Parent Molecule Research Articles

Exploring the Influence of Engineering the Linker between the Donor and Acceptor Fragments on Thermally Activated Delayed Fluorescence Characteristics.

We have expounded the unique molecular design architecture for efficient thermally activated delayed fluorescence (TADF) materials based on a donor-linker-acceptor-linker-donor (D-L-A-L-D) framework, which can be employed as predecessors of organic light-emitting diode (OLED) devices. Different from traditional donor-acceptor-type (D-A-type) TADF scaffolds, the D-L-A-L-D structural design avoids direct coupling amid the D and A fragments allowing the highest occupied molecular orbitals (HOMOs) and the lowest unoccupied molecular orbitals (LUMOs) to be spatially separated. It results in a reduced overlap between HOMOs and LUMOs, thus realizing fairly a slight singlet-triplet energy gap (ΔE ST) and higher photoluminescence quantum yield (Φ). We revealed that manipulating a linker between D and A fragments in intramolecular charge transfer compounds is an auspicious approach for realizing small ΔE ST. Herein, we report a group of organic electroluminescent D-L-A-L-D-type molecules with different electron-donating and electron-accepting moieties using density functional theory calculations and time-dependent density functional theory calculations. Two types of linkers, the π-conjugated phenylene (-C6H4-) and aliphatic alkyl chains or σ-spacer (-CH2- and -CH2-CH2-), were exploited between D and A fragments. In principle, the conjugation in D-π-A-π-D-type molecules and hyperconjugation in D-σ-A-σ-D type molecules encourage the spatial separation of the HOMO-LUMO causing a reduction in the ΔE ST. All the designed molecules show a blue-shift in the emission wavelengths (λem) over the directly linked parent molecules except DPA-DPS-C6H4 and BTPA-DPS-C6H4 which show a red-shift. Violet-blue to green-yellow (376-566 nm) λem was observed from all of the investigated molecules. Other important properties that affect the efficiency of emission quantum yields like frontier molecular orbital analysis, natural population analysis, electron excitation analysis, exciton binding energies, ionization potentials, electronic affinities, and reorganization energies of the designed molecules were also inspected. We are confident that our work will effectively give a straightforward and distinctive approach to building incredibly effective TADF-OLEDs and a new perspective on their structural design.

Synthesis and structural variations of mixed, hydronium, ammonium salts of indium carboxylates

The reaction of indium bis(trimethylsilyl)amide with a series of sterically varied carboxylic acids in toluene followed by the addition of methanol led to the isolation of a series of hydronium-ammonium indium carboxylates (([H3O] x [NH4] y )In(ORc) z ). These derivatives were structurally characterized as 3([H3O]0.20[NH4]0.80)[In(OFc)6] (1), ([H3O]0.45[NH4]0.55)[In(OAc)4] (2), ([H3O]0.35[NH4]0.65)[In(OBc)4]·3H-OBc (3) and ([H3O]0.70[NH4]0.30)[In(ONc)4]·2H-ONc (4), where OFc = O2CH, OAc = O2CCH3, OPc = O2CCH(CH3)2, OBc = O2CC(CH3)3, ONc = O2CCH2C(CH3)3 and py = pyridine. For 1, an octahedral arrangement of six OFc ligands coordinated to the In metal center was solved, with three counter cations located in the lattice to balance the charge. Based on population refinements that yielded values larger than unity for NH4 + only, a mixed [H3O]:[NH4] cation ratio was proposed, evaluated, and found to yield a better structure for 1 with an approximate 20:80 ratio. For 2–4, the distorted dodecahedral metal centers are chelated by four ORc moieties and charge balanced by a single, mixed [H3O]:[NH4] cation (see formulas above for ratios) in the lattice. For 3 and 4, H-ORc ligands were also located in the lattice with extensive H-bonding to the parent molecule. The OPc derivatives were only isolable in the presence of pyridine forming crystals of [In(OPc)3]·NH3 (5) and [In(k 2-OPc)2(µ-OPc)(py)]n (5a).

