Chemistry

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Shiv Nadar University

Herein we have reported the discovery of a pentacyclic building block comprised of fused indole-quinoline and piperidinone from the natural product perophoramidine as a formidable anticancer agent. The compounds were synthesized in six steps where the key steps involved a blue LED mediated intramolecular cyclopropanation of the indole intermediates and concomitant reduction of the associated aryl nitro moiety to nitroso in the molecule. Cytotoxicity screening of the compounds against an array of cancer cells that is, MCF7, HCT116 and A549 demonstrated 0.6 to 9 μM IC50s by few of the compounds. γH2AX immunofluorescence assay of the two most potent molecules from the phenotypic screening with anti-γ-H2AX Alexa Fluor 488 antibody revealed extensive DNA damage of the A549 cells which indicated probable PARP inhibition (similar to Perophoramidine). Through molecular docking and molecular dynamic (MD) simulation studies the binding efficiency of our compounds with poly(ADP-ribose)polymerase 1 (PARP 1) enzyme was determined. Chemiluminescent PARP Assay with Histone-coated strips indicated that the most active compounds from the phenotypic screening induced PARP-1 inhibition with IC50s of 1.3→1.5 μM. © 2022 Wiley-VCH GmbH.

World University root node

(SoNS) School of Natural Sciences

Chemistry - A European Journal

Capturing a Pentacyclic Fragment-Based Library Derived from Perophoramidine: Their Design, Synthesis and Evaluation as Anticancer Compounds by DNA Double-Strand Breaks (DSB) and PARP-1 Inhibition

Tuberculosis (TB) is a serious communicative disease caused by Mycobacterium tuberculosis. Although there are vaccines and drugs available to treat the disease, they are not efficient, moreover, multidrug-resistant TB (MDR-TB) become a major hurdle in its therapy. These MDR strains utilize the multidrug efflux pump as a decisive weapon to fight against antitubercular drugs. Tap membrane protein was observed as a crucial multidrug efflux pump in M. tuberculosis and its critical implication in MDR-MTB development makes it an effective drug target. In the present study, we have utilized various in silico approaches to predict the applicability of FDA-approved ion channel inhibitors and blockers as therapeutic leads against Tuberculosis by targeting multidrug efflux protein; Tap in MTB. Tap protein structure is predicted by Phyre2 server followed by model refinement, validation, physio-chemical catheterization and target prediction. Further, the interaction between Tap protein and ligands were analysed by molecular docking and MD simulation run of 100 ns. Based on implication and compatibility, 18 FDA-approved ion channel inhibitors and blockers are selected as a ligand against the Tap protein and eventually observed five ligands; Glimepiride, Flecainide, Flupiritine, Nimodipine and Amlodipine as promising compounds which have exhibited the significant stable interaction with Tap protein and are proposed to modulate or interfere with its activity. These compounds illustrated the substantial docking score and total binding enthalpy more than −7 kcal/mol and −42 kcal/mol respectively which implies that the selected FDA-approved compounds can spontaneously interact with the Tap protein to modulate its function. This study proposed Tap protein as a prominent drug target in MTB and investigated compounds that show considerable interaction with the Tap protein as potential therapeutic molecules. These interactions may lead to modulating or inhibit the activity of drug efflux protein thereby making MTB susceptible to antitubercular drugs. © 2022 Elsevier Ltd

Computers in Biology and Medicine

A multidrug efflux protein in Mycobacterium tuberculosis; tap as a potential drug target for drug repurposing

Hydrogen peroxide plays a crucial role in the melanogenesis process by regulating the activity of the key melanin-forming enzyme tyrosinase, responsible for the browning of fruits, vegetables, and seafood. Therefore, a molecule with dual activities, both efficient tyrosinase inhibition and strong hydrogen peroxide degrading ability, may act as a promising antibrowning agent. Herein, we report highly efficient selone-based mushroom tyrosinase inhibitors 2 and 3 with remarkable glutathione peroxidase (GPx) enzyme-like activity. The presence of benzimidazole moiety enhances the tyrosinase inhibition efficiency of selone 2 (IC50= 0.4 μM) by almost 600 times higher than imidazole-based selone 1 (IC50= 238 μM). Interestingly, the addition of another aromatic ring to the benzimidazole moiety has led to the development of an efficient lipid-soluble tyrosinase inhibitor 3 (IC50= 2.4 μM). The selenium center and the -NH group of 2 and 3 are extremely crucial to exhibit high GPx-like activity and tyrosinase inhibition potency. The hydrophobic moiety of the inhibitors (2 and 3) further assists them in tightly binding at the active site of the enzyme and facilitates the C═Se group to strongly coordinate with the copper ions. Inhibitor 2 exhibited excellent antibrowning and polyphenol oxidase inhibition properties in banana and apple juice extracts. © 2022 American Chemical Society. All rights reserved.

