Literature Review on Conjugated Polymers as Light-Sensitive Materials for Photovoltaic and Light-Emitting Devices in Photonic Biomaterial Applications.

Due to their extended p-orbital delocalization, conjugated polymers absorb light in the range of visible-NIR frequencies. We attempt to exploit this property to create materials that compete with inorganic semiconductors in photovoltaic and light-emitting materials. Beyond competing for applications in photonic devices, organic conjugated compounds, polymers, and small molecules have also been extended to biomedical applications like phototherapy and biodetection. Recent research on conjugated polymers has focused on bioapplications based on the absorbed light energy conversions in electric impulses, chemical energy, heat, and light emission. In this review, we describe the working principles of those photonic devices that have been applied and researched in the field of biomaterials.

Peroxide derivatives as SARS-CoV-2 entry inhibitors.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Host cell invasion is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD). In this work, bio-layer interferometry (BLI) was used to screen a series of fifty-two peroxides, including aminoperoxides and bridged 1,2,4 - trioxolanes (ozonides), with the aim of identifying small molecules that interfere with the RBD-ACE2 interaction. We found that two compounds, compound 21 and 29, exhibit the activity to inhibit RBD-ACE2. They are further demonstrated to inhibit SARS-CoV-2 cell entry, as shown in pseudovirus assay and experiment with authentic SARS-CoV-2. A comprehensive in silico analysis was carried out to study the physicochemical and pharmacokinetic properties, revealing that both compounds have good physicochemical properties as well as good bioavailability. Our results highlight the potential of small molecules targeting RBD inhibitors as potential therapeutic drugs for COVID-19.

Synthesis, docking studies and biological evaluation of 1H-1,2,3-triazole-7-chloroquinoline derivatives against SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded enveloped positive RNA virus and the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Chloroquine (CQ), an antimalarial drug, was reported to be active against several viruses including coronaviruses. The mechanism of host cell invasion by SARS-CoV-2 involves the interaction of angiotensin-converting enzyme (ACE2) with receptor-binding domain (RBD) of spike protein (S). The main protease (Mpro/3CLpro) is an attractive drug target due to its vital function in regulation of polyprotein translated from viral RNA. In this study, a series of novel quinoline-triazole hybrid compounds was synthesized and subjected to evaluations on their cytotoxicity, interactions with different variants of RBD in SARS-CoV-2 and with 3CLpro enzyme by experimental and computational techniques to identify their ability of counteracting viral infection. The results of bio-layer interferometry showed that quinoline derivative 11 has good interaction with delta plus and omicron RBD variants (KD = 3.46 × 10-5 and 6.38 × 10-5 M) while derivative 1 is the best binder for recent variant omicron (KD = 26.9 µM) among the series. Potent compounds 1-4 and 11 also demonstrated a suppressive effect on 3CLpro activity in a non-dose-dependent manner. Further docking study revealed that these compounds interacted within the same area of RBD, while no correlation was found for 3CLpro. Furthermore, the molecular dynamics simulations were carried out to assess the conformational stability of docked complexes for preliminary verification.

Chemo-/Regio-Selective Synthesis of Novel Functionalized Spiro[pyrrolidine-2,3'-oxindoles] under Microwave Irradiation and Their Anticancer Activity.

A novel series of nitrostyrene-based spirooxindoles were synthesized via the reaction of substituted isatins 1a-b, a number of α-amino acids 2a-e and (E)-2-aryl-1-nitroethenes 3a-e in a chemo/regio-selective manner using [3+2] cycloaddition (Huisgen) reaction under microwave irradiation conditions. The structure elucidation of all the synthesized spirooxindoles were done using 1H and 13C NMR and HRMS spectral analysis. The single crystal X-ray crystallographic study of compound 4l was used to assign the stereochemical arrangements of the groups around the pyrrolidine ring in spiro[pyrrolidine-2,3'-oxindoles] skeleton. The in vitro anticancer activity of spiro[pyrrolidine-2,3'-oxindoles] analogs 4a-w against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines shows promising results. Out of the 23 synthesized spiro[pyrrolidine-2,3'-oxindoles], while five compounds (4c, 4f, 4m, 4q, 4t) (IC50 = 34.99-47.92 µM; SI = 0.96-2.43) displayed significant in vitro anticancer activity against human lung (A549) cancer cell lines, six compounds (4c, 4f, 4k, 4m, 4q, 4t) (IC50 = 41.56-86.53 µM; SI = 0.49-0.99) displayed promising in vitro anticancer activity against human liver (HepG2) cancer cell lines. In the case of lung (A549) cancer cell lines, these compounds were recognized to be more efficient and selective than standard reference artemisinin (IC50 = 100 µM) and chloroquine (IC50 = 100 µM; SI: 0.03). However, none of them were found to be active as compared to artesunic acid [IC50 = 9.85 µM; SI = 0.76 against lung (A549) cancer cell line and IC50 = 4.09 µM; SI = 2.01 against liver (HepG2) cancer cell line].

Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies.

Leishmaniasis is a neglected tropical disease, and there is an emerging need for the development of effective drugs to treat it. To identify novel compounds with antileishmanial properties, a novel series of functionalized spiro[indoline-3,2'-pyrrolidin]-2-one/spiro[indoline-3,3'-pyrrolizin]-2-one 23a-f, 24a-f, and 25a-g were prepared from natural-product-inspired pharmaceutically privileged bioactive sub-structures, i.e., isatins 20a-h, various substituted chalcones 21a-f, and 22a-c amino acids, via 1,3-dipolar cycloaddition reactions in MeOH at 80 °C using a microwave-assisted approach. Compared to traditional methods, microwave-assisted synthesis produces higher yields and better quality, and it takes less time. We report here the in vitro antileishmanial activity against Leishmania donovani and SAR studies. The analogues 24a, 24e, 24f, and 25d were found to be the most active compounds of the series and showed IC50 values of 2.43 µM, 0.96 µM, 1.62 µM, and 3.55 µM, respectively, compared to the standard reference drug Amphotericin B (IC50 = 0.060 µM). All compounds were assessed for Leishmania DNA topoisomerase type IB inhibition activity using the standard drug Camptothecin, and 24a, 24e, 24f, and 25d showed potential results. In order to further validate the experimental results and gain a deeper understanding of the binding manner of such compounds, molecular docking studies were also performed. The stereochemistry of the novel functionalized spirooxindole derivatives was confirmed by single-crystal X-ray crystallography studies.

Next generation of boron neutron capture therapy (BNCT) agents for cancer treatment.

Boron neutron capture therapy (BNCT) is one of the most promising treatments among neutron capture therapies due to its long-term clinical application and unequivocally obtained success during clinical trials. Boron drug and neutron play an equivalent crucial role in BNCT. Nevertheless, current clinically used l-boronophenylalanine (BPA) and sodium borocaptate (BSH) suffer from large uptake dose and low blood to tumor selectivity, and that initiated overwhelm screening of next generation of BNCT agents. Various boron agents, such as small molecules and macro/nano-vehicles, have been explored with better success. In this featured article, different types of agents are rationally analyzed and compared, and the feasible targets are shared to present a perspective view for the future of BNCT in cancer treatment. This review aims at summarizing the current knowledge of a variety of boron compounds, reported recently, for the application of BCNT.

Overcoming Suppressive Tumor Microenvironment by Vaccines in Solid Tumor.

Conventional vaccines are widely used to boost human natural ability to defend against foreign invaders, such as bacteria and viruses. Recently, therapeutic cancer vaccines attracted the most attention for anti-cancer therapy. According to the main components, it can be divided into five types: cell, DNA, RNA, peptide, and virus-based vaccines. They mainly perform through two rationales: (1) it trains the host immune system to protect itself and effectively eradicate cancer cells; (2) these vaccines expose the immune system to molecules associated with cancer that enable the immune system to recognize and destroy cancer cells. In this review, we thoroughly summarized the potential strategies and technologies for developing cancer vaccines, which may provide critical achievements for overcoming the suppressive tumor microenvironment through vaccines in solid tumors.

Combining computational and experimental evidence on the activity of antimalarial drugs on papain-like protease of SARS-CoV-2: A repurposing study.

The development of inhibitors that target the papain-like protease (PLpro) has the potential to counteract the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent causing coronavirus disease 2019 (COVID-19). Based on a consideration of its several downstream effects, interfering with PLpro would both revert immune suppression exerted by the virus and inhibit viral replication. By following a repurposing strategy, the current study evaluates the potential of antimalarial drugs as PLpro inhibitors, and thereby the possibility of their use for treatment of SARS-CoV-2 infection. Computational tools were employed for structural analysis, molecular docking, and molecular dynamics simulations to screen antimalarial drugs against PLpro, and in silico data were validated by in vitro experiments. Virtual screening highlighted amodiaquine and methylene blue as the best candidates, and these findings were complemented by the in vitro results that indicated amodiaquine as a µM PLpro deubiquitinase inhibitor. The results of this study demonstrate that the computational workflow adopted here can correctly identify active compounds. Thus, the highlighted antimalarial drugs represent a starting point for the development of new PLpro inhibitors through structural optimization.

