrate a one‐pot, three‐component, enantioselective synthesis of sulfinamides using N−H oxaziridine reagents. [ABSTRACT FROM AUTHOR]

Dearomatization has emerged as a powerful tool for rapid construction of 3D molecular architectures from simple, abundant, and planar (hetero)arenes. The field has evolved beyond simple dearomatization driven by new synthetic technology development. With the renaissance of photocatalysis and expansion of the activation mode, the last few years have witnessed impressive developments in innovative photochemical dearomatization methodologies, enabling skeletal modifications of dearomatized structures. They offer truly efficient and useful tools for facile construction of highly complex structures, which are viable for natural product synthesis and drug discovery. In this review, we aim to provide a mechanistically insightful overview on these innovations based on the degree of skeletal alteration, categorized into dearomative functionalization and skeletal editing, and to highlight their synthetic utilities. [ABSTRACT FROM AUTHOR]

Tempted by the unique medicinal and biological potential of indole‐containing heterocycles, chemists, especially those specializing in heterocycle synthesis and drug discovery, are actively pursuing their efficient construction. This review spotlights the latest advancements in microwave‐assisted (M. W.) synthesis of diverse indole‐based heterocyclic compounds. We systematically categorize the reported methods based on the specific indole substitution patterns. This review concise the microwave assisted synthesis of indole based‐pyridine derivatives, indole based‐pyrimidine, indole based‐oxindole, spiro‐oxindole, Fischer indole Heck‐isomerization derivatives, functionalized indole, substituted indoles, indolyl quinoline, indole triazole and indolylnicotinonitriles derivatives. Ultimately, this review aims to provide organic and medicinal chemists with a concise yet informative guide to recent methodologies employing indole derivatives in the microwave‐powered synthesis of heterocycles. [ABSTRACT FROM AUTHOR]

In the realm of organic and green chemistry, the functionalization of cyclobutanes presents a significant challenge, given their unique structural properties and biological relevance. Particularly, the introduction of difluoromethyl groups into cyclobutane frameworks is a burgeoning area of interest due to their potential in drug design and synthesis. However, the construction of difluoromethyl cyclobutanes heavily relies on the environmentally burdensome fluorination of cyclobutyl ketones. Methods to efficiently and directly introduce difluoromethyl groups into cyclobutanes remain underexplored. This study introduces a novel photochemical protocol for the selective difluoromethylation or bromo difluoromethylation of bicyclobutanes, leveraging green solvent-controlled reactions. Remarkably, this method exhibits the merits of both green chemistry and organic chemistry such as renewable visible light as reaction power, high atom economy and fully controlled chemo-selectivity. This work also reveals the mechanism behind the remarkable selectivity achieved. Emphasizing the importance of difluoromethyl cyclobutane scaffolds as bioisosteres, this research not only broadens the chemical space in organic synthesis but also offers new avenues for pharmaceutical discovery. The findings demonstrate the robustness and versatility of the method, including its applicability to drug modifications, addressing a crucial gap in the green synthesis of complex medicinal molecules. [ABSTRACT FROM AUTHOR]

High-throughput continuous flow technology has emerged as a revolutionary approach in chemical synthesis, offering accelerated experimentation and improved efficiency. With the aid of process analytical technology and automation, this system not only enables rapid optimisation of reaction conditions at the millimole to the picomole scale, but also facilitates automated scale-up synthesis. It can even achieve the self-planning and self-synthesis of small drug molecules with artificial intelligence incorporated in the system. The versatility of the system is highlighted by its compatibility with both electrochemistry and photochemistry, and its significant applications in organic synthesis and drug discovery. This highlight summarises its recent developments and applications, emphasising its significant impact on advancing research across multiple disciplines. [ABSTRACT FROM AUTHOR]

Protein‐templated fragment ligation was established as a method for the rapid identification of high affinity ligands, and multicomponent reactions (MCR) such as the Ugi four‐component reaction (Ugi 4CR) have been efficient in the synthesis of drug candidates. Thus, the combination of both strategies should provide a powerful approach to drug discovery. Here, we investigate protein‐templated Ugi 4CR quantitatively using a fluorescence‐based enzyme assay, HPLC‐QTOF mass spectrometry (MS), and native protein MS with SARS‐CoV‐2 main protease as template. Ugi reactions were analyzed in aqueous buffer at varying pH and fragment concentration. Potent inhibitors of the protease were formed in presence of the protein via Ugi 4CR together with Ugi three‐component reaction (Ugi 3CR) products. Binding of inhibitors to the protease was confirmed by native MS and resulted in the dimerization of the protein target. Formation of Ugi products was, however, more efficient in the non‐templated reaction, apparently due to interactions of the protein with the isocyanide and imine fragments. Consequently, in‐situ ligation screening of Ugi 4CR products was identified as a superior approach to the discovery of SARS‐CoV‐2 protease inhibitors. [ABSTRACT FROM AUTHOR]