Journal of Agricultural and Food Chemistry

Regulation of Tyrosinase Enzyme Activity by Glutathione Peroxidase Mimics

This review explains various strategies for developing fluorescent probes to detect reactive carbonyl species (RCS). There are several mono and diacarbonyls among 30 varieties of reactive carbonyl species (RCSs) so far discovered, which play pivotal roles in pathological processes such as cancer, neurodegenerative diseases, cardiovascular disease, renal failure, and diabetes mellitus. These RCSs play essential roles in maintaining ion channel regulation, cellular signaling pathways, and metabolisms. Among RCSs, carbon monoxide (CO) is also utilized for its cardioprotective, anti-inflammatory, and anti-apoptotic effects. Fluorescence-based non-invasive optical tools have come out as one of the promising methods for analyzing the concentrations and co-localizations of these small metabolites. There has been a tremendous eruption in developing fluorescent probes for selective detection of specific RCSs within cellular and aqueous environments due to their high sensitivity, high spatial and temporal resolution of fluorescence imaging. Fluorescence-based sensing mechanisms such as intramolecular charge transfer (ICT), photoinduced electron transfer (PeT), excited-state intramolecular proton transfer (ESIPT), and fluorescence resonance energy transfer (FRET) are described. In particular, probes for dicarbonyls such as methylglyoxal (MGO), malondialdehyde (MDA), along with monocarbonyls that include formaldehyde (FA), carbon monoxide (CO) and phosgene are discussed. One of the most exciting advances in this review is the summary of fluorescent probes of dicarbonyl compounds. © 2022 Wiley-VCH GmbH.

Chemistry - An Asian Journal

Activity-Based Fluorescent Probes for Sensing and Imaging of Reactive Carbonyl Species (RCSs)

Triplet energy harvesting via either thermally activated delayed fluorescence (TADF) or room-temperature phosphorescence (RTP) from pure organic systems has attracted great attention in the field of organic light-emitting diodes, sensing, and bioimaging. However, the realization of dual electroluminescence via TADF and RTP in single molecules remains elusive. Herein, we report two phenoxazine-quinoline conjugates (DPQ and DPQM) in which two phenoxazine donors are covalently attached to the 6,8-positions of 2,4-diphenylquinoline and/or 7-methyl-2,4-diphenylquinoline acceptors. Experimental and quantum chemistry calculations combining reference compounds (o-PQP, p-PQP, Phox, and QPP) reveal that both conjugates show TADF (with different rate constants of reverse intersystem crossing, krISC= 0.43-1.30 × 106s-1) via reverse intersystem crossing from the charge transfer triplet (3CT) to singlet (1CT) states mediated by vibronic coupling among 1CT, local triplet (3LE), and 3CT states due to close energy gaps. Further, RTP with quantum yields (φP) of ca. 21-24% features was also observed due to the radiative decay of 3LE states. Phosphorescence measurements of DPQM at low temperatures (T = 77, 10 K) ensure a distinct zero-field splitting of T1(CT) into substates. Both compounds showed dual electroluminescence with external quantum efficiencies of ca. 11-12% due to the efficient triplet harvesting from both TADF and RTP channels. © 2022 American Chemical Society. All rights reserved.

