Identification of imidazole-based small molecules to combat cognitive disability caused by Alzheimer's disease: A molecular docking and MD simulations based approach.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is the primary cause of dementia. It is characterised by the gradual loss of brain cells, which results in memory loss and cognitive dysfunction. One of the hallmarks of AD is an abnormally upregulated glutaminyl-peptide cyclotransferase (QPCT or QC) enzyme. Not only AD, but QC has also been implicated with pathological conditions like Huntington's disease (HD), melanomas, carcinomas, atherosclerosis, and septic arthritis. Therefore, the inhibition of QC emerged as a potential strategy for preventing multiple pathological conditions. Considering this, we screened a library of 153,536 imidazole-based compounds against a doubly mutant (Y115E-Y117E) QC target. Molecular docking based virtual screening and absorption, distribution, metabolism, excretion/toxicity (ADME/T) predictions identified five compounds, namely 118981836, 136459842, 139388116, 139388226, and 139958725. Furthermore, molecular dynamics (MD) simulations of 500 ns were conducted to investigate the behaviour of the identified compounds with the target receptor. The results were compared to the co-ligand by analysing RMSD, RMSF, and SASA parameters. To our knowledge, this is the first computational study that employed a protein with double mutation to identify new imidazole-based QC-inhibitors.

Water-Soluble Small Organic Fluorophores for Oncological Theragnostic Applications: Progress and Development.

Cancer is one of the major noncommunicable diseases, responsible for millions of deaths every year worldwide. Though various cancer detection and treatment modalities are available today, many deaths occur owing to its late-stage detection and metastatic nature. Noninvasive detection using luminescence-based imaging tools is considered one of the promising techniques owing to its low cost, high sensitivity, and brightness. Moreover, these tools are unique and valuable as they can detect even the slightest changes in the cellular microenvironment. To achieve this, a fluorescent probe with strong tumor uptake and high spatial and temporal resolution, especially with high water solubility, is highly demanded. Recently, several water-soluble molecules with emission windows in the visible (400-700 nm), first near-infrared (NIR-I, 700-1000 nm), and second near-infrared (NIR-II, 1000-1700 nm) windows have been reported in literature. This review highlights recently reported water-soluble small organic fluorophores/dyes with applications in cancer diagnosis and therapeutics. We systematically highlight and describe the key concepts, structural classes of fluorophores, strategies for imparting water solubility, and applications in cancer therapy and diagnosis, i.e., theragnostics. We discuss examples of water-soluble fluorescent probes based on coumarin, xanthene, boron-dipyrromethene (BODIPY), and cyanine cores. Some other emerging classes of dyes based on carbocyclic and heterocyclic cores are also discussed. Besides, emerging molecular engineering methods to obtain such fluorophores are discussed. Finally, the opportunities and challenges in this research area are also delineated.

Synthesis, Characterization, Cytotoxicity, Cellular Imaging, Molecular Docking, and ADMET Studies of Piperazine-Linked 1,8-Naphthalimide-Arylsulfonyl Derivatives.

To reduce the mortality and morbidity associated with cancer, new cancer theranostics are in high demand and are an emerging area of research. To achieve this goal, we report the synthesis and characterization of piperazine-linked 1,8-naphthalimide-arylsulfonyl derivatives (SA1-SA7). These compounds were synthesized in good yields following a two-step protocol and characterized using multiple analytical techniques. In vitro cytotoxicity and fluorescent cellular imaging of the compounds were assessed against non-cancerous fibroblast (3T3) and breast cancer (4T1) cell lines. Although the former study indicated the safe nature of the compounds (viability = 82-95% at 1 µg/mL), imaging studies revealed that the designed probes had good membrane permeability and could disperse in the whole cell cytoplasm. In silico studies, including molecular docking, molecular dynamics (MD) simulation, and ADME/Tox results, indicated that the compounds had the ability to target CAIX-expressing cancers. These findings suggest that piperazine-linked 1,8-naphthalimide-arylsulfonyl derivatives are potential candidates for cancer theranostics and a valuable backbone for future research.