α,α-Disubstituted α-amino acids (α-AAs) have improved properties compared to other types of amino acids. They serve as modifiers of peptide conformation and as precursors of bioactive compounds. Therefore, it has been a long-standing goal to construct this highly valuable scaffold efficiently in organic synthesis and drug discovery. However, access to α,α-disubstituted α-AAs is highly challenging and largely unexplored due to their steric constraints. To overcome these, remarkable advances have been made in the last decades. Emerging strategies such as synergistic enantioselective catalysis, visible-light-mediated photocatalysis, metal-free methodologies and CO2 fixation offer new avenues to access the challenging synthesis of α,α-disubstituted α-AAs and continuously bring additional contributions to this field. This review article aims to provide an overview of the recent advancements since 2015 and discuss existing challenges for the synthesis of α,α-disubstituted α-AAs and their derivatives. α,α-Disubstituted α-amino acids (α-AAs) have improved properties compared to other amino acids. Here, the authors provide an overview of the recent advancements since 2015 and discuss existing challenges for their synthesis. [ABSTRACT FROM AUTHOR]

Chemists in the medicinal chemistry field are constantly searching for alternatives towards more sustainable and eco-friendly processes for the design and synthesis of drug candidates. The pharmaceutical industry is one of the most polluting industries, having a high E-factor, which is driving the adoption of more sustainable processes not only for new drug candidates, but also in the production of well-established active pharmaceutical ingredients. Deep eutectic systems (DESs) have emerged as a greener alternative to ionic liquids, and their potential to substitute traditional organic solvents in drug discovery has raised interest among scientists. With the use of DESs as alternative solvents, the processes become more attractive in terms of eco-friendliness and recyclability. Furthermore, they might be more effective through making the process simpler, faster, and with maximum efficiency. This review will be focused on the role and application of deep eutectic systems in drug discovery, using biocatalytic processes and traditional organic chemical reactions, as new environmentally benign alternative solvents. Furthermore, herein we also show that DESs, if used in the pharmaceutical industry, may have a significant effect on lowering production costs and decreasing the impact of this industry on the quality of the environment. [ABSTRACT FROM AUTHOR]

This article discusses the synthesis of functionalized spirooxindole polycycles, which are found in many bioactive natural products. The authors describe strategies for the concise synthesis of these complex molecules, including enantiomerically enriched derivatives. They utilize cyclic 1,3-dione derivatives as reactants or as condition-tuning molecules to form the polycyclic systems. The article also explores the formation of spirooxindole pyran polycycles through dynamic stereoselective aldol-oxacyclization cascade reactions. Additionally, the authors discuss the asymmetric construction of spirooxindole polycycles bearing furan-fused rings through Michael-Henry reactions. The use of cyclic 1,3-dione derivatives is shown to alter the reaction conditions and products. The authors conclude by highlighting the potential applications of their synthesis strategies in drug discovery and biomedical research. [Extracted from the article]

Flavin-dependent monooxygenases (FMOs) have raised substantial interest as catalysts in monooxygenation reactions, impacting diverse fields such as drug metabolism, environmental studies, and natural product synthesis. Their application in biocatalysis boasts several advantages over conventional chemical catalysis, such as heightened selectivity, safety, sustainability, and eco-friendliness. In the realm of biomedicine, FMOs are pivotal in antibiotic research, significantly influencing the behavior of natural products, antimicrobial agents, and the pathways critical to drug synthesis They are also underscored as potential pharmaceutical targets, pivotal in opposing disease progression and viable for therapeutic intervention. Additionally, FMOs play a substantial role in environmental science, especially in pesticide processing and in preserving plant vitality. Their involvement in the biosynthesis of compounds like polyethers, tropolones, and ω-hydroxy fatty acids, with remarkable regio- and stereoselectivity, renders them indispensable in drug discovery and development. As our comprehension of FMOs' catalytic mechanisms and structures advances, through the use of cutting-edge biotechnologies like computational design and directed evolution, FMOs are poised to occupy an increasingly significant role in both scientific exploration and industrial applications. [ABSTRACT FROM AUTHOR]