Journal of Physical Chemistry C

Thermally Activated Delayed Fluorescence and Room-Temperature Phosphorescence in Asymmetric Phenoxazine-Quinoline (D2-A) Conjugates and Dual Electroluminescence

Sulfur-doped graphite (S-DG) was synthesized using a sustainable method. Low-cost cellulose fiber and carbon disulfide (CS2) were used as precursors for carbon and sulfur (S) sources, respectively, and a multistep chemical and thermochemical synthesis process was employed to obtain S-DG. Advanced microscopic and spectroscopic techniques and porosimetry analyses were performed to probe the surface morphology, surface area, microstructures, and chemical bonding states of S-DG. Interestingly, X-ray photoelectron spectroscopy revealed that the S loads were 3.81 and 7.02 atom % when reactions were carried out in aqueous and dimethyl sulfoxide (DMSO) media, respectively. The specific surface areas were calculated as 522.77 and 693.27 m2g-1for the two materials, respectively. To our best knowledge, the 7.02 atom % S load is the highest S doping reported so far in a graphite material where laboratory chemicals have been used as precursors. Both materials, i.e., S-DGWaterand S-DGDMSO, were tested as supercapacitor electrodes in a portable electrochemical cell with a three-electrode system to check their potential and stability for the fabrication of renewable energy storage devices. Cyclic voltammetry and galvanostatic charging-discharging techniques were performed within a potential window of 1 V in the presence of 1 M Na2SO4as an electrolyte. The maximum specific capacitances (CSp) of S-DGWaterand S-DGDMSOwere obtained as 155.61 and 261.43 F g-1(at a scan rate of 10 mV s-1), respectively. The result concluded that the extent of S doping appeared to be the key factor for control of the peak current. Importantly, our investigation suggests that the S load in graphite facilitates a diffusion-driven storage mechanism and a higher amount of S may enhance surface-controlled storage as well. Both materials show excellent cyclic stability with &gt;98% retention of the initial specific capacitance over 10000 cycles of charging-discharging. © 2022 American Chemical Society. All rights reserved.

ACS Applied Nano Materials

Hydrothermally Synthesized Sulfur-Doped Graphite as Supercapacitor Electrode Materials

Room-temperature phosphorescence (RTP) from organic compounds has attracted increasing attention in the field of data security, sensing, and bioimaging. However, realization of RTP with an aggregate induced phosphorescence (AIP) feature via harvesting supersensitive excited charge transfer triplet (3CT) energy under visible light excitation (VLE) in single-component organic systems at ambient conditions remains unfulfilled. Organic donor-acceptor (D-A) based orthogonal structures can therefore be used to harvest the energy of the 3CT state at ambient conditions under VLE. Here we report three phenoxazine-quinoline conjugates (PQ, PQCl, PQBr), in which D and A parts are held in orthogonal orientation around the C-N single bond; PQCl and PQBr are substituted with halogens (Cl, Br) while PQ has no halogen atom. Spectroscopic studies and quantum chemistry calculations combining reference compounds (Phx, QPP) reveal that all the compounds in film at ambient conditions show fluorescence and green-RTP due to (i) radiative decay of both singlet charge transfer (1CT) and triplet CT (3CT) states under VLE, (ii) energetic nondegeneracy of 1CT and 3CT states (1CT- 3CT, 0.17-0.21 eV), and (iii) spatial separation of highest and lowest unoccupied molecular orbitals. Further, we found in a tetrahydrofuran-water mixture (fw = 90%, v/v) that both PQCl (10-5 M) and PQBr (10-5 M) show concentration-dependent AIP with phosphorescence quantum yields (φP) of ∼25% and ∼28%, respectively, whereas aggregate induced quenching (ACQ) was observed in PQ. The phosphorescence lifetimes (τP) of the PQCl and PQBr aggregates were shown to be ∼22-62 μs and ∼22-59 μs, respectively. The φP of the powder samples is found to be 0.03% (PQ), 15.6% (PQCl), and 13.0% (PQBr), which are significantly lower than that of the aggregates (10-5 M, fw = 90%, v/v). Film (Zeonex, 0.1 wt %) studies revealed that φP of PQ (7.1%) is relatively high, while PQCl and PQBr exhibit relatively low φP values (PQCl, 9.7%; PQBr, 8.8%), as compared with that of powder samples. In addition, we found in single-crystal X-ray analysis that multiple noncovalent interactions along with halogen···halogen (Cl···Cl) interactions between the neighboring molecules play an important role to stabilize the 3CT caused by increased rigidity of the molecular backbone. This design principle reveals a method to understand nondegeneracy of 1CT and 3CT states, and RTP with a concentration-dependent AIP effect using halogen substituted twisted donor-acceptor conjugates. © 2022 American Chemical Society. All rights reserved.