Awareness raising and dealing with methanol poisoning based on effective strategies

Intoxication with methanol most commonly occurs as a consequence of ingesting, inhaling, or coming into contact with formulations that include methanol as a base. Clinical manifestations of methanol poisoning include suppression of the central nervous system, gastrointestinal symptoms, and decompensated metabolic acidosis, which is associated with impaired vision and either early or late blindness within 0.5–4 h after ingestion. After ingestion, methanol concentrations in the blood that are greater than 50 mg/dl should raise some concern. Ingested methanol is typically digested by alcohol dehydrogenase (ADH), and it is subsequently redistributed to the body's water to attain a volume distribution that is about equivalent to 0.77 L/kg. Moreover, it is removed from the body as its natural, unchanged parent molecules. Due to the fact that methanol poisoning is relatively uncommon but frequently involves a large number of victims at the same time, this type of incident occupies a special position in the field of clinical toxicology. The beginning of the COVID-19 pandemic has resulted in an increase in erroneous assumptions regarding the preventative capability of methanol in comparison to viral infection. More than 1000 Iranians fell ill, and more than 300 of them passed away in March of this year after they consumed methanol in the expectation that it would protect them from a new coronavirus. The Atlanta epidemic, which involved 323 individuals and resulted in the deaths of 41, is one example of mass poisoning. Another example is the Kristiansand outbreak, which involved 70 people and resulted in the deaths of three. In 2003, the AAPCC received reports of more than one thousand pediatric exposures. Since methanol poisoning is associated with high mortality rates, it is vital that the condition be addressed seriously and managed as quickly as feasible. The objective of this review was to raise awareness about the mechanism and metabolism of methanol toxicity, the introduction of therapeutic interventions such as gastrointestinal decontamination and methanol metabolism inhibition, the correction of metabolic disturbances, and the establishment of novel diagnostic/screening nanoparticle-based strategies for methanol poisoning such as the discovery of ADH inhibitors as well as the detection of the adulteration of alcoholic drinks by nanoparticles in order to prevent methanol poisoning. In conclusion, increasing warnings and knowledge about clinical manifestations, medical interventions, and novel strategies for methanol poisoning probably results in a decrease in the death load.

Design new organic material based on triphenylamine (TPA) with D-π-A-π-D structure used as an electron donor for organic solar cells: A DFT approach

Because of the increasing scarcity of fossil fuels and the growing need for energy, it has become necessary to research new renewable energy resources. In this study, five new high-performance materials (TP-FA1F-TP - TP-FA5F-TP) of the D-π-A-π-D configuration based on triphenylamine (TPA) were theoretically investigated by applying DFT and TD-DFT methods for future application as heterojunction organic solar cells (BHJ). The influence of the modification of the acceptor (A) of the parent molecule TP-FTzF-TP on the structural, electronic, photovoltaic and optical properties of the TP-FA1F-TP - TP-FA5F-TP organic molecules was investigated in detail. TP-FA1F-TP - TP-FA5F-TP showed Egap in the interval of 1.44–2.01 eV with λabs in the range of 536–774 nm, open-circuit voltage (Voc) values varied between 0.3 and 0.56 V and power conversion efficiencies (PCE) ranging from (3-6) %. Our results also show that the donor molecules suggested in this research exhibit an improved performance compared to the recently synthesized TP-FTzF-TP, such as a lowest HOMO energy, a smaller Egap, and a greater absorption spectrum, and can lead to higher performance. Indeed, this theoretical research could lead to the future synthesis of better compounds as active substances used in BHJ.