Synthesis, Characterization, Antiglycation Evaluation, Molecular Docking, and ADMET Studies of 4-Thiazolidinone Derivatives.

The design and development of new small-molecule glycation inhibitors are essential for preventing various chronic diseases, including diabetes mellitus, immunoinflammation, cardiovascular, and neurodegenerative diseases. 4-Thiazolidinone or thiazolidine-4-one is a well-known heterocyclic compound with the potential to inhibit the formation of advanced glycation end products. In the present work, we report the synthesis and characterization of four new 5-arylidene 3-cyclopropyl-2-(phenylimino)thiazolidin-4-one (1-4) compounds and their human serum albumin glycation inhibitory activity. One of the compounds 5-(2H-1,3-benzodioxol-5-ylmethylidene)-3-cyclopropyl-2-(phenylimino)-1,3-thiazolidin-4-one (3) showed potent inhibition in the synthesis of initial, intermediary, and final products of glycation reactions. Besides, conformational changes in the α-helix and ß-sheet (due to hyperglycemia) were also found to be reversed upon the addition of (3). Experimental findings were complemented by computational [molecular docking, ADME/Tox, and density functional theory (DFT)] studies. The docking scores of the compounds were in order 1 > 3 > 2 > 4, indicating the importance of the polar group at the 5-arylidene moiety. The results of ADME/Tox and DFT calculations revealed the safe nature of the compounds with high drug-likeness and stability. Overall, we speculate that the results of this study could provide valuable insights into the biological activity of 4-thiazolidinones.

Synthesis, anticancer activity, molecular docking and molecular dynamics studies of some pyrazole-chalcone hybrids.

Four new hybrid compounds (H1-H4) bearing pyrazole (S1 and S2) and chalcone (P1 and P2) fragments were synthesized and characterized. Compounds were assayed for their ability to inhibit the proliferation of human lung (A549) and colon (Caco-2) cancer cell lines. Besides, toxicity against normal cells was determined using the human umbilical vein endothelial cells (HUVEC). In silico molecular docking, molecular dynamics (MD) simulation and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were carried out to predict the binding modes, protein stability, drug-likeness and toxicity of the reported compounds. The in vitro anticancer activity of the tested compounds revealed dose-dependent cell-specific cytotoxicity. In silico studies revealed that the compounds have a good binding affinity, possess appropriate drug-likeness properties and have low toxicity profiles.Communicated by Ramaswamy H. Sarma.

In silico evaluation of 4-thiazolidinone-based inhibitors against the receptor for advanced glycation end products (RAGE).

Non-enzymatic glycation of biomolecules by reducing sugars led to several products, including the advanced glycation end products (AGEs), the accumulation of which has been linked to various life-threatening diseases. The binding of AGEs to their respective protein receptors for advanced glycation end products (RAGE) can initiate a cascade of reactions, which may alter physiological conditions. The present work investigates the potential of 4-thiazolidinones as RAGE inhibitors. We performed an extensive computational study to identify the structural requirements needed to act as RAGE inhibitors. To achieve this goal, 4-thiazolidinone-based compounds available in PubChem, ZINC15, ChEMBL, and ChEBI databases were screened against RAGE (PDB: 4LP5), leading to the identification of top five drug-like candidates with a high binding affinity to RAGE V-domain catalytic region. Drug likeness, absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the top-scoring compounds have been studied and discussed. Global molecular descriptors, chemical reactivity, hardness, softness, etc., have been estimated. Finally, molecular dynamics (MD) simulations at 100 ns were carried out to check the stability and other properties. Overall, we believe that the identified compounds can potentially attenuate RAGE-AGE interactions.Communicated by Ramaswamy H. Sarma.