Organosilicon compounds have shown tremendous potential in drug discovery and their synthesis stimulates wide interest. Multicomponent cross-coupling of alkenes with silicon reagents is used to yield complex silicon-containing compounds from readily accessible feedstock chemicals but the reaction with simple alkenes remains challenging. Here, we report a regioselective silylalkylation of simple alkenes, which is enabled by using a stable Ni(II) salt and an inexpensive trans−1,2-diaminocyclohexane ligand as a catalyst. Remarkably, this reaction can tolerate a broad range of olefins bearing various functional groups, including alcohol, ester, amides and ethers, thus it allows for the efficient and selective assembly of a diverse range of bifunctional organosilicon building blocks from terminal alkenes, alkyl halides and the Suginome reagent. Moreover, an expedient synthetic route toward alpha-Lipoic acid has been developed by this methodology. Multicomponent cross-coupling of alkenes with silicon reagents is used to yield complex silicon-containing compounds from readily accessible feedstock chemicals but the reaction with simple alkenes remains challenging. Here, the authors report a regioselective silylalkylation of simple alkenes, which is enabled by using a stable Ni(II) salt and an inexpensive trans-1,2-diaminocyclohexane ligand as a catalyst. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: L‐Hexoses are key components of many biologically relevant natural products and pharmaceuticals. As rare sugars, L‐hexoses are not readily obtained from natural sources. Access to L‐hexose building blocks from commercially available and inexpensive D‐sugars is highly desirable from the viewpoints of organic synthesis and drug discovery. As demonstrated by the convenient preparation of L‐glucosyl, L‐galactosyl, and L‐mannosyl fluorides from readily available β‐D‐C‐glucosyl, β‐D‐C‐mannosyl, and β‐D‐C‐galactosyl derivatives, we describe a novel and efficient approach to the demanding L‐glycosyl fluorides. The transformation features the installation of anomeric hydroxymethyl group under mild conditions and C1‐to‐C5 switch of sugar rings through radical decarboxylative fluorination of uronic acids. The power of this protocol is highlighted by the first assembly of a pentasaccharide repeating unit of Pseudomonas ATCC 31554 extracellular polysaccharide (S‐88). This synthesis relies on the efficient extension of sugar chain at the sterically hindered hydroxy group and the facile introduction of L‐mannosyl unit using L‐mannosyl fluoride as glycosylating agent. The methods developed in this work would provide new tools to the arsenal of synthesis of L‐sugar building blocks and of assembly of glycans containing L‐sugar moieties. [ABSTRACT FROM AUTHOR]

Herein, a direct and efficient electrochemical method for the synthesis of monofluoroalkene products was promoted using gem-difluoroalkenes and unactivated alkyl halides as starting materials with a nickel catalyst. A plausible mechanism involving an alkyl radical intermediate was proposed based on detailed mechanistic studies. Accompanied by the advantages of electrochemistry, the broad substrate scope of primary, secondary, and tertiary alkyl halides, and excellent functional group tolerance, as well as good Z-selectivity and late-stage modification of bio-relevant molecules made the established method greener and more economic, which could make it further applicable in organic synthesis and drug discovery. [ABSTRACT FROM AUTHOR]

Biocatalysis has emerged as a transformative approach in sustainable drug synthesis. This article provides an extensive overview of key enzymes harnessed in biocatalysis and their diverse applications in eco-friendly drug development. Cytochrome P450 enzymes enable the hydroxylation of drug precursors, metabolite generation for toxicity assessment and chiral drug intermediate synthesis. Lipases contribute to asymmetric ester prodrug synthesis and racemic mixture resolution, while proteases are instrumental in peptide bond formation and peptide-based drug synthesis. Transaminases facilitate chiral amine synthesis and amino acid derivative production for drugs. Dehydrogenases allow stereoselective ketone reduction and chiral alcohol production. Aldolases enable enantioselective aldol reactions and key drug intermediate formation. DNA ligases aid in DNA-based drug development and targeted drug delivery. Nitrilases promote nitrile hydrolysis and green amide synthesis. Kinases play roles in prodrug activation and drug target validation. Methyltransferases are vital for small molecule methylation and epigenetic drug discovery. Oxidoreductases enable redox reactions and aldehyde-ketone interconversion. Glycosyltransferases contribute to drug candidate glycosylation and bioconjugation. Biocatalysis offers a sustainable alternative, aligning with pharmaceutical industries’ commitment to environmentally responsible drug discovery and production, as supported by the referenced literature. [ABSTRACT FROM AUTHOR]

The processes used by academic and industrial scientists to discover new drugs have recently experienced a true renaissance, with many new and exciting techniques being developed over the past 5–10 years alone. Drug design and discovery, and the search for new safe and well-tolerated compounds, as well as the ineffectiveness of existing therapies, and society's insufficient knowledge concerning the prophylactics and pharmacotherapy of the most common diseases today, comprise a serious challenge. This can influence not only the quality of human life, but also the health of whole societies, which became evident during the COVID-19 pandemic. In general, the process of drug development consists of three main stages: drug discovery, preclinical development using cell-based and animal models/tests, clinical trials on humans and, finally, forward moving toward the step of obtaining regulatory approval, in order to market the potential drug. In this review, we will attempt to outline the first three most important consecutive phases in drug design and development, based on the experience of three cooperating and complementary academic centers of the Visegrád group; i.e., Medical University of Lublin, Poland, Masaryk University of Brno, Czech Republic, and Comenius University Bratislava, Slovak Republic. [ABSTRACT FROM AUTHOR]

