Chemistry

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Pyrrole and indole derivatives are functionalizedviaa green initiative with the dimethyl malonate derived phenyl iodonium ylide4ain the presence of a blue LEDviaC-H functionalization of the respective heterocycles in methanol to generate the desired compounds5-7in moderate to good yields. Control experiments provide insight into the probable reaction mechanism. Finally, the strategy is successfully applied in the generation of azepino[4,5-b]indole12a/b. © The Royal Society of Chemistry 2021.

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Organic and Biomolecular Chemistry

A sustainable C-H functionalization of indoles, pyrroles and furans under a blue LED with iodonium ylides

Glycosyltransferases (GTs) catalyze the formation of glycosidic bonds in carbohydrates and glycoconjugates, with various outcomes depending not only on the acceptor molecules they bind but also on the type of glycosidic bond they form (C-O, C-N, C-S, or C-C). Here we show that the glucosyltransferase UGT1 from the indigo plant Polygonum tinctorium catalyzes either N-, O-, or S-glycosylation with similar rates. We solve the structure of the enzyme in complex with its donor and acceptor substrates and elucidate the molecular basis of N-, O-, and S-specificities using experimental mutagenesis and QM/MM simulations, revealing distinct mechanisms for N-, O-, and S-glycosylation. We also show that the active site can be engineered to increase or favor one of the three glycosylation activities over another. These results will foster the design of more active and specific enzyme variants for production of glycosides. ©

ACS Catalysis

O-/ N-/ S-Specificity in Glycosyltransferase Catalysis: From Mechanistic Understanding to Engineering

Background: Despite numerous efforts to eradicate the disease, malaria continues to remain one of the most dangerous infectious diseases plaguing the world. In the absence of any effective vaccines and with emerging drug resistance in the parasite against the majority of anti-malarial drugs, the search for new drugs is urgently needed for effective malaria treatment. Methods: The goal of the present study was to examine the compound library, based on indoles generated through diversity-oriented synthesis belonging to four different architecture, i.e., 1-aryltetrahydro/dihydro-β-carbolines and piperidine/pyrrolidine-fused indole derivatives, for their in vitro anti-plasmodial activity. Trifluoroacetic acid catalyzed transformation involving tryptamine and various aldehydes/ketones provided the library. Results: Among all the compounds screened, 1-aryltetrahydro-β-carbolines 2 and 3 displayed significant anti-plasmodial activity against both the artemisinin-sensitive and artemisinin-resistant strain of Plasmodium falciparum. It was observed that these compounds inhibited the overall parasite growth in intra-erythrocytic developmental cycle (IDC) via reactive oxygen species-mediated parasitic death and thus could be potential anti-malarial compounds. Conclusion: Overall the compounds 2 and 3 identified in this study shows promising anti-plasmodial activity that can kill both artemisinin-sensitive and artemisinin-resistant strains of P. falciparum. © 2021, The Author(s).

Life Sciences

Malaria Journal

Diversity-oriented synthesis derived indole based spiro and fused small molecules kills artemisinin-resistant Plasmodium falciparum

Full-visible color-tunable new fluorophores are essential in bioimaging research. However, it is significantly challenging to design fluorophores with the desired optical and biological properties owing to their structural complexity. We report a unified design of an interesting molecular framework, IndiFluors, based on the principle of a donor-acceptor-donor (D1-A-D2) system. The IndiFluors comprise pyrylium, pyridinium, and pyridine derivatives, which exhibit full-visible emission color (375-700 nm) by varying donor and acceptor strengths of the core scaffolds. With a minimal change of structure, the bright fluorophores (φ: 0.96) can be tuned to become nonfluorescent (φ: 0.01), which is well explained by time-dependent density functional theory (TD-DFT/PCM) by oscillator strengths in the S1 state. Within IndiFluors, pyridinium offers several advantages, including a large Stokes shift (∼154 nm) and excellent stability, compared to pentacyclic pyrylium fluorophores. Especially, the designed probe, PM-Mito-OH, demonstrated specific colocalization in mitochondria and a monitored ratiometric pH change during mitochondrial damage, autolysosomes, and the mitophagy process. Hence, IndiFluors and the derived probe show great potential for cellular pH imaging in live cells while exhibiting minimal cytotoxicity. ©

ACS Sensors

IndiFluors: A New Full-Visible Color-Tunable Donor-Acceptor-Donor (D1-A-D2) Fluorophore Family for Ratiometric pH Imaging during Mitophagy

An enzyme which is capable of catalyzing C–H amination reactions is considered to be a dream tool for chemists due to its pharmaceutical potential and greener approach. Recently{,} the Arnold group achieved this feat using an engineered CYP411 enzyme{,} which further undergoes a random directed evolution which increases its efficiency and selectivity. The present study provides mechanistic insight and the root cause of the success of these mutations to enhance the reactivity and selectivity of the mutant enzyme. This is achieved by means of comprehensive MD simulations and hybrid QM/MM calculations. The study shows that the efficient C–H amination by the engineered CYP411 is a combined outcome of electronic and steric effects. The mutation of the axial cysteine ligand to serine relays electron density to the Fe ion in the heme{,} and thereby enhances the bonding capability of the heme-iron to the nitrogen atom of the tosyl azide. In comparison{,} the native cysteine-ligated P450 cannot bind the tosyl azide. Additionally{,} the A78V and A82L mutations in P411 provide ‘bulk’ to the active site which increases the enantioselectivity via a steric effect. At the same time{,} the QM/MM calculations elucidate the C–H amination by the iron nitrenoid{,} revealing a mechanism analogous to Compound I in the native C–H hydroxylation by P450.