Antimalarial and Anticancer Activity Evaluation of Bridged Ozonides, Aminoperoxides, and Tetraoxanes.

Bridged aminoperoxides, for the first time, were investigated for the in vitro antimalarial activity against the chloroquine-resistant Plasmodium falciparum strain K1 and for their cytotoxic activities against immortalized human normal liver (LO2) and lung (BEAS-2B) cell lines as well as human liver (HepG2) and lung (A549) cancer cell lines. Aminoperoxides exhibit good cytotoxicity against lung A549 cancer cell line. Synthetic ozonides were shown to have high activity against the chloroquine-resistant P. falciparum. A cyclic voltammetry study of peroxides was performed, and most of the compounds did not show a direct correlation in oxidative capacity-activity. Peroxides were analyzed for ROS production to understand their mechanism of action. However, none of the compounds has an impact on ROS generation, suggesting that ozonides induce apoptosis in HepG2 cells through ROS-independent dysfunction pathway.

Antimalarial and antitumour activities of the steroidal quinone-methide celastrol and its combinations with artemiside, artemisone and methylene blue.

Artemisinin, isolated from the traditional Chinese medicinal plant qing hao (Artemisia annua) and its derivatives are used for treatment of malaria. With treatment failures now being recorded for the derivatives and companion drugs used in artemisinin combination therapies new drug combinations are urgently required. The amino-artemisinins artemiside and artemisone display optimal efficacies in vitro against asexual and sexual blood stages of the malaria parasite Plasmodium falciparum and are active against tumour cell lines. In continuing the evolution of combinations of the amino-artemisinins with new drugs, we examine the triterpenoid quinone methide celastrol isolated from the traditional Chinese medicinal plant léi gong téng (Tripterygium wilfordii). This compound is redox active, and has attracted considerable attention because of potent biological activities against manifold targets. We report that celastrol displays good IC50 activities ranging from 0.50-0.82 µM against drug-sensitive and resistant asexual blood stage Pf, and 1.16 and 0.28 µM respectively against immature and late stage Pf NF54 gametocytes. The combinations of celastrol with each of artemisone and methylene blue against asexual blood stage Pf are additive. Given that celastrol displays promising antitumour properties, we examined its activities alone and in combinations with amino-artemisinins against human liver HepG2 and other cell lines. IC50 values of the amino-artemisinins and celastrol against HepG2 cancer cells ranged from 0.55-0.94 µM. Whereas the amino-artemisinins displayed notable selectivities (SI > 171) with respect to normal human hepatocytes, in contrast, celastrol displayed no selectivity (SI < 1). The combinations of celastrol with artemiside or artemisone against HepG2 cells are synergistic. Given the promise of celastrol, judiciously designed formulations or structural modifications are recommended for mitigating its toxicity.

Biological Evaluation in Resistant Cancer Cells and Study of Mechanism of Action of Arylvinyl-1,2,4-Trioxanes.

1,2,4-trioxane is a pharmacophore, which possesses a wide spectrum of biological activities, including anticancer effects. In this study, the cytotoxic effect and anticancer mechanism of action of a set of 10 selected peroxides were investigated on five phenotypically different cancer cell lines (A549, A2780, HCT8, MCF7, and SGC7901) and their corresponding drug-resistant cancer cell lines. Among all peroxides, only 7 and 8 showed a better P-glycoprotein (P-gp) inhibitory effect at a concentration of 100 nM. These in vitro results were further validated by in silico docking and molecular dynamic (MD) studies, where compounds 7 and 8 exhibited docking scores of -7.089 and -8.196 kcal/mol, respectively, and remained generally stable in 100 ns during MD simulation. Further experiments revealed that peroxides 7 and 8 showed no significant effect on ROS accumulations and caspase-3 activity in A549 cells. Peroxides 7 and 8 were also found to decrease cell membrane potential. In addition, peroxides 7 and 8 were demonstrated to oxidize a flavin cofactor, possibly elucidating its mechanism of action. In conclusion, apoptosis induced by 1,2,4-trioxane was shown to undergo via a ROS- and caspase-3-independent pathway with hyperpolarization of cell membrane potential.

Exploring SARS-CoV-2 Delta variant spike protein receptor-binding domain (RBD) as a target for tanshinones and antimalarials.