Chemometrics and machine learning are artificial intelligence-based methods stirring a transformative change in chemistry. Organic synthesis, drug discovery and analytical techniques are incorporating machine learning techniques at an accelerated pace. However, machine-assisted chemistry faces challenges while solving critical problems in chemistry due to complex relationships in data sets. Even with increasing publishing volumes on machine learning, its application in areas of chemistry is not a straightforward endeavour. A particular concern in applying machine learning in chemistry is data availability and reproducibility. The present review article discusses the various chemometric methods, expert systems, and machine learning techniques developed for solving problems of organic synthesis and drug discovery with selected examples. Further, a concise discussion on chemometrics and ML deployed in analytical techniques such as, spectroscopy, microscopy and chromatography are presented. Finally, the review reflects the challenges, opportunities and future perspectives on machine learning and automation in chemistry. The review concludes by pondering on some tough questions on applying machine learning and their possibility of navigation in the different terrains of chemistry. [ABSTRACT FROM AUTHOR]

Droplet-based microfluidics offer great opportunities for applications in various fields, such as diagnostics, food sciences, and drug discovery. A droplet provides an isolated environment for performing a single reaction within a microscale-volume sample, allowing for a fast reaction with a high sensitivity, high throughput, and low risk of cross-contamination. Owing to several remarkable features, droplet-based microfluidic techniques have been intensively studied. In this review, we discuss the impact of droplet microfluidics, particularly focusing on drug screening and development. In addition, we surveyed various methods of device fabrication and droplet generation/manipulation. We further highlight some promising studies covering drug synthesis and delivery that were updated within the last 5 years. This review provides researchers with a quick guide that includes the most up-to-date and relevant information on the latest scientific findings on the development of droplet-based microfluidics in the pharmaceutical field. [ABSTRACT FROM AUTHOR]

Diazomethane is a powerful reagent for numerous chemical reactions such as esterifications and the homologation of carboxylic acids. Unfortunately, the synthetic utility of diazomethane is severely limited by its toxicity and highly explosive nature. Diazald® is typically used for ex situ synthesis, however it requires cumbersome and hazardous transfer of diazomethane from a caustic aqueous phase to the reaction medium. Herein, we present a low temperature and base‐free in situ synthesis of diazomethane via a "click and release" reaction between an enamine and sulfonyl azide. Its utility is exemplified by the synthesis of diverse methyl esters in yields of up to 93%. Moreover, diazoketone synthesis from in situ generated diazomethane and acid chlorides was demonstrated for the first time. Finally, trideuteromethylation was achieved using acetone‐d6 as the deuterium source. We anticipate that this method will enable the safer use of diazomethane in organic synthesis and drug discovery programs. [ABSTRACT FROM AUTHOR]

Acid-base dissociation constant (p K a) is a key physicochemical parameter in chemical science, especially in organic synthesis and drug discovery. Current methodologies for p K a prediction still suffer from limited applicability domain and lack of chemical insight. Here we present MF-SuP-p K a (multi-fidelity modeling with subgraph pooling for p K a prediction), a novel p K a prediction model that utilizes subgraph pooling, multi-fidelity learning and data augmentation. In our model, a knowledge-aware subgraph pooling strategy was designed to capture the local and global environments around the ionization sites for micro-p K a prediction. To overcome the scarcity of accurate p K a data, low-fidelity data (computational p K a) was used to fit the high-fidelity data (experimental p K a) through transfer learning. The final MF-SuP-p K a model was constructed by pre-training on the augmented ChEMBL data set and fine-tuning on the DataWarrior data set. Extensive evaluation on the DataWarrior data set and three benchmark data sets shows that MF-SuP-p K a achieves superior performances to the state-of-the-art p K a prediction models while requires much less high-fidelity training data. Compared with Attentive FP, MF-SuP-p K a achieves 23.83% and 20.12% improvement in terms of mean absolute error (MAE) on the acidic and basic sets, respectively. Integrating domain knowledge into deep learning techniques significantly boosts model performance on p K a prediction. The proposed MF-SuP-p K a achieves state-of-the-art accuracy with higher robustness, and is capable of handling ionized molecules. [Display omitted] [ABSTRACT FROM AUTHOR]

Artificial intelligence technology shows the advantages of improving efficiency, reducing costs, shortening time, reducing the number of staff on site and achieving precise operations, making impressive research progress in the fields of drug discovery and development, but there are few reports on application in energetic materials. This paper addresses the high safety risks in the current nitrification process of energetic materials, comprehensively analyses and summarizes the main safety risks and their control elements in the nitrification process, proposes possibilities and suggestions for using artificial intelligence technology to enhance the "essential safety" of the nitrification process in energetic materials, reviews the research progress of artificial intelligence in the field of drug synthesis, looks forward to the application prospects of artificial intelligence technology in the nitrification of energetic materials and provides support and guidance for the safe processing of nitrification in the propellants and explosives industry. [ABSTRACT FROM AUTHOR]