ACS Omega

Phenoxazine-Quinoline Conjugates: Impact of Halogenation on Charge Transfer Triplet Energy Harvesting via Aggregate Induced Phosphorescence

The adaptability of the active site to amplify the secondary function is supposed to be the fundamental cause of the promiscuity and the evolution of new functions in enzymes. In most cases, mutations occur close to the active site and/or in the catalytic site to change the active site plasticity to accommodate the non-native substrate. In the present study, using MD simulations and hybrid QM/MM calculations, we have shown a way to enhance the promiscuity, i. e., the allostery-driven promiscuity. Using a case study of the AEE enzyme where the capping loop recognizes the substrate, herein, we show that a single site mutation (D321G) far from the capping loop can induce a large conformational change in the capping loop to recognize different substrates for different functions. The QM/MM calculations for the WT and mutated enzyme provide a first validation of the mechanism of 1,1-proton transfer and dehydration by the AEE enzyme. Since AEE epimerase possesses a highly conserved TIM-barrel fold, we believe that our study provides a crucial lead to understanding the mechanism of emergence of secondary function which can be useful to repurpose ancient enzymes for modern usage. © 2022 Wiley-VCH GmbH.

Fulltext

Combined MD and QM/MM Calculations Reveal Allostery-Driven Promiscuity in Dipeptide Epimerases of Enolase Family

Industrial applications of the upcoming class of high-performance biobased polybenzoxazines are currently impeded by the requirement of high polymerization temperatures. Valorization of elemental sulfur (S8), petroleum waste, has provided attractive technological opportunities. However, achieving sulfur copolymers at a low temperature remains a challenging task. Here, a unique facile synthetic strategy was adopted to form a fully sustainable solution-processable benzoxazine-sulfur copolymer via a ring-opening polymerization reaction of isoeugenol-furfurylamine (IE-fa, sourced from naturally abundant biobased feedstocks) and S8at room temperature. The IE-fa benzoxazine monomer was synthesized under neat conditions and reacted with varying percentages of S8as sodium polysulfide (Na2Sx) at unprecedented low temperatures (25 and 50 °C) under catalyst-free conditions. The covalent fixation of sulfur (90 wt %), via inverse vulcanization, within ring-opened benzoxazine resulted in an amorphous copolymer as supported by various techniques. The formation of S-rich and Bz-rich domains in the copolymers is governed by the feed-in ratio of monomers and reaction temperature. Copolymers exhibited high glass transition temperatures (10-86 °C) due to the synergistic effects induced by H-bonded ring-opened benzoxazine structures. The present work demonstrates the first example of benzoxazine as a comonomer to form low-temperature solution-processable benzoxazine sulfur benign random copolymers with mid-wave infrared transparency and may advance benzoxazine chemistry toward transparent optics. © 2022 American Chemical Society. All rights reserved.

ACS Sustainable Chemistry and Engineering

Facile Strategy for Room Temperature Knitting of Sulfur in Polybenzoxazine: A New Class of Solution Processable Copolymers

A direct functionalization of numerous 1,4-quinones with various aryl boronic acids is reported under blue light-emitting diodes (LEDs). This reaction occurs at room temperature in an open flask without any catalysts, base, and oxidants in acetonitrile (ACN) and is scalable in grams. With diverse 1,4-quinones like 1,4-benzo-, naphtho-, anthra-, and 4-bromonaphthoquinones as substrates, facile cross coupling reactions occur with aryl and alkyl boronic acids without assistance from any photocatalysts. 2-Alkylated cyclohexene-1,4-diones were obtained when the 1,4-quinones were reacted with alkyl boronic acids under standard reaction conditions. However, slight warming of the reaction mixture afforded the desired alkylated 1,4-quinones. The reaction is believed to proceed through the blue LED-induced radical formation of the aryl rings assisted by the 1,4-quinones. © 2022 American Chemical Society. All rights reserved.