Unlocking the Anticancer Potential of Frankincense Essential Oils (FEOs) Through Nanotechnology: A Review.

Cancer is a group of heterogeneous diseases that occur when cells in the body proliferate and divide uncontrollably. As the current treatment modalities have pros and cons, the discovery of new chemotherapeutic agents with the least side effects is one of the most investigated research areas. In this context, plant-based natural products are a rich source of drugs and have served humanity for ages. Frankincense essential oils (FEOs) are among the most promising plant-based oils in Gulf countries. In addition to their high cultural value, FEOs are also famous for their engaging biological activities, including anti-cancerous. However, the practical application of FEOs is often hindered/by their low water solubility, limited bioavailability, high volatility, and sensitivity toward heat, humidity, light, or oxygen. Thus, a significant demand for technological advancement would improve their ability to target particular cells and tissues. Nanotechnology emerged as an exciting approach in this context. Through suitable nano-formulation (functionalization or encapsulation into a nanostructure), issues arising due to solubility, targeting capability, and delivery can be controlled.

Chemical, biological and in silico assessment of date (P. dactylifera L.) fruits grown in Ha'il region.

Background: Dates palm (Phoenix dactylifera L.) fruits are among the most widely used fruits in the Middle East and African nations. Numerous researchers confirmed the presence of phytochemicals in P. dactylifera L. fruit and its by-products with broad-ranging biological activities. Objectives: In the present work, phytochemical and biological assessments of two different cultivars of date fruit (Shishi M1 and Majdool M2 grown in the Ha'il region of Saudi Arabia) have been carried out. Methods: Date fruits were extracted and analyzed by gas chromatography-mass spectrometry (GS-MS),liquid chromatography-mass spectrometry (LC-MS) and Fourier-transform infrared spectroscopy (FT-IR)techniques. The lyophilized methanolic extracts were analyzed for their in-vitro antiproliferative andcytotoxicity against colon cancer (HCT116) cell line. To identify the possible constituents responsible for the bioactivity, in-silico molecular docking and molecular dynamics (MD) simulation studies were carried out. Results: Both cultivars exhibited in-vitro anticancer activity (IC50 = 591.3 µg/mL and 449.9 µg/mL for M1 and M2, respectively) against colon cancer HCT-116 cells. The computational analysis results indicated procyanidin B2 and luteolin-7-O-rutinoside as the active constituents. Conclusion: Based on these results, we conclude that these cultivars could be a valuable source for developing health promoter phytochemicals, leading to the development of the Ha'il region, Saudi Arabia.

Non-covalent interactions (NCIs) in π-conjugated functional materials: advances and perspectives.

The design and development of functional materials with real-life applications are highly demanding. Understanding and controlling inter- and intra-molecular interactions provide opportunities to design new materials. A judicious manipulation of the molecular structure significantly alters such interactions and can boost selected properties and functions of the material. There is burgeoning evidence of the beneficial effects of non-covalent interactions (NCIs), showing that manipulating NCIs may generate functional materials with a wide variety of physical properties leading to applications in catalysis, drug delivery, crystal engineering, etc. This prompted us to review the implications of NCIs on the molecular packing, optical properties, and applications of functional π-conjugated materials. To this end, this tutorial review will cover different types of interactions (electrostatic, π-interactions, metallophilic, etc.) and their impact on π-conjugated materials. Attempts have also been made to delineate the effects of weak interactions on opto-electronic (O-E) applications.

Synthesis of Mixed Arylalkyl Tertiary Phosphines via the Grignard Approach.

Trialkyl and triaryl phosphines are important classes of ligands in the field of catalysis and materials research. The wide usability of these low-valent phosphines has led to the design and development of new synthesis routes for a variety of phosphines. In the present work, we report the synthesis and characterization of some mixed arylalkyl tertiary phosphines via the Grignard approach. A new asymmetric phosphine is characterized extensively by multi-spectroscopic techniques. IR and UV-Vis spectra of some selected compounds are also compared and discussed. Density functional theory (DFT)-calculated results support the formation of the new compounds.