Majority of drugs act by interacting with chiral counterparts, e.g., proteins, and we are, unfortunately, well-aware of how chirality can negatively impact the outcome of a therapeutic regime. The number of chiral, non-racemic drugs on the market is increasing, and it is becoming ever more important to prepare these compounds in a safe, economic, and environmentally sustainable fashion. Asymmetric organocatalysis has a long history, but it began its renaissance era only during the first years of the millennium. Since then, this field has reached an extraordinary level, as confirmed by the awarding of the 2021 Chemistry Nobel Prize. In the present review, we wish to highlight the application of organocatalysis in the synthesis of enantio-enriched molecules that may be of interest to the pharmaceutical industry and the medicinal chemistry community. We aim to discuss the different activation modes observed for organocatalysts, examining, for each of them, the generally accepted mechanisms and the most important and developed reactions, that may be useful to medicinal chemists. For each of these types of organocatalytic activations, select examples from academic and industrial applications will be disclosed during the synthesis of drugs and natural products. [ABSTRACT FROM AUTHOR]

Carbon‐Carbon bond forming reactions are ubiquitous in nature and important for chemical and drug synthesis. Modern methods mostly utilize activated reactants, and despite recent developments in organic synthesis, and theoretical understanding, these have had limited success with unactivated C−H bonds. Here we apply a simple yet powerful Bond Dissociation Energy (BDE)‐based Reaction Enthalpy (BDERE) analysis to model C−C cross‐coupling reactions. BDERE appears in classical textbooks (halogenation of alkanes) but has not been applied to cross‐coupling reactions. BDERE allows one to rationalize the ease of coupling reactions for both homolytic and heterolytic mechanisms for all six C−C bond hybridization types. It facilitates the identification of a simple but unexplored reaction for ethane synthesis. BDERE values give valuable insights into recent advancements in C−C cross‐couplings of fully unfunctionalized (UFCC) and semi‐functionalized (SFCC) reactants that utilize metal, photoredox, organo, and biocatalysis. BDERE analysis may enable others to investigate and design novel cross‐coupling reactions. [ABSTRACT FROM AUTHOR]

The introduction of fluorine‐containing groups into organic molecules can significantly affect their physical and chemical properties and has long been used as an effective strategy for drug discovery and development. Consequently, the development of catalytic asymmetric methods for the synthesis of fluorine‐containing heterocycles is highly desirable and sought after. Herein, we describe a nickel‐catalyzed defluorinative asymmetric cyclization of fluoroalkyl‐substituted 1,6‐enynes, providing an expedient access to synthetically attractive 4‐fluorovinyl‐substituted 2‐pyrrolidones in good yields with remarkable high levels of chemo‐, regio‐, and enantioselectivities (90–99 % ee,>35 examples). This protocol features readily available starting materials and excellent functional group compatibility, and exhibits complementary regioselectivity. The utility of this strategy was demonstrated in the enantioselective synthesis of the antiepileptic drug Seletracetam. [ABSTRACT FROM AUTHOR]

The synthesis and functionalization of nitrogen‐containing compounds continue to be important due to their wide applications. In particular, the preparation of nitriles and amides applying cost‐effective and green methodologies is of central importance because these products represent valuable fine and bulk chemicals and serve as key precursors and central intermediates in organic synthesis and drug discovery as well as materials. Here, the preparation of nitriles and primary amides from alcohols and ammonia by a heterogeneous Cu‐catalyzed aerobic oxidation process is reported. The optimal catalyst for this synthesis is based on supported copper oxide‐nanoparticles, which are prepared by the impregnation and pyrolysis of simple copper nitrate on carbon. Applying these reusable nanoparticles, various simple, substituted, and functionalized aromatic, heterocyclic, and aliphatic nitriles are synthesized starting from inexpensive and easily accessible alcohols and ammonia in the presence of air. In addition, the synthesis of selected primary amides in a water medium is also performed using these Cu nanoparticles. [ABSTRACT FROM AUTHOR]

The processes used by academic and industrial scientists to discover new drugs have recently experienced a true renaissance, with many new and exciting techniques being developed over the past 5–10 years alone. Drug design and discovery, and the search for new safe and well-tolerated compounds, as well as the ineffectiveness of existing therapies, and society’s insufficient knowledge concerning the prophylactics and pharmacotherapy of the most common diseases today, comprise a serious challenge. This can influence not only the quality of human life, but also the health of whole societies, which became evident during the COVID-19 pandemic. In general, the process of drug development consists of three main stages: drug discovery, preclinical development using cell-based and animal models/tests, clinical trials on humans and, finally, forward moving toward the step of obtaining regulatory approval, in order to market the potential drug. In this review, we will attempt to outline the first three most important consecutive phases in drug design and development, based on the experience of three cooperating and complementary academic centers of the Visegrád group; i.e., Medical University of Lublin, Poland, Masaryk University of Brno, Czech Republic, and Comenius University Bratislava, Slovak Republic.