In Vitro and In Silico Studies of Glycyrrhetinic Acid Derivatives as Antitubercular Agents

Background: Glycyrrhetinic acid (GA) is a biologically active triterpenoid acid, isolated from the root of the Glycyrrhiza plant species. In our earlier studies, the semisynthetic analogs of GA have been reported to possess improved anticancer activities against various cell lines, antimalarial, and antifilarial activities. Method: GA was isolated and characterized from roots of Glycyrrhiza glabra and converted to its various C-3 aryl ester derivatives via the protection of C-30 carboxylic group. Antitubercular activity was determined against Mycobacterium tuberculosis H37Ra by Agar dilution assay. The in-silico docking was performed for the most active analogue against three antitubercular targets, catalase peroxidase, dihydrofolate reductase and enoyl-ACP reductase. Results: The derivatives, Methyl glycyrrhetinate (GA-1), 3-O-(4-methyl-phenyl)-ethanoyl methyl glycyrrhetinate (GA-1a), 3-O-(4-fluoro phenyl)-ethanoyl methyl glycyrrhetinate (GA-1c), 3-O-(4-methoxy trans cinnamyl)-ethanoyl methyl glycyrrhetinate (GA-1e) and 3-O-{(4-chlorophenyl)-ethanoyl methyl glycyrrhetinate (GA-1g) showed improved antitubercular activity (in the range 38.76 to 51.546 mM) over the parent molecule (MIC >106.157 mM). The derivative, 3-O-(4-aminobenzoyl)- methyl glycyrrhetinate (GA-1h) was found most active (MIC 20.695 mM) which was further supported by high binding affinity with the selected antitubercular target proteins in in silico docking studies. Conclusion: Synthetic modifications on GA led to C-3 aryl ester derivatives with improved antitubercular activities. Further studies for the development of GA-1h as potential antitubercular lead is therefore warranted.

Intentional overdose of glargine insulin: Determination of the parent compound in postmortem blood by LC‐HRMS

Insulin glargine is a long-acting insulin analog that is converted after enzymatic cleavage of the arginine pair of the β-chain into its main metabolite M1 (21A -Gly-insulin), which is responsible for the hypoglycemic activity. In all the overdose cases described in the literature, only M1 concentrations have been reported, whereas insulin glargine was always absent or below the limit of quantitation. In this study, we present a case of suicide of a young nurse by injection of insulin glargine in which the parent molecule was found at a toxic concentration in blood. The determination and the discrimination of insulin glargine from human insulin and other synthetic analogs in the blood specimen were performed by liquid chromatography coupled to high-resolution mass spectrometry (Waters XEVO G2-XS QToF) and extraction after precipitation in the presence of bovine insulin (internal standard), with a mixture of acetonitrile/methanol +1% formic acid followed by purification on solid phase extraction cartridges C18. Glargine insulin tested highly positive in the blood with a concentration of 1.06 mg/L. Due to the difficulty in obtaining a M1 pure standard, the metabolite could not be dosed. This unique presence of the parent molecule, reported for the first time, can be explained by inter-individual variability in the rate of conversion to metabolite. Intravenous injection versus subcutaneous injection can also explain the presence of insulin glargine. Finally, the dose injected may have been so high that saturation of the proteolytic enzymes responsible for conversion to M1 should have occurred.

An investigation to understand the correlation between the experimental and density functional theory calculations of noscapine

AbstractNoscapine has anti‐cancerous properties as it ceases cell division at metaphase stage. It is popular for it's anti‐antitussive properties. Various derivatives of noscapine have significant potential to act as a anticancerous ability than the parent molecule. As noscapine has low toxicity, high bioactivity and good availability, it is being explored extensively. Poor solubility of noscapine has somewhat restricted the use of noscapine. Therefore, authors aim to study the nature of noscapine in different solvents using computational methods or theoretically. Density functional theory (DFT) calculations and time‐dependent density functional theory (TD‐DFT) calculations were performed to explore the electronic structure, infrared spectrum, nuclear magnetic resonance spectrum and ultraviolet‐visible spectrum of noscapine. In dimethyl sulfoxide (DMSO), noscapine had a minimum or least free energy of −8.99 × 105 kcal/mol and a maximum dipole moment of 4.183 debye (D), followed by 2.942 D in chloroform. Physiochemical descriptors indicated that noscapine would interact with other molecules when DMSO or chloroform are taken as a solvent, as its polarizability and acidic character is more in DMSO and chloroform. The ability of noscapine to consume free radicles is also predicted to increase in DMSO. A red shift was observed when noscapine was taken in polar solvents as the energy gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) was reduced. The authors also performed linear regression analysis on infrared and carbon‐13 nuclear magnetic resonance (13C‐NMR) spectra obtained from computational and experimental methods to check the correlation in their results.