From Waste to Schiff Base: Upcycling of Aminolysed Poly(ethylene terephthalate) Product.

Recycling plastic waste into valuable materials is one of the contemporary challenges. Every year around 50 million tons of polyethylene terephthalate (PET) bottles are used worldwide. The fact that only a part of this amount is being recycled is putting a burden on the environment. Therefore, a technology that can convert PET-based waste materials into useful ones is highly needed. In the present work, attempts have been made to convert PET-based waste materials into a precursor for others. We report an aminolysed product (3) obtained by aminolysis reaction of PET (1) with 1,2 diaminopropane (DAP, 2) under solvent and catalytic free conditions. The highest amount of monomeric product was obtained upon heating the mixture of diamine and PET at 130 °C. The resulting aminolysed product was then converted to a Schiff-base (5) in 25% yield. The chemical structure of the synthesized compounds was confirmed using multi-spectroscopic techniques. The results of this study will be a valuable addition to the growing body of work on plastic recycling.

Synthesis and characterization of a new meso-tetrakis (2,4,6-trimethylphenyl) porphyrinto) zinc(II) supported sodium alginate gel beads for improved adsorption of methylene blue dye.

Chemical modification of a biopolymer offers a simple strategy to realize new materials with added benefits. In this paper, meso-tetrakis(2,4,6-trimethylphenyl) porphyrinto) zinc(II) supported sodium alginate gel beads were successfully prepared, characterized, and used for the removal of a cationic dye from aqueous solution. The chemical structure of the prepared composite beads was confirmed by FT-IR, SEM, XRD and TGA/DTG techniques. Analytical data suggested that the sodium alginate beads and meso-tetrakis(2,4,6-trimethylphenyl) porphyrinto) zinc(II) complex interacted via non-covalent interaction (H-bonding) mode. The morphological micrographs showed spherical and smooth composite beads. The crosslinking of hydroxyl and carboxylate groups of the biopolymer with calcium ions and the incorporation of meso-tetrakis(2,4,6-trimethylphenyl) porphyrinto) zinc(II) into alginate matrix resulted in a small decrease of residual mass. The maximum adsorption capacities of methylene blue, at 20 °C, were found to be 52.3 mg/g and 34.8 mg/g for sodium alginate composite beads (3%) and plain sodium alginate beads, respectively. The adsorption process followed Freundlich isotherm and pseudo second order kinetics. The thermodynamic study displayed an exothermic and non-spontaneous process.

Synthesis, characterization, anticancer and in silico studies of a pyrazole-tethered thiazolidine-2,4-dione derivative.

A new pyrazole-tethered thiazolidine-2,4-dione derivative (8) has been synthesized by the Knoevenagel condensation of 3-(4-nitrophenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (4) and 3-(2,4-dioxothiazolidin-3-yl)propanenitrile (7). The structure of the final compound was confirmed by standard spectroscopic techniques including IR spectroscopy, 1H-NMR spectroscopy, and ESI-MS mass spectrometry. Molecular features including frontier molecular orbital (HOMO-LUMO) energies, reactivity descriptors and molecular electrostatic potential (ESP) of the title molecule were determined using density functional theory (DFT) calculation. The in vitro cytotoxicity of both the intermediate (4) and final (8) compounds were investigated against cancerous (SW-480 and MCF-7) and normal (HEK-293) cell lines by MTT assay. Compound (8) displayed higher activity than (4) with higher sensitivity against breast cancer cell line and lesser toxicity. The experimental data were further complemented by docking and absorption, distribution, metabolism, and excretion (ADME) studies.Communicated by Ramaswamy H. Sarma.

Heterometal Grafted Metalla-ynes and Poly(metalla-ynes): A Review on Structure-Property Relationships and Applications.

