Synthesis Of Bioactive Molecules Research Articles

Special Issue: “Rational Design and Synthesis of Bioactive Molecules”

The rational design of novel bioactive molecules is a critical but challenging task in drug discovery [...]

Salinity Stress Acclimation Strategies in Chlamydomonas sp. Revealed by Physiological, Morphological and Transcriptomic Approaches.

Climate changes may include variations in salinity concentrations at sea by changing ocean dynamics. These variations may be especially challenging for marine photosynthetic organisms, affecting their growth and distribution. Chlamydomonas spp. are ubiquitous and are often found in extreme salinity conditions. For this reason, they are considered good model species to study salinity adaptation strategies. In the current study, we used an integrated approach to study the Chlamydomonas sp. CCMP225 response to salinities of 20‱ and 70‱, by combining physiological, morphological, and transcriptomic analyses, and comparing differentially expressed genes in the exponential and stationary growth phases under the two salinity conditions. The results showed that the strain is able to grow under all tested salinity conditions and maintains a surprisingly high photosynthetic efficiency even under high salinities. However, at the highest salinity condition, the cells lose their flagella. The transcriptomic analysis highlighted the up- or down-regulation of specific gene categories, helping to identify key genes responding to salinity stress. Overall, the findings may be of interest to the marine biology, ecology, and biotechnology communities, to better understand species adaptation mechanisms under possible global change scenarios and the potential activation of enzymes involved in the synthesis of bioactive molecules.

Catalytic Asymmetric Dearomative [2 + 2] Photocycloaddition/Ring-Expansion Sequence of Indoles with Diversified Alkenes.

Developing novel strategies for catalytic asymmetric dearomatization (CADA) reactions is highly valuable. Visible light-mediated photocatalysis is demonstrated to be a powerful tool to activate aromatic compounds for further synthetic transformations. Herein, a catalytic asymmetric dearomative [2 + 2] photocycloaddition/ring-expansion sequence of indoles with simple alkenes was reported, providing a facile access to enantioenriched cyclopenta[b]indoles with good to high yields and enantioselectivities by means of chiral lanthanide photocatalysis. This protocol exhibited a broad substrate scope and good functional group tolerance, as well as potential applications in the synthesis of bioactive molecules. Mechanistic studies, including control experiments, UV-vis absorption spectroscopy, emission spectroscopy, and DFT calculations, were carried out, shedding insights into the reaction mechanism and the origin of enantioselectivity.

Enantio- and Z-Selective δ-Hydroarylation of Aryl-Substituted 1,3-Dienes via Rh-Catalyzed Conjugate Addition.

Metal-catalyzed enantioselective conjugate arylations of electron-poor alkenes are highly selective processes for C(sp2)-C(sp3) bond formation. δ-Selective hydroarylations of electron-poor 1,3-dienes are less well developed and reactions that deliver high enantioselectivity while giving single alkene isomer products are elusive. Here we report the Rh-catalyzed δ-arylation of aryl-substituted 1,3-dienes that gives nearly exclusive Z-1,4-addition products (generally with >95 : 5 positional and geometrical selectivity). This remote functionalization provides access to chiral diarylated alkenes from readily available precursors poised for further functionalization, including in the synthesis of bioactive molecules. Mechanistic studies suggest that protonolysis of a Rh-allyl intermediate generated by diene insertion into a Rh-aryl is the turnover limiting step and occurs by an inner-sphere proton transfer pathway.

Enantio‐ and Z‐Selective δ‐Hydroarylation of Aryl‐Substituted 1,3‐Dienes via Rh‐Catalyzed Conjugate Addition

AbstractMetal‐catalyzed enantioselective conjugate arylations of electron‐poor alkenes are highly selective processes for C(sp2)−C(sp3) bond formation. δ‐Selective hydroarylations of electron‐poor 1,3‐dienes are less well developed and reactions that deliver high enantioselectivity while giving single alkene isomer products are elusive. Here we report the Rh‐catalyzed δ‐arylation of aryl‐substituted 1,3‐dienes that gives nearly exclusive Z‐1,4‐addition products (generally with >95 : 5 positional and geometrical selectivity). This remote functionalization provides access to chiral diarylated alkenes from readily available precursors poised for further functionalization, including in the synthesis of bioactive molecules. Mechanistic studies suggest that protonolysis of a Rh‐allyl intermediate generated by diene insertion into a Rh‐aryl is the turnover limiting step and occurs by an inner‐sphere proton transfer pathway.