A Brief Review on the Synthesis of the N-CF3 Motif in Heterocycles

The trifluoromethyl group is widely recognized for its significant role in the fields of medicinal chemistry and material science due to its unique electronic and steric properties that can alter various physiochemical properties of the parent molecule, such as lipophilicity, acidity, and hydrogen bonding capabilities. Compared to the well-established C-trifluoromethylation, N-trifluoromethylation has received lesser attention. Considering the extensive contribution of nitrogen to drug molecules, it is predicted that constructing N-trifluoromethyl (N-CF3) motifs will be of great significance in pharmaceutical and agrochemical industries. This review is mainly concerned with the synthesis of heterocycles containing this motif. In three-membered heterocycles containing the N-CF3 motif, the existing literature mostly demonstrated the synthetic strategy, as it does for four- and larger-membered heterocycles. Certain structures, such as oxaziridines, could serve as an oxidant or building blocks in organic synthesis. In five-membered heterocycles, it has been reported that N-CF3 azoles showed a higher lipophilicity and a latent increased metabolic stability and Caco-2-permeability compared with their N-CH3 counterparts, illustrating the potential of the N-CF3 motif. Various N-CF3 analogues of drugs or bioactive molecules, such as sildenafil analogue, have been obtained. In general, the N-CF3 motif is developing and has great potential in bioactive molecules or materials. Give the recent development in this motif, it is foreseeable that its synthesis methods and applications will become more and more extensive. In this paper, we present an overview of the synthesis of N-CF3 heterocycles, categorized on the basis of the number of rings (three-, four-, five-, six- and larger-membered heterocycles), and focus on the five-membered heterocycles containing the N-CF3 group.

Structurally modified Cyclovirobuxine-D Buxus alkaloids as effective analgesic agents through Cav3.2 T-Type calcium channel inhibition

Cyclovirobuxine-D (CVB-D) is a Buxus alkaloid and a major active constituent in the Chinese medicinal herb Buxus microphylls. Traditionally, the natural alkaloid cyclovirobuxine-D has a long history of use as a traditional Chinese medicine for cardiovascular diseases as well as to treat a wide variety of medical conditions. As we found that CVB-D inhibited T-type calcium channels, we designed and synthesized a variety of fragments and analogues and evaluated them for the first time as new Cav3.2 inhibitors. Compounds 2–7 exhibited potency against Cav 3.2 channels, and two of them were more active than their parent molecules. As a result of the in vivo experiments, both compounds 3 and 4 showed significantly reduced writhes in the acetic acid-induced writhing test. Studies of molecular modeling have identified possible mechanism(s) of Cav3.2 binding. Moreover, the relationship between structure and activity was studied in a preliminary manner. Our results indicated that compounds 3 and 4 could play an important role in the discovery and development of novel analgesics.

Excited states of aurocarbons: CASPT2 and CCSD(T) calculations of C2Au2 and C2Au4

AbstractWe present CASPT2 calculations of vertical excitation energies for low‐lying singlet and triplet states of auroderivatives of acetylene and ethylene representing small model aurocarbons. Data are supplemented by CCSD(T) results for triplet states. All four considered species, namely linear C2Au2 molecule and three conformers of the C2Au4 molecule—Au2C2Au2 (tetraauroethylene, the analog of the parent ethylene molecule) and – and –adducts of the Au2 molecule with the auroacetylene exhibit considerable lowering of low‐lying excitation energies when compared with their parent acetylene and ethylene molecules. Singlet and triplet excitation energies of diauroacetylene drop by 57% and 48%, respectively, and of tetraauroethylene, by 68% and 56% when compared with their respective parent molecules. Even more is lowered the singlet–triplet energy gap. We stress the importance of the dynamical correlation in CASPT2 calculations and discuss problems with selection of the appropriate active space in aurocarbons.