Chem. Sci.

MD simulations and QM/MM calculations reveal the key mechanistic elements which are responsible for the efficient C–H amination reaction performed by a bioengineered P450 enzyme

Mild blue light-mediated N-H insertion of indole and its derivatives into aryldiazoesters has been reported in a batch and flow strategy to afford the corresponding N-alkylated product in moderate-to-excellent yield. Detailed high-performance liquid chromatography-based reaction kinetics measurements, control experiments, and kinetic isotope effect reveal that 3-substituted indoles with electron-withdrawing groups such as -CN and -CHO facilitated the product formation, whereas the electron-donating group retarded the process. The neutral indole performed in between them. Furthermore, Hammett plot and density functional theory-based transition-state optimization studies showed substantial correlation of the electronic nature of the substituents at the C3 position of indoles with the rate of the N-H insertion reaction. The strategy was utilized to synthesize a key intermediate for the natural product (-)-psychotrimine. ©

Journal of Organic Chemistry

Blue LED-Mediated N-H Insertion of Indoles into Aryldiazoesters at Room Temperature in Batch and Flow: Reaction Kinetics, Density Functional Theory, and Mechanistic Study

Due to their outstanding and versatile properties, polybenzoxazines have quickly occupied a great niche of applications. Developing the ability to polymerize benzoxazine resin at lower temperatures than the current capability is essential in taking advantage of these exceptional properties and remains to be most challenging subject in the field. The current review is classified into several parts to achieve this goal. In this review, fundamentals on the synthesis and evolution of structure, which led to classification of PBz in different generations, are discussed. Classifications of PBzs are defined depending on building block as well as how structure is evolved and property obtained. Progress on the utility of biobased feedstocks from various bio‐/waste‐mass is also discussed and compared, wherever possible. The second part of review discusses the probable polymerization mechanism proposed for the ring‐opening reactions. This is complementary to the third section, where the effect of catalysts/initiators has on triggering polymerization at low temperature is discussed extensively. The role of additional functionalities in influencing the temperature of polymerization is also discussed. There has been a shift in paradigm beyond the lowering of ring‐opening polymerization (ROP) temperature and other areas of interest, such as adaptation of molecular functionality with simultaneous improvement of properties. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Polymers

Review on the accelerated and low‐temperature polymerization of benzoxazine resins: Addition polymerizable sustainable polymers

Formaldehyde (FA), a simple reactive carbonyl molecule, is endogenously produced in the cell at various physiological condition. At elevated level, FA causes severe cell toxicity as well as damage in macromolecules such proteins and DNA. For detecting FA in living cell, we identify a small but effective fluorescent turn on probe comprising single benzene-based orothophenylenediamine compound. Further study reveals that carboxylic group in orothophenylenediamine plays the important role in enhancing fluorescent signal than another electron withdrawing group. It is even interesting to observe the occurrence of fluorescent enhancement in glutathione (GSH) environment which is generally abundant in every cell. Our probe enables to detect FA over other bio-analytes efficiently with limit of detection of 123 nM and 355-fold of enhancement in cellular mimicking conditions. Moreover, this probe could be useful in discriminating cell that has high concentration of FA as well as GSH. © 2020 Elsevier B.V.

Journal of Photochemistry and Photobiology B: Biology

A single benzene fluorescent probe for efficient formaldehyde sensing in living cells using glutathione as an amplifier

The HisA enzyme catalyzes the first step of histidine biosynthesisviathe Amadori rearrangement of the substrate ProFAR. Since it possesses the most conserved and ancient TIM-barrel fold, it provides an ideal framework for bioengineering of a new function from ancestral enzymes. In the present study, first, the catalytic mechanism of HisA biosynthesis was elucidated using hybrid Quantum Mechanical/Molecular Mechanical calculations, and thereafter, key residues contributing towards the promiscuity for TrpF activity were revealed using several MD simulations of a wild type enzyme and its variant with the native (ProFAR) and promiscuous (PRA) substrates. Our study reveals that the two loops (βα)1and (βα)5on the catalytic site of the HisA enzyme have incredible adaptability for the native and promiscuous substrates. The conformational interplay between these two loops is substrate driven and precise bioengineering targeting these loops is key to the emergence of new functions. Furthermore, the study reveals a key role of the Arg 15 residue which is close to the catalytic center of the enzyme in the bifunctionality of the HisA enzyme by increasing the loop flexibility. Therefore, our study provides crucial information for future bioengineering work to use the HisA enzyme as a scaffold for new enzymatic activity. © The Royal Society of Chemistry 2021.

Simulations reveal the key role of Arg15 in the promiscuous activity in the HisA enzyme

A fully biobased benzoxazine monomer, V-fa (using vanillin and furfurylamine) was grafted onto chitosan (CS) at different weight ratios (CXVY) using “grafting to” benign Schiff base chemistry. Incorporation of V-fa onto CS increased the tensile strength and improved chemical resistance of the CS-graft-V-fa films. Reversible labile linkages, expansion of CS galleries and leaching out of phenolic species from biobased polymer films led to an improved antibacterial activity against Staphylococcus aureus, which is ∼125 times higher than the bare CS film, V-fa and oligomeric V-fa. The leached out species from films were analyzed extensively by NMR, FTIR, GPC, ABTS and HRMS analysis. Oxidative-stress seems to be responsible for antibacterial activity. Current work illustrates an attractive synthetic approach and the improved antibacterial performance of biobased CS-graft-poly(V-fa) films which may hold as a potential alternative for wound-healing and implant applications in future. © 2020 Elsevier Ltd