This document is an editorial from the journal Frontiers in Chemistry titled "Medicinal chemistry of active pharmaceutical ingredients of drug products." It discusses the importance of active pharmaceutical ingredients (APIs) in drug products and the need for suitable APIs to comply with specific dosage form characteristics. The editorial highlights three research studies related to medicinal chemistry. The first study explores the anti-ulcerative colitis effects of extracts from Calliandra haematocephala. The second study focuses on the quality evaluation of compounds in leaves of six Taxus species. The third study investigates the chemical fingerprinting and biological properties of the essential oil from Eucalyptus globulus leaves. The authors conclude that these studies provide valuable insights into potential therapeutic approaches for various diseases. [Extracted from the article]

A domino cyclization of oxime esters and imines has been achieved by dual photoredox/copper catalysis. A variety of structurally diverse fully substituted dihydropyrimidines have been forged in 37–88% yields at room temperature. This synthetic protocol provides N‐heterocycles with high molecular complexity and functional group diversity. The present reaction is amenable to gram‐scale synthesis, which is expected to find potential applications in organic synthesis and drug discovery. A plausible reaction mechanism is proposed. [ABSTRACT FROM AUTHOR]

Amines and alcohols with a fully substituted α-carbon are structures of great value in organic synthesis and drug discovery. While conventional methods towards these motifs often rely on enantioselective carbon-carbon or carbon-heteroatom bond formation reactions, a desymmetric method is developed here by selectively hydrosilylating one of the esters of easily accessible α-substituted α-amino- and -oxymalonic esters. The desymmetrization is enabled by a suite of dinuclear zinc catalysts with pipecolinol-derived tetradentate ligands and can accommodate a diverse panel of heteroatom substituents, including secondary amides, tertiary amines, and ethers of different sizes. The polyfunctionalized reduction products, in return, have provided expeditious approaches to enantioenriched nitrogen- and oxygen-containing molecules, including dipeptides, vitamin analogs, and natural metabolites. Chiral α-tertiary amines and tertiary alcohols are prevalent in bioactive molecules yet challenging targets to access. Here, the authors provide a dinuclear zinc-catalyzed desymmetric approach based on readily available malonic esters. [ABSTRACT FROM AUTHOR]

Unpredicted drug safety issues constitute the majority of failures in the pharmaceutical industry according to several studies. Some of these preclinical safety issues could be attributed to the non-selective binding of compounds to targets other than their intended therapeutic target, causing undesired adverse events. Consequently, pharmaceutical companies routinely run in-vitro safety screens to detect off-target activities prior to preclinical and clinical studies. Hereby we present an open source machine learning framework aiming at the prediction of our in-house 50 off-target panel activities for ~ 4000 compounds, directly from their structure. This framework is intended to guide chemists in the drug design process prior to synthesis and to accelerate drug discovery. We also present a set of ML approaches that require minimum programming experience for deployment. The workflow incorporates different ML approaches such as deep learning and automated machine learning. It also accommodates popular issues faced in bioactivity predictions, as data imbalance, inter-target duplicated measurements and duplicated public compound identifiers. Throughout the workflow development, we explore and compare the capability of Neural Networks and AutoML in constructing prediction models for fifty off-targets of different protein classes, different dataset sizes, and high-class imbalance. Outcomes from different methods are compared in terms of efficiency and efficacy. The most important challenges and factors impacting model construction and performance in addition to suggestions on how to overcome such challenges are also discussed. [ABSTRACT FROM AUTHOR]

Biocatalysis is constantly providing novel options for the synthesis of active pharmaceutical ingredients (APIs). In addition to drug development and manufacturing, biocatalysis also plays a role in drug discovery and can support many active ingredient syntheses at an early stage to build up entire scaffolds in a targeted and preparative manner. Recent progress in recruiting new enzymes by genome mining and screening or adapting their substrate, as well as product scope, by protein engineering has made biocatalysts a competitive tool applied in academic and industrial spheres. This is especially true for the advances in the field of nonribosomal peptide synthesis and enzyme cascades that are expanding the capabilities for the discovery and synthesis of new bioactive compounds via biotransformation. Here we highlight some of the most recent developments to add to the portfolio of biocatalysis with special relevance for the synthesis and late-stage functionalization of APIs, in order to bypass pure chemical processes. [ABSTRACT FROM AUTHOR]

Majority of drugs act by interacting with chiral counterparts, e.g., proteins, and we are, unfortunately, well-aware of how chirality can negatively impact the outcome of a therapeutic regime. The number of chiral, non-racemic drugs on the market is increasing, and it is becoming ever more important to prepare these compounds in a safe, economic, and environmentally sustainable fashion. Asymmetric organocatalysis has a long history, but it began its renaissance era only during the first years of the millennium. Since then, this field has reached an extraordinary level, as confirmed by the awarding of the 2021 Chemistry Nobel Prize. In the present review, we wish to highlight the application of organocatalysis in the synthesis of enantio-enriched molecules that may be of interest to the pharmaceutical industry and the medicinal chemistry community. We aim to discuss the different activation modes observed for organocatalysts, examining, for each of them, the generally accepted mechanisms and the most important and developed reactions, that may be useful to medicinal chemists. For each of these types of organocatalytic activations, select examples from academic and industrial applications will be disclosed during the synthesis of drugs and natural products.