Computational insights into the antioxidant and antidiabetic mechanisms of cannabidiol: An in vitro and in silico study

The present study was aimed at investigating the molecular mechanism involved the antioxidant and antidiabetic activities of cannabidiol using in vitro and in silico models. The antioxidant activities of cannabidiol were determined by assaying its ability to scavenge 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical and reduce ferric ion (Fe3+). The antidiabetic activity of cannabidiol was determined by its ability to inhibit α-glucosidase activity. The DPPH scavenging activity of cannabidiol was further investigated using the Density Functional Theory (DFT) analysis. The molecular interactions of cannabidiol and α-glucosidase activity was determined via molecular docking and molecular dynamics simulation. Cannabidiol significantly scavenged DPPH radical and reduced Fe3+, with IC50 values of 211.93 and 101.72 μg/mL, respectively. It also inhibited the activity of α-glucosidase, with an IC50 value of 311.26 μg/mL. DFT analysis revealed sequential proton loss followed by electron transfer (SPLET) as the preferred mechanism by which cannabidiol scavenge DPPH, followed by hydrogen atom transfer (HAT) and single electron transfer followed by proton transfer (SET-PT). The highest occupied molecular orbital (HOMO) orbitals were delocalised on the benzene ring and OH groups, while the lowest energy orbital (LUMO) orbitals were distributed on both the parent and substituent molecules. Cannabidiol bounded favourably to α-glucosidase enzyme, with ΔG, root mean square deviation (RMSD), root mean square fluctuation (RMSF) values of −28.49 kcal/mol, 1.36 Å and 0.835 Å as well as higher correlated motions. Therefore, the antioxidant activity of cannabidiol involves the abstraction of its H1 by the radical and delocalization of the radical’s unpaired electron. Its antidiabetic activity can be attributed to the potent inhibitory effect on α-glucosidase, as well as its high affinity with the enzyme.

Triplet state generation followed by the excited-state intramolecular proton transfer in 3-sulfanylchromen-4-one

We theoretically study the triplet formation dynamics of tautomers associated with the excited-state intramolecular proton transfer of 3-sulfanylchromen-4-one (3-SC). The S1-T3 intersystem crossing pathway is expected to compete with the intramolecular thiol proton transfer upon photoexciting the normal tautomer (parent molecule) to its S1 state. The triplet formation via the S1′-T2′ intersystem crossing tends to be the dominant nonradiative process in the proton-transferred tautomer. The wavepacket transfer to the respective accessible receiver triplet state is more pronounced in the proton-transferred tautomer than its parent tautomer, implying an efficient triplet formation followed by the proton transfer via S1 in 3-SC.

Discovery of LL-K8-22: A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex.

The CDK8-cyclin C complex is an important anti-tumor target, but unlike CDK8, cyclin C remains undruggable. Modulators regulating cyclin C activity directly are still under development. Here, a series of hydrophobic tagging-based degraders of the CDK8-cyclin C complex were designed, synthesized, and evaluated to identify the first dual degrader, LL-K8-22, which induced selective and synchronous degradation of CDK8 and cyclin C. Proteomic and immunoblot studies exhibited that LL-K8-22 significantly degraded CDK8 without reducing CDK19 and did not degrade other cyclin proteins except cyclin C. Moreover, LL-K8-22 showed enhanced anti-proliferative effects over its parental molecule, BI-1347, with potency increased by 5-fold in MDA-MB-468 cells. LL-K8-22 exhibited more pronounced effects on CDK8-cyclin C downstream signaling than BI-1347, suppressing STAT1 phosphorylation more persistently. RNA-sequencing analysis revealed that LL-K8-22 inhibited E2F- and MYC-driven carcinogenic transcriptional programs. Overall, LL-K8-22 is the first-in-class degrader of cyclin C and would be useful for studying the unknown functions of cyclin C.