The interaction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD) of spike protein with angiotensin-converting enzyme 2 (ACE2) mediates cell invasion. While this interaction mechanism is conserved, the RBD is affected by amino acid mutations in variants such as Delta and Omicron, resulting in enhanced transmissibility and altered ligand binding. Tanshinones are currently investigated as multi-target antiviral agents, but the studies were limited to the original SARS-CoV-2. This study aims at investigating the interaction of tanshinones with the Delta RBD. Chloroquine, methylene blue and pyronaridine, antimalarials previously identified as SARS-CoV-2 RBD binders, were studied for reference. Docking indicated the best scores for tanshinones, while bio-layer interferometry and molecular dynamics highlighted methylene blue as the best Delta RBD binder, although with decreased affinity with respect to the original strain.

Functionalized Boron Nanoparticles as Potential Promising Antimalarial Agents.

Boron nanoparticles (BNPs), functionalized with hydroxyl groups, were synthesized in situ by a cascade process, followed by bromination and hydrolyzation reactions. These functionalized BNPs, (B m (OH) n ), were characterized using 1H and 11B NMR spectra, Fourier-transform infrared (FT-IR) spectroscopy, inductively coupled plasma-optical emission spectroscopy (ICP-OES), transmission electron microscopy (TEM), dynamic light scattering (DLS), and X-ray photoelectron spectroscopy (XPS) methods. These nanoparticles were also evaluated in vitro for their antimalarial activity against Plasmodium falciparum (3D7 strain) with an IC50 value of 0.0021 µM and showed low toxicity to Uppsala 87 malignant glioma (U87MG) cell lines, malignant melanoma A375 cell lines, KB human oral cancer cell lines, rat cortical neuron cell lines, and rat fibroblast-like synoviocyte (FLS) cell lines.

Pyronaridine induces apoptosis in non-small cell lung cancer cells by upregulating death receptor 5 expression and inhibiting epidermal growth factor receptor.

Lung cancer is the leading cause of cancer death. Pyronaridine, a synthetic drug of artemisinin, has been used in China for over 30 years for the treatment of malaria, but its effect on non-small cell lung cancer (NSCLC) cells is rarely reported. In this study, we determined the efficacy of pyronaridine in four different NSCLC cell lines and explored its mechanism in H1975. The data showed that pyronaridine could upregulate the expression of TNF-related apoptosis-inducing ligand (TRAIL)-mediated death receptor 5 to promote cellular apoptosis. Meanwhile, the JNK (c-Jun N-terminal kinase) level was detected to be significantly increased after treating with pyronaridine. We used JNK inhibitor and found that it could partially inhibit cell apoptosis. The results showed that epidermal growth factor receptor (EGFR), PI3K, and AKT were downregulated after the treatment of pyronaridine. In summary, pyronaridine can selectively kill NSCLC by regulating TRAIL-mediated apoptosis and downregulating the protein level of EGFR. It is a promising anticancer drug for NSCLC.

Computational and experimental insights on the interaction of artemisinin, dihydroartemisinin and chloroquine with SARS-CoV-2 spike protein receptor-binding domain (RBD).

The mechanism of host cell invasion of severe acute respiratory syndrome coronavirus-2 SARS-CoV-2 is connected with the interaction of spike protein (S) with angiotensin-converting enzyme 2 (ACE2) through receptor-binding domain (RBD). Small molecules targeting this assembly are being investigated as drug candidates to contrast SARS-CoV-2. In this context, chloroquine, an antimalarial agent proposed as a repurposed drug to treat coronavirus disease-19 (COVID-19), was hypothesized to bind RBD among its other mechanisms. Similarly, artemisinin and its derivatives are being studied as potential antiviral agents. In this work, we investigated the interaction of artemisinin, its metabolite dihydroartemisinin and chloroquine with RBD by means of computational tools and in vitro. Docking studies showed that the compounds interfere with the same region of the protein and molecular dynamics (MD) simulations demonstrated the stability of the predicted complexes. Bio-layer interferometry showed that chloroquine dose-dependently binds RBD (KD = 35.9 µM) more efficiently than artemisinins. [Formula: see text].

A new benzophenone, and the antiplasmodial activities of the constituents of Securidaca longipedunculata fresen (Polygalaceae).