C2-formyl indoles are important building blocks for the organic synthesis of alkaloids and small molecules with broad biological activities. Generally, its preparation involves both direct formylation of indoles at the activated C2-position with as unstable carbonyl sources and oxidative cleavage of tedious prepared tetrahydro- β -carbolines (TH β Cs) in the harsh conditions. In continuation of our research on the oxidative functionalization of indoles, in this letter, we report that straightforward effectively oxidation of easily available 2-methylindoles bearing C3-heteroatom functional group proceeds regioselectively C2-formyl indoles in good and excellent yields employing an oxidative combination of NCS/DMSO. This methodology presents a reasonably broad substrate scope and excellent functional group tolerance, thus enabling the preparation of highly versatile building blocks susceptible to further functionalization. An additional feature of this approach includes high efficiency, ease of operation, facile purification, and short reaction time, making it a promising strategy for organic synthesis and drug discovery. To create your abstract, type over the instructions in the template box below.Fonts or abstract dimensions should not be changed or altered. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Commentary on when and how drug metabolite synthesis fits into the overall drug development pathway and the influence of regulatory guidelines. • The tool box of techniques used by a specialist contract research organisation to make phase I and II metabolites. • Case studies illustrating recent examples, including the significance of selected drug metabolites and their synthesis. The drug discovery and development process encompasses the interrogation of metabolites arising from the biotransformation of drugs. Here we look at why, when and how metabolites of small-molecule drugs are synthesised from the perspective of a specialist contract research organisation, with particular attention paid to projects for which regulatory oversight is relevant during this journey. To illustrate important aspects, we look at recent case studies, trends and learnings from our experience of making and identifying metabolites over the past ten years, along with with selected examples from the literature. [ABSTRACT FROM AUTHOR]

[Display omitted] Reactions for drug synthesis under cell-like conditions or even inside living cells can potentially be used e.g. , to minimize toxic side effects, to maximize bioactive compound efficacy and/or to address drug delivery problems. Those reactions should be bioorthogonal to enable the generation of drug-like compounds with sufficiently good yields. In the known bioorthogonal Michael reactions, using thiols and phosphines as nucleophiles (e.g. , in C S and C P bond formation reactions) is very common. No bioorthogonal Michael addition with a carbon nucleophile is known yet. Therefore, the development of such a reaction might be interesting for future drug discovery research. In this work, the metal-free Michael addition between cyclohexanone and various trans-β- nitrostyrenes (C C bond formation reaction), catalysed by a dipeptide salt H-Pro-Phe-O-Na+, was investigated for the first time in the presence of glutathione (GSH) and in phosphate-buffered saline (PBS). We demonstrated that with electron-withdrawing substituents on the aromatic ring and in β -position of the trans-β- nitrostyrene yields up to 64% can be obtained under physiological conditions, indicating a potential bioorthogonality of the studied Michael reaction. In addition, the selected Michael products demonstrated activity against human ovarian cancer cells A2780. This study opens up a new vista for forming bioactive compounds via C C bond formation Michael reactions under physiological (cell-like) conditions. [ABSTRACT FROM AUTHOR]

I "The most exciting thing about my research is sticking to the basic synthesis of target molecules, avoiding fancy materials with the objective to come up with something fundamental, appealing and accessible ... My greatest achievement has been striking a work-life balance. B The most exciting thing about my research is b sticking to the basic synthesis of target molecules, avoiding fancy materials with the objective to come up with something fundamental, appealing and accessible. B My favorite piece of research is b the frustrated Lewis pairs (FLP) chemistry developed by Prof. Douglas W. Stephan for the activation of small molecules. [Extracted from the article]

I "The most exciting thing about my research is sticking to the basic synthesis of target molecules, avoiding fancy materials with the objective to come up with something fundamental, appealing and accessible ... My greatest achievement has been striking a work-life balance. B The most exciting thing about my research is b sticking to the basic synthesis of target molecules, avoiding fancy materials with the objective to come up with something fundamental, appealing and accessible. B My favorite piece of research is b the frustrated Lewis pairs (FLP) chemistry developed by Prof. Douglas W. Stephan for the activation of small molecules. [Extracted from the article]