Vibrational studies of 2,3,5,6-tetrachloro-1,4-benzoquinone and its reactivity: An ab-initio computational method

The IR spectrum of 2,3,5,6-Tetrachloro-1,4-benzoquinone (p-chloranil) has been recorded in the solid phase in the range 4000 – 400 cm-1. ab initio calculations have been performed using Gaussian 03 program to compute optimized geometry, harmonic vibrational frequencies along with intensities in IR and Raman spectra and atomic charges at RHF/6–31+G*, B3LYP/6-31+G*, B3LYP/6-31++G** and B3LYP/6-311++G** levels for p-chloranil and parent molecule p-benzoquinone. The optimized molecular structures are found to be planar and possess D2h point group symmetry for both the molecules. The C=C bond lengths are larger whereas the C=O bond lengths are shorter in p-chloranil as compared to p-benzoquinone which is also reflected in the corresponding vibrational frequencies. The atomic arrangements in p-benzoquinone and p-chloranil possess two concentric hexagonal arrays and both the arrays of p-benzoquinone contain mixed charges. In the case of the p-chloranil molecule, the outer array is negatively charged and the inner array is positively charged which leads to increased susceptibility at the sites to which chlorine atoms are attached in p-chloranil towards the nucleophile. Consequently, p-chloranil is a good candidate for synthesis of many derivatives of 1,4-benzoquinone. The optimized geometrical structures along with the atomic charges on the atomic sites of p-benzoquinone and p-chloranil reveal the reactivity of p-chloranil molecules towards nucleophilic substitution reactions as compared to p-benzoquinone.

Analog-based Design and Development of Novel Molecules as Anti-tubercular Agents

Abstract: Background: The burden of tuberculosis is immense as most of the drugs developed resistance to Mycobacterium tuberculosis (Mtb). This issue shall be addressed by developing new drugs acting through novel mechanisms. GSK 2556286 (GSK-286) is a phase 1 clinical candidate with a novel mechanism of action related to cholesterol catabolism, hence it was selected as template/ parent molecules for our analogue-based drug design strategy. Materials and Methods: The novel-designed molecules were initially checked to be drug-like using ‘Lipinski’s rule of five and synthesized with good yields. The obtained compounds were evaluated for anti-tubercular activity against Mtb H37Rv, antibacterial activity against S. aureus and E. coli, cytotoxicity screening against mammalian VERO cells and BBB permeability against Porcine Brain Lipid. Docking was also performed against HsaA monooxygenase (PDB ID: 3AFF) to understand the possible mechanism of action. Results and Conclusion: The compounds 3a and 7a exhibited promising anti-tubercular activity at MIC of 3.13 μg/mL. Further, the compounds proved to be effective towards S. aureus at 0.98 μg/mL and E. coli at 7.81 μg/mL. The molecules 3a and 7a produced good docking scores of -9.2 and -9.3 kcal/mole respectively. The association between docking results and anti-tubercular activity has postulated that the molecules could act through novel mechanisms by inhibiting HsaA monooxygenase. Moreover, all the compounds in the study produced very less cytotoxicity at CC50 > 190 μg/mL against mammalian VERO cells and also showed minimal BBB permeability in PAMPA assay. The effective anti-tubercular activity of the lead molecules with additional safety against mammalian VERO cells with reduced BBB permeability could provide a new standpoint in anti-tubercular drug discovery. Keywords: Analog-based Design, Anti-tubercular activity, BBB permeability, GSK 2556286, VERO cells.