Computational design of myoglobin-based carbene transferases for monoterpene derivatization

Carbene transfer reactions have emerged as pivotal methodologies for the synthesis of complex molecular architectures. Heme protein-catalyzed carbene transfer reactions have shown promising results on model compounds. However, their limited substrate scope has hindered their application in natural product functionalization. Building upon the foundation of previously published work on a carbene transferase-myoglobin variant, this study employs computer-aided protein engineering to design myoglobin variants, using either docking or the deep learning-based LigandMPNN method. These variants were utilized as catalysts in carbene transfer reactions with a selection of monoterpene substrates featuring C–C double bonds, leading to seven target products. This cost-effective methodology broadens the substrate scope for heme protein-catalyzed reactions, thereby opening novel pathways for research in heme protein functionalities and offering fresh perspectives in the synthesis of bioactive molecules.

One pot conversion of phenols and anilines to aldehydes and ketones exploiting α gem boryl carbanions

Functional group interconversion is an important asset in organic synthesis. Phenols/anilines being naturally abundant and the carbonyl being the most common in a wide range of bioactive molecules, an efficient conversion is of prime interest. The reported methods require transition metal catalyzed cross coupling which limits its applicability. Here we have described a method for synthesizing various aldehydes and ketones, starting from phenol and protected anilines via Csp2-O/N bond cleavage in a one-pot/stepwise manner. Our synthetic method is found to be compatible with a diverse range of phenols and anilines carrying sensitive functional groups including halides, esters, ketal, hydroxyl, alkenes, and terminal alkynes as well as the substitution on the aryl cores. A short-step synthesis of bioactive molecules and their functionalization have been executed. Starting from BINOL, a photocatalyst has been designed. Here, we have developed a transition metal-free protocol for the conversion of phenols and anilines to aldehydes and ketones.

Enantioselective synthesis of chiral α,α-dialkyl indoles and related azoles by cobalt-catalyzed hydroalkylation and regioselectivity switch

General, catalytic and enantioselective construction of chiral α,α-dialkyl indoles represents an important yet challenging objective to be developed. Herein we describe a cobalt catalyzed enantioselective anti-Markovnikov alkene hydroalkylation via the remote stereocontrol for the synthesis of α,α-dialkyl indoles and other N-heterocycles. This asymmetric C(sp3)−C(sp3) coupling features high flexibility in introducing a diverse set of alkyl groups at the α-position of chiral N-heterocycles. The utility of this methodology has been demonstrated by late-stage functionalization of drug molecules, asymmetric synthesis of bioactive molecules, natural products and functional materials, and identification of a class of molecules exhibiting anti-apoptosis activities in UVB-irradiated HaCaT cells. Ligands play a vital role in controlling the reaction regioselectivity. Changing the ligand from bi-dentate L6 to tridentate L12 enables CoH-catalyzed Markovnikov hydroalkylation. Mechanistic studies disclose that the anti-Markovnikov hydroalkylation involves a migratory insertion process while the Markovnikov hydroalkylation involves a MHAT process.

Methyl Pyruvate Oxime as a Carbonyl Synthon: Synthesis of Ureas, Carbamates, Thiocarbamates, and Anilides.

A new strategy for the synthesis of unsymmetrical ureas, carbamates, thiocarbamates, and anilides was developed with methyl pyruvate oxime as the carbonyl synthon. The intrinsic reactivity of the reagent enabled consecutive disubstitution involving direct amidation and one-pot deoximative substitution with various nucleophiles. The utility of the method was demonstrated with the synthesis of bioactive molecules.

Catalytic Asymmetric Construction of α,α-Diaryl Aldehydes via Oxo-Hydroarylation of Terminal Alkynes.