Metalla-ynes and poly(metalla-ynes) have emerged as unique molecular scaffolds with fascinating structural features and intriguing photo-luminescence (PL) properties. Their rigid-rod conducting backbone with tunable photo-physical properties has generated immense research interests for the design and development of application-oriented functional materials. Introducing a second d- or f-block metal fragment in the main-chain or side-chain of a metalla-yne and poly(metalla-yne) was found to further modulate the underlying features/properties. This review focuses on the photo-physical properties and opto-electronic (O-E) applications of heterometal grafted metalla-ynes and poly(metalla-ynes).

Functional Materials Based on Cyclometalated Platinum(II) ß-Diketonate Complexes: A Review of Structure-Property Relationships and Applications.

Square planar organoplatinum(II) complexes have garnered immense interest in the area of materials research. The combination of the Pt(II) fragment with mono-, bi- tri- and tetradentate organic ligands gives rise to a large variety of complexes with intriguing properties, especially cyclometalated Pt(II) complexes in which ligands are connected through covalent bonds demonstrate higher stability, excellent photoluminescence properties, and diverse applications. The properties and applications of the Pt(II)-based materials can be smartly fine-tuned via a judicious selection of the cyclometalating as well as ancillary ligands. In this review, attempts have been made to provide a brief review of the recent developments of neutral Pt(II) organometallic complexes bearing bidentate cyclometalating ligands and ß-diketonate ancillary ligands, i.e., (C^N)Pt(O^O) and (C^C)Pt(O^O) derivatives. Both small (monomeric, dimeric) and large (polymeric) materials have been considered. We critically assessed the role of functionalities (ligands) on photophysical properties and their impact on applications.

Synthesis and structural characterization of hexa-µ2-chlorido-µ4-oxido-tetra-kis-{[4-(phenyl-ethyn-yl)pyridine-κN]copper(II)} di-chloro-methane monosolvate.

In the crystal structure of the title compound, [Cu4Cl6O(C13H9N)4]·CH2Cl2, the core mol-ecular structure consists of a Cu4 tetra-hedron with a central inter-stitial O atom. Each edge of the Cu4 tetra-hedron is bridged by a chlorido ligand. Each copper(II) cation is coordinated to the central O atom, two chlorido ligands and one N atom of the 4-phenyl-ethynyl-pyridine ligand. In the crystal, the mol-ecules are linked by inter-molecular C-H⋯Cl inter-actions. Furthermore, C-H⋯π and π-π inter-actions also connect the mol-ecules, forming a three-dimensional network. Hirshfeld surface analysis indicates that the most important contributions for the packing arrangement are from H⋯H and C⋯H/H⋯C inter-actions.

Electronic and steric effects of platinum(ii) di-yne and poly-yne substituents on the photo-switching behaviour of stilbene: experimental and theoretical insights.

A series of mono-, di-, and poly(platina-ynes) incorporating stilbene spacer units with the formulae trans-[R-C[triple bond, length as m-dash]C-Pt(PBu3)2-C[triple bond, length as m-dash]C-R] (R = (E)-1,2-diphenylethene), trans-[(Ph)-(Et3P)2PtC[triple bond, length as m-dash]C-R-C[triple bond, length as m-dash]CPt(PEt3)2(Ph)] (R = (E)-1,2-diphenylethene), and trans-[-(PnBu3)2PtC[triple bond, length as m-dash]C-R-C[triple bond, length as m-dash]C-]n (R = (E)-1,2-diphenylethene), respectively, have been synthesized and characterized to explore the effects of ligand topology on the photoisomerization and photophysical properties of these materials. The structural and photophysical properties of the complexes have been investigated and compared with those of the previously reported mono-, di- and poly(platina-ynes) incorporating azobenzene spacers. We found that the organometallic species 1M, 2M and 1P undergo topology-dependent reversible trans-to-cis photoisomerization in CH2Cl2 solution. Computational modelling supported the experimental findings.