Role of Tailor-Made Additives in Crystallization from Solution: A Review

Additives which share a similar molecular structure with the crystallizing parent molecule are called tailor-made additives (TMAs). The inclusion of well-chosen TMAs often has a significant impact on crystallization behaviors. However, how TMAs affect the solution crystallization has seldom been systematically summarized in recent years. Herein this paper reviews the role of TMAs in solution crystallization. First, the effects and action mechanisms of TMAs on crystal nucleation and growth are discussed, respectively. Next, the applications of TMAs in the regulation of crystal properties including the polymorphism, crystal habit, crystal size, and chirality are introduced. Then the recent progress of molecular simulation in predicting the role of TMAs is discussed. Finally, we analyze the existing problems in this field and give an outlook on the future development. This paper is helpful and useful to readers interested in the use of TMAs to control crystallization and design crystals with desired properties.

Design, synthesis and evaluation of a series of potential prodrugs of a Bruton's tyrosine kinase (BTK) inhibitor.

BTK has become a particularly attractive therapeutic target in autoimmune diseases and B-cell malignancies, making BTK inhibitors a valuable and important therapeutic option. We present the design, synthesis, and evaluation of a series of prodrugs of a BTK inhibitor with an insoluble 2,5-diaminopyrimidine structure. Tails containing different solubilizing groups were added to the parent molecule via an ester linkage. Prodrug 5a showed good aqueous solubility and could be efficiently converted to the parent in a human plasma stability study. The rational prodrug design was supported by molecular studies and a dramatically reduced BTK kinase-inhibitory potential. Taken together, the chemical, biological, and molecular studies suggest that prodrug derivatization of the 2,5-diaminopyrimidine scaffold could be a potential strategy for advancing this series of BTK inhibitors into the therapeutic arena.

Electromagnetic enhanced ignition of octogen explosive at subnormal temperatures: A numerical study

The thermal decomposition and ignition of high-performance high explosives occur via a mechanism where the solid phase sublimes and the parent molecules decompose rapidly in the gas phase to form unstable and charged intermediates. These intermediates continue to react and form the final products to release energy and do work. We have observed that the presence of electromagnetic energy significantly reduces the ignition temperature of a common high explosive, and data suggest that this occurs via electromagnetic interactions with the charged gas-phase intermediates. Here, we modified the thermal decomposition kinetic expressions for octogen (High Melt eXplosive, HMX) to couple the effects of an incident microwave (MW) field. This modified kinetic model is used to investigate our previous experimental work which showed that the surface temperature at ignition of HMX powder is reduced by the MW field. The Fridman–Macheret α-model is a common approach in plasma chemistry and was incorporated into the Henson/Smilowitz HMX kinetics; this effectively reduces the activation energy (Ea) by vibronically excited charged reactive intermediates. A modified kinetic model was implemented into the COMSOL Multiphysics Software. The thermal time to ignition was validated; as a result, plasma formation reduced the surface temperature by ∼23 °C compared to thermal ignition. With a validated kinetic model that can simulate both pure thermal ignition and mixed thermal/plasma ignition, we are able to simulate our previous experimental work showing that plasma ignition reduces the surface temperature at ignition compared to thermal initiation.

DFT and Molecular Docking Analysis of Newly Synthesized Compound (2E)-3-[3-(Benzyloxy) Phenyl]-1-(4’-Chlorophe-Nyl)- 2-Propen-1-One [Bpclpo