Chiral aldehydes containing a tertiary stereogenic center are versatile building blocks in organic chemistry. In particular, such structural motifs bearing an α,α-diaryl moiety are very challenging scaffolds and their efficient asymmetric synthesis is not reported. In this work, a phosphoric acid-catalyzed enantioselective synthesis of α,α-diaryl aldehydes from simple terminal alkynes is presented. This approach yields a wide range of highly enolizable α,α-diaryl aldehydes in good yields with excellent enantioselectivities. Facile transformations of the products, as well as an efficient synthesis of bioactive molecules, including an effective anti-smallpox agent and an FDA-approved antidepressant drug (+)-sertraline, are demonstrated.

Human gut microbiome, diet, and mental disorders.

Diet is one of the most important external factor shaping the composition and metabolic activities of the gut microbiome. The gut microbiome plays a crucial role in host health, including immune system development, nutrients metabolism, and the synthesis of bioactive molecules. In addition, the gut microbiome has been described as critical for the development of several mental disorders. Nutritional psychiatry is an emerging field of research that may provide a link between diet, microbial function, and brain health. In this study, we have reviewed the influence of different diet types, such as Western, Mediterranean, vegetarian, and ketogenic, on the gut microbiota composition and function, and their implication in various neuropsychiatric and psychological disorders.

Visible light-induced 3H-indole hydrogenation using tetramethylethene as an inert hydrogen source

Nitrogen heterocycles play a crucial role in the synthesis of bioactive molecules, prompting extensive research into efficient synthetic strategies. Among these, imine hydrogenation stands out as a vital transformation, with various methodologies developed, including metal-catalyzed and Brønsted acid-catalyzed approaches. However, visible-light-induced imine hydrogenation, a relatively recent advancement, introduces unique opportunities for greener and milder reaction conditions. Herein, we report a novel approach utilizing tetramethylethene as an inert hydrogen source for the visible light-induced hydrogenation of 3H-indoles. The non-metal photocatalyst, thioxanthone-TfOH complex (9-HTXTF), demonstrated efficient catalysis under mild conditions, yielding diverse substituted indoline species.

A Practical and Regioselective Strategy for Aromatic C-H Difunctionalization via Site-Selective C-H Thianthrenation.

Herein, we present a novel Catellani-type reaction that employed aryl-thianthrenium salts as aryl substrates to trigger the subsequent palladium/norbornene cooperatively catalyzed progress. This strategy can achieve site-selective C-H difunctionalization of aryl compounds without directing groups or a known initiating reagent. A series of functionalized syntheses of bioactive molecules further demonstrated the potential of this strategy.

Divergent Synthesis of Fluoroalkyl Ketones through Controlling the Reactivity of Organoboronate Complexes.

Herein, we report a divergent synthesis of fluoroalkyl ketones through visible-light-induced reactions between readily available organoboronic esters and fluoroalkyl acylsilanes. Selective control of the reactivity of the in situ generated organoboronate complexes is the key to achieving divergent transformations. Under basic conditions, the organoboronate complexes undergo deboronative fluoride elimination, resulting in the formation of enol silyl ethers as intermediates that react with various electrophiles to generate defluorinated ketones as the products. Moreover, in combination with peroxide, a 1,2-shift of fluoroalkyl group is favored over deboronative fluoride elimination to generate ketal intermediates, leading to the formation of ketones as the products. This transition-metal-free reaction is operationally simple, and aryl, alkenyl, and alkyl boronic esters are all suitable substrates. The synthetic potential has been demonstrated by gram-scale reactions and facile synthesis of bioactive molecules including zifrosilone and its fluoroalkyl analogs.

Antimicrobial activity and molecular docking studies of some imidazo[2,1-b]thiazole derivatives

The synthesis of bioactive molecules is of major importance in the pharmaceutical industry. In this context, the study was conducted to determine the antimicrobial and antifungal potential of four chalcone-based imidazo[2,1-b]thiazole derivatives already synthesized by our research group. The synthetized compounds obtained in good yield were evaluated for their antibacterial and antifungal activities against E. coli, Staphylococcus aureus, Pseudomonas aeruginosa and Fusarium, the results obtained are compared with the standard. Molecular docking studies were utilized to forecast the potential of these molecules as antimicrobial agents, the results obtained in vitro antibacterial were well confirmed by this method.