Correction: Utilization of a Pt(II) di-yne chromophore incorporating a 2,2'-bipyridine-5,5'-diyl spacer as a chelate to synthesize a green and red emitting d-f-d heterotrinuclear complex.

Correction for 'Utilization of a Pt(ii) di-yne chromophore incorporating a 2,2'-bipyridine-5,5'-diyl spacer as a chelate to synthesize a green and red emitting d-f-d heterotrinuclear complex' by Idris Juma Al-Busaidi et al., Dalton Trans., 2021, DOI: 10.1039/d0dt04198j.

Utilization of a Pt(ii) di-yne chromophore incorporating a 2,2'-bipyridine-5,5'-diyl spacer as a chelate to synthesize a green and red emitting d-f-d heterotrinuclear complex.

A new heterotrinuclear (d-f-d) complex [Eu(btfa)31c] (btfa = 4,4,4-trifluoro-1-phenyl-1,3-butanedione and 1c = [(Ph)(Et3P)2Pt-C[triple bond, length as m-dash]C-R-C[triple bond, length as m-dash]C-Pt(Et3P)2(Ph)] (R = 2,2'-bipyridine-5,5'-diyl) has been synthesized by utilizing the N,N-donor sites of the organometallic chromophore. The complex was characterized by analytical and spectroscopic methods. Photophysical properties of the complex were analysed in detail using both steady-state and time-resolved emission and excitation spectroscopy. The optical absorption spectrum of the complex is dominated by the spin allowed π-π* transitions of the btfa and 1c units in the UV-visible region (200-418 nm) and thus is excitable over a wide range of wavelengths across the UV into the visible region of the electromagnetic spectrum. The complex displays typical red Eu(iii) emission when excited at 345 nm. However, it also shows green emission when excited at 464 nm and, thus could be an interesting candidate for full colour display applications. The change in the colour could be a result of the high value of the energy back-transfer rate (6.73 × 105 s-1) from the triplet state of the organometallic chromophore to the 5D1 state of Eu(iii). Judd-Ofelt (J-O) intensity parameters (Ω2 and Ω4), radiative (AR), non-radiative (AR) decay rates and intrinsic quantum yield (Q) have been calculated.

Two Is Better than One? Investigating the Effect of Incorporating Re(CO)3Cl Side Chains into Pt(II) Diynes and Polyynes.

Pt(II) diynes and polyynes incorporating 5,5'- and 6,6'-disubstituted 2,2'-bipyridines were prepared following conventional Sonogashira and Hagihara dehydrohalogenation reaction protocols. Using Pt(II) dimers and polymers as a rigid-rod backbone, four new heterobimetallic compounds incorporating Re(CO)3Cl as a pendant functionality in the 2,2'-bipyridine core were obtained. The new heterobimetallic Pt-Re compounds were characterized by analytical and spectroscopic techniques. The solid-state structures of a Re(I)-coordinated diterminal alkynyl ligand and a representative model compound were determined by single-crystal X-ray diffraction. Detailed photophysical characterization of the heterobimetallic Pt(II) diynes and polyynes was carried out. We find that the incorporation of the Re(CO)3Cl pendant functionality in the 2,2'-bipyridine-containing main-chain Pt(II) diynes and polyynes has a synergistic effect on the optical properties, red shifting the absorption profile and introducing strong long-wavelength absorptions. The Re(I) moiety also introduces strong emission into the monomeric Pt(II) diyne compounds, whereas this is suppressed in the polyynes. The extent of the synergy depends on the topology of the ligands. Computational modeling was performed to compare the energetic stabilities of the positional isomers and to understand the microscopic nature of the major optical transitions. We find that 5,5'-disubstituted 2,2'-bipyridine systems are better candidates in terms of yield, photophysical properties, and stability than their 6,6'-substituted counterparts. Overall, this work provides an additional synthetic route to control the photophysical properties of metallaynes for a variety of optoelectronic applications.