Background: The parent molecule in the skeleton of this chalcone is the benzyloxy phenyl, which is linked to the chlorophenylpropen at C-3. The hydrophobic phenyl groups are naturally resistant to oxidation and reduction. Antiviral, antimalarial, antibacterial, anti-inflammatory, anticancer, antioxidant, antitubercular, and anti-Alzheimer activities are among the many pharmacological properties of chalcone derivatives. As a result, chalcone-based compounds are investigated using molecular docking and molecular modelling calculations to determine their suitability for drug formulation. Aims: To synthesise (2E)-3-[3-(benzyloxy) phenyl]-1-(4’-chlorophenyl)-2-propen-1-one [BPClPO] and perform DFT and molecular docking analysis of the synthesized compound to better understand its medicinal properties. Objective: The characterization of BPClPO is investigated in this study using various approaches, including wavefunction analysis and spectral analysis, which are associated with quantum chemical calculations to investigate its medicinal properties. Methods: The Gaussian 09W programme was used to perform computational chemistry calculations. The BPClPO's molecular structure was optimised, and the vibrational frequencies, Natural Bond Orbital (NBO), Fukui function, electronic properties and Nuclear Magnetic Resonance (NMR) chemical shifts were calculated using the B3LYP/6-311G (d, p) as the basis set. The VMD user interface and Multiwfn (3.4.1) software were used to conduct topological analyses of the Electron Localization Function (ELF), Localized Orbital Locator (LOL) and Reduced Density Gradient (RDG). The binding sites of active cancer proteins were calculated using the auto dock and auto grid. Results: Theoretical reaction path investigation was done for BPClPO to detect reactions from the parent chemical to the synthesized compound. Theoretical bond lengths and bond angles are compared with XRD values. Theoretical values of vibrations caused by electron-rich and electrondeficient centres were investigated. The electronic spectra of λmax were examined under UV-Vis light and the electron absorbance spectrum was absorbance wavelength and oscillator strength compared to theoretical values. The electron-rich carbon atoms are de-shielded in NMR, resulting in stronger fields and chemical shifts. The Harmonic Oscillator Model of Aromaticity (HOMA)and the retain ability of aromaticity in the addition and removal of electrons are examined in the Nucleus Independent Chemical Shift (NICS) study. The stability of the compound was investigated using Thermo- Gravimetric analysis and Differential Scanning Calorimeter (TG/DSC) analysis. Four cancer proteins with the reactive site were studied in docking simulations. Conclusions: The NBO analysis determined the intramolecular charge transfer within the molecule of high stabilization transition from C34-C37 donor to C35-C39 acceptor of (22.31 Kcal/mol) (π→π*) due to phenyl transition belonging to Cl atom in the ring. In the solvent phase, UV-visible spectra reveal a prominent peak at 300 λmax, with an absorbance range of intensity of 0.6983. (a.u.). According to TG/DSC experiments, the molecule begins to break around 290-370°C, and total decomposition occurs at 300°C. The molecule was found to have a higher bioactivity than and was employed related more to medicinal properties mechanism(s) of action in drug docking investigations.

Discovery and Optimization of Neutralizing SARS-CoV-2 Antibodies Using ALTHEA Gold Plus Libraries™.

We recently reported the isolation and characterization of anti-SARS-CoV-2 antibodies from a phage display library built with the VH repertoire of a convalescent COVID-19 patient, paired with four naïve synthetic VL libraries. One of the antibodies, called IgG-A7, neutralized the Wuhan, Delta (B.1.617.2) and Omicron (B.1.1.529) strains in authentic neutralization tests (PRNT). It also protected 100% transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE-2) from SARS-CoV-2 infection. In this study, the four synthetic VL libraries were combined with the semi-synthetic VH repertoire of ALTHEA Gold Libraries™ to generate a set of fully naïve, general-purpose, libraries called ALTHEA Gold Plus Libraries™. Three out of 24 specific clones for the RBD isolated from the libraries, with affinity in the low nanomolar range and sub-optimal in vitro neutralization in PRNT, were affinity optimized via a method called "Rapid Affinity Maturation" (RAM). The final molecules reached sub-nanomolar neutralization potency, slightly superior to IgG-A7, while the developability profile over the parental molecules was improved. These results demonstrate that general-purpose libraries are a valuable source of potent neutralizing antibodies. Importantly, since general-purpose libraries are "ready-to-use", it could expedite isolation of antibodies for rapidly evolving viruses such as SARS-CoV-2.