Chiral bisphosphine Ph-BPE ligand: a rising star in asymmetric synthesis.

Chiral 1,2-bis(2,5-diphenylphospholano)ethane (Ph-BPE) is a class of optimal organic bisphosphine ligands with C2-symmetry. Ph-BPE with its excellent catalytic performance in asymmetric synthesis has attracted much attention of chemists with increasing popularity and is growing into one of the most commonly used organophosphorus ligands, especially in asymmetric catalysis. Over two hundred examples have been reported since 2012. This review presents how Ph-BPE is utilized in asymmetric synthesis and how powerful it is as a chiral ligand or even a catalyst in a wide range of reactions including applications in the total synthesis of bioactive molecules.

Visible-light-enabled cascade cross-dehydrogenative-coupling/cyclization to construct α-chromone substituted α-amino acid derivatives.

Organophotocatalytic cascade cross-dehydrogenative-coupling/cyclization reaction of o-hydroxyarylenaminones with α-amino acid derivatives for the construction of α-chromone substituted α-amino acid derivatives was developed. Various N-arylglycine esters, amides and dipeptides underwent the cascade cyclization reaction well with o-hydroxyarylenaminones to afford the corresponding 3-aminoalkyl chromones in good to excellent yields. This approach consists of visible-light-promoted oxidation of α-amino acid derivatives, the Mannich reaction, and intramolecular nucleophilic cyclization under acidic conditions, and features a wide reaction scope, a simple operation and mild reaction conditions, which may have the potential to be used for the synthesis of bioactive molecules.

Anti-Markovnikov hydrosilylation and Markovnikov hydroboration of alkenes by a phenanthroline-based tridentate manganese catalyst

The divergent regioselective hydrosilylation and hydroboration of alkenes by a single manganese catalyst are disclosed. Using the Mn catalyst bearing the tridentate phenanthroline scaffold, alkenes were found to undergo anti-Markovnikov hydrosilylation, while the hydroboration of alkenes afforded Markovnikov's products. Both the hydrosilylation and the hydroboration of alkenes proceed under mild conditions (room temperature, neat conditions) with low catalyst loadings (1 mol%) using NaOtBu (3 mol%) as an activator. The reactions are atom-economical, exhibiting a broad substrate scope (46 examples), and excellent functional group tolerance (including aromatic and aliphatic alkenes). Importantly, the presented catalytic systems are suitable for various synthetic applications, and could be extended to the synthesis of bioactive molecules. Mechanistic studies supported that the Mn-H species are crucially important for the catalytic process.

Cobalt-Catalyzed Enantioselective C–H Annulation of Benzylamines with Alkynes: Application to the Modular and Asymmetric Syntheses of Bioactive Molecules

Cobalt-Catalyzed Enantioselective C–H Annulation of Benzylamines with Alkynes: Application to the Modular and Asymmetric Syntheses of Bioactive Molecules

Photoredox/Enzymatic Catalysis Enabling Redox-Neutral Decarboxylative Asymmetric C-C Coupling for Asymmetric Synthesis of Chiral 1,2-Amino Alcohols.

Photocatalysis offers tremendous opportunities for enzymes to access new functions. Herein, we described a redox-neutral photocatalysis/enzymatic catalysis system for the asymmetric synthesis of chiral 1,2-amino alcohols via decarboxylative radical C-C coupling of N-arylglycines and aldehydes by combining an organic photocatalyst, eosin Y, and carbonyl reductase RasADH. Notably, this protocol avoids using any sacrificial reductants. A possible reaction mechanism proposed is that the transformation proceeds through sequential photoinduced decarboxylative radical addition to an aldehyde and a photoenzymatic deracemization pathway. This redox-neutral photoredox/enzymatic strategy is promising not only for effective synthesis of a series of chiral amino alcohols in a green and sustainable manner but also for the design of other novel C-C radical coupling transformations for the synthesis of bioactive molecules.