Drug discovery and development are among the most important translational science activities that contribute to human health and wellbeing. However, the development of a new drug is a very complex, expensive, and long process which typically costs 2.6 billion USD and takes 12 years on average. How to decrease the costs and speed up new drug discovery has become a challenging and urgent question in industry. Artificial intelligence (AI) combined with new experimental technologies is expected to make the hunt for new pharmaceuticals quicker, cheaper, and more effective. We discuss here emerging applications of AI to improve the drug discovery process. AI has enormous potential to revolutionize drug discovery. Computational prediction of atomic and molecular properties is the foundation of most de novo design strategies. Machine learning, a branch of AI, can now predict the physical and chemical properties of small molecules at quantum mechanics-level accuracy with much lower time-cost. AI is also able to search for correlations between molecular representations and biological and toxicological activities. AI-based algorithms are also being developed to efficiently probe the pathways of synthesis of novel drug candidates. In combination with robotic platforms, the chemical space for novel reactions can be explored by learning from automated analysis of reaction feasibility. [ABSTRACT FROM AUTHOR]

Background: Synthetic lethality describes a relationship between two genes where single loss of either gene does not trigger significant impact on cell viability, but simultaneous loss of both gene functions results in lethality. Targeting synthetic lethal interactions with drug combinations promises increased efficacy in tumor therapy. Materials and methods: We established a set of synthetic lethal interactions using publicly available data from yeast screens which were mapped to their respective human orthologs using information from orthology databases. This set of experimental synthetic lethal interactions was complemented by a set of predicted synthetic lethal interactions based on a set of protein meta-data like e.g. molecular pathway assignment. Based on the combined set, we evaluated drug combinations used in late stage clinical development (clinical phase III and IV trials) or already in clinical use for ovarian cancer with respect to their effect on synthetic lethal interactions. We furthermore identified a set of drug combinations currently not being tested in late stage ovarian cancer clinical trials that however have impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer. Results: Twelve of the tested drug combinations addressed a synthetic lethal interaction with the anti-VEGF inhibitor bevacizumab in combination with paclitaxel being the most studied drug combination addressing the synthetic lethal pair between VEGFA and BCL2. The set of 84 predicted drug combinations for example holds the combination of the PARP inhibitor olaparib and paclitaxel, which showed efficacy in phase II clinical studies. Conclusion: A set of drug combinations currently not tested in late stage ovarian cancer clinical trials was identified having impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer. [ABSTRACT FROM AUTHOR]

• Multicomponent reactions helps to swiftly synthesize and evaluate for activity. • This review covers synthesis of dihydropyrimidines and their biological activities. • Novel dihydropyrimidines can be potential anticancer therapeutics. • This review reports all the patented and marketed dihydropyrimidines as drugs. • This review reports future perspectives of dihydropyrimidines in drug discovery. One of the largest classes of organic molecules are dihydropyrimidines and its derivatives. They are widely used in a variety of pharmacological and industrial applications. Their biological and pharmacological activities include antihypertensive, antidiabetic, anti-inflammatory, antibacterial, antifungal, anticancer, and antiviral activities. The presence of pyrimidine and pyrimidine-containing rings in the substructures of therapeutically effective drugs has drawn considerable interest amongst the scientific fraternity. The potential therapeutic use of these heterocycles has prompted medicinal chemists to synthesize drugs that contain these heterocycles. Against this backdrop, this review examines the one-pot multicomponent reaction, that is, the Biginelli reaction and its mechanism. Also, we reviewed various synthetic approaches for the synthesis of dihydropyrimidines and their diverse pharmacological activities reported in the last two decades. We highlight different marketed drugs with dihydropyrimidine as a pharmacophore as well as patented dihydropyrimidines in the recent past. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Identification, characterization, pharmacological and toxicological evaluation of metabolites. • Reveal activity of metabolite: superior or toxic. • Strategies for artificial metabolite synthesis. • Tool for new drug discovery, novel biomarker and drug target identification. • Helpful in metabolite profiling and synthesizing novel bioanalytical standards. Biotransformation was previously viewed as merely the structural characterization of drug metabolites, and it was performed only when drug candidates entered clinical development. The synthesis of drug metabolites is crucial to the drug development process because it generates either pharmacologically active, inactive, or reactive molecules and hence their characterization and comprehensive pharmacological evaluation is necessary. The chemical metabolite synthesis is very challenging due to the complex structures of many drug molecules, presence of multiple stereocenters, poor reaction yields, and the formation of unwanted by-products. Drug metabolites and their chemical synthesis have immense significance in the drug discovery process. The chemical synthesis of metabolites facilitates on- or off-target pharmacological and toxicological evaluations at the easiest. In a broader view metabolite could be a target lead molecule for drug design, toxic reactive metabolites, pharmaceutical standards for bioanalytical methods, etc. Collectively these metabolite information dossiers will aid regulatory agencies such as the EMA and FDA in maintaining strict vigilance over drug manufacturers with regard to the safety of NCE's and their hidden metabolites. Herein, we are presenting a systematic compilation of chemical and biocatalytic strategies reported to date for pharmaceutical drug metabolite synthesis. This review report is very useful for the laboratory synthesis of new drug metabolites, and their preclinical biological evaluation could aid in the detection of early threats (alerts) in drug discovery, eliminate the toxicity profile, explore newer pharmacology, and delivering a promising and safe drug candidate to humankind. [ABSTRACT FROM AUTHOR]