Extracts from Securidaca longipedunculata showed antiplasmodial activities against reference clones and clinical isolates using SYBR Green I method. A new benzophenone, 2,3,4,5-tetramethoxybenzophenone (1) was isolated and characterized along with seven known compounds: 4-hydroxy-2,3-dimethoxybenzophenone (2); 3-hydroxy-5-methoxybiphenyl (3), methyl-2-hydroxy-6-methoxybenzoate (4), benzyl-2-hydroxy-6-methoxybenzoate (5), 2-hydroxy-6-methoxybenzoic acid (6), 2,4,5-trimethoxybenzophenone (7) and 2-methoxy-3,4-methylenedioxybenzophenone (8). Compounds 1 and 2 showed ex vivo antiplasmodial activities (IC50 28.8 µM and 18.6 µM, respectively); while 5 and 8 showed in vivo activities (IC50 19.7 µM and 14.5 µM, respectively) against D6 strain. In a cytotoxicity assay, all the extracts (with an exception of the MeOH extract of the leaves) and pure compounds were not toxic to the normal LO2 and BEAS cell-lines, while the methanol roots extract (IC50 66.4 µg/mL against A549, and 77.4 µg/mL against HepG2), compounds 6 (IC50 22.2 µM against A549) and 7 (IC50 45.2 µM against HepG2) were weakly active against cancerous cell-lines.

Antileishmanial and cytotoxic activity of secondary metabolites from Taberneamontana ventricosa and two aloe species.

In this study, the antileishmanial and cytotoxic activities of secondary metabolites isolated from Tabernaemontana ventricosa Hochst. ex A. DC., Aloe tororoana Reynolds, and Aloe schweinfurthii var. labworana Reynolds were investigated. Overall, nineteen known compounds were isolated from the three plant species. The compounds were characterized based on their spectroscopic data. Voacristine and aloenin were the most active compounds against promastigotes of antimony-sensitive Leishmania donovani (IC50 11 ± 5.2 µM and 26 ± 6.5 µM, respectively) with low toxicity against RAW264.7, murine monocyte/macrophage-like cells. The in silico docking evaluation and in vitro NO generation assay also substantially support the antileishmanial effects of these compounds. In a cytotoxicity assay against cancer and normal cell lines, ursolic acid highly inhibited proliferation of lung cancer cells, A549 (IC50 6.61 ± 0.7 µM) while voacristine was moderately active against human liver cancer cells, HepG2 (IC50 23.0 ± 0.0 µM). All other compounds were inactive against the test parasites and cell lines. [Formula: see text].

Synthesis and Coordination Properties of a Water-Soluble Material by Cross-Linking Low Molecular Weight Polyethyleneimine with Armed Cyclotriveratrilene.

In this study, a full organic and water-soluble material was synthesized by coupling low molecular weight polyethylenimine (PEI-800) with cyclotriveratrilene (CTV). The water-soluble cross-linked polymer contains hydrophobic holes with a high coordination capability towards different organic drug molecules. The coordinating capability towards hydrophilic drugs (doxorubicin, gatifloxacin and sinomenine) and hydrophobic drugs (camptothecin and celastrol) was analyzed in an aqueous medium by using NMR, UV-Vis and emission spectroscopies. The coordination of drug molecules with the armed CTV unit through hydrophobic interactions was observed. In particular, celastrol exhibited more ionic interactions with the PEI moiety of the hosting system. In the case of doxorubicin, the host-guest detachment was induced by the addition of ammonium chloride, suggesting that the intracellular environment can facilitate the release of the drug molecules.

A Drug Repurposing Approach for Antimalarials Interfering with SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD) and Human Angiotensin-Converting Enzyme 2 (ACE2).

Host cell invasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD). In this work, computational and experimental techniques were combined to screen antimalarial compounds from different chemical classes, with the aim of identifying small molecules interfering with the RBD-ACE2 interaction and, consequently, with cell invasion. Docking studies showed that the compounds interfere with the same region of the RBD, but different interaction patterns were noted for ACE2. Virtual screening indicated pyronaridine as the most promising RBD and ACE2 ligand, and molecular dynamics simulations confirmed the stability of the predicted complex with the RBD. Bio-layer interferometry showed that artemisone and methylene blue have a strong binding affinity for RBD (KD = 0.363 and 0.226 µM). Pyronaridine also binds RBD and ACE2 in vitro (KD = 56.8 and 51.3 µM). Overall, these three compounds inhibit the binding of RBD to ACE2 in the µM range, supporting the in silico data.

Cytotoxicity of isoflavones from Millettia dura.

The first phytochemical investigation of the flowers of Millettia dura resulted in the isolation of seven isoflavones, a flavonol and a chalcone. Eleven isoflavones and a flavonol isolated from various plant parts from this plant were tested for cytotoxicity against a panel of cell lines, and six of these showed good activity with IC50 values of 6-14 µM. Durmillone was the most active with IC50 values of 6.6 µM against A549 adenocarcinomic human alveolar basal epithelial cancer cell line with low cytotoxicity against the non-cancerous cell lines BEAS-2B (IC50 = 58.4 µM), LO2 hepatocytes (IC50 78.7 µM) and CCD19Lu fibroblasts (IC50 >100 µM).