Structure-activity Relationship Analysis Research Articles

Surface defect and carbonyl engineering of CNTs via oxygen-plasma etching: Oriented production of singlet oxygen from peroxymonosulfate activation

A facile oxygen-plasma strategy was used to engineer carbon nanotubes (CNTs) surface with defects and carbonyl groups for organic water decontamination. The plasma-treated CNTs (E-CNTs) displayed a remarkable efficacy to catalyze peroxymonosulfate (PMS) activation for degrading electron-rich pollutants across a broad range of pH levels and under natural water conditions. Moreover, the kinetic constant for E-CNTs was found to be 4.1 times that of raw CNTs, attaining 97 % 2,4-DCP degradation in 20 min. The in situ capturing by electron paramagnetic resonance, chemical probing, and selectively scavenging tests collectively reveal that singlet oxygen (1O2) was the dominant reactive species with 54.9 % contribution to 2,4-DCP removal. The structure–activity relationship analysis and density functional theory (DFT) revealed that defects and carbonyl groups were the intrinsic catalytic sites for PMS activation. A comprehensive degradation pathway was proposed based on the properties of pollutant and degradation products from HPLC-MS and DFT calculations. Based on the ECOSAR analyses, the toxicity of the treated water (degradation intermediates) dramatically declined except for a polymerized bipolymer TP6 (m/z = 266.9). This article provides a novel method to create PMS-oriented active sites on carbon materials for selective singlet oxygen production and water purification.

Visible-light photocatalytic activity of rare-earth-metal-doped TiO2: Experimental analysis and machine learning for virtual design

Modification with rare-earth (RE) metals has emerged as an important approach for enhancing the properties of titanium dioxide. Herein, the visible-light photocatalytic activity of RE-TiO2 (RE: Tm, Er, Nd, Dy, Lu, La, Ho, Pr, Tb, Sc, Ce, Yb, Sm, Gd, Y, or Eu) was investigated using a combination of computer simulations and experimental techniques. The RE-TiO2 photocatalysts were characterised using advanced experimental techniques, including X-ray diffraction, X-ray photoelectron spectroscopy, luminescence, diffuse reflectance spectroscopy, and specific surface area measurements. Furthermore, a quantitative structure–activity relationship analysis was conducted by applying a partial least-squares machine learning algorithm. The Ho-TiO2 sample exhibited the highest photocatalytic activity under visible-light irradiation. Notably, the observed activity was not due to an up-conversion process, originating instead from slight bandgap narrowing caused by new sub-bandgap states from the RE 4 f levels.

Discovery of ent-labdane derivatives from Andrographis paniculata and their anti-inflammatory activity

The plant Andrographis paniculata has a long history of cultivation in Southeast Asia, especially its extensive anti-inflammatory activity, and the famous natural antibiotic andrographolide comes from this plant. In China, A. paniculata, as the main crop, has become a major source of traditional Chinese medicine (TCM) for the clinical treatment of inflammation. To further explore the diverse diterpene lactones with better anti-inflammatory activity from A. paniculata, twenty-one ent-labdanes, including six undescribed compounds (andropanilides D-I), were isolated. Their structures with absolute configurations were thoroughly determined by comprehensive NMR spectroscopic data, HRESIMS analysis and quantum chemical calculations. All isolated compounds were evaluated for anti-inflammatory activities based on the Griess method. Meanwhile, after structure-activity relationships analysis, the anti-inflammatory activity of andropanilide D (1) (IC50 = 2.31 μM) was found to be better than that of the positive control drug (dexamethasone, IC50 = 6.52 μM) and andrographolide (IC50 = 5.89 μM). Further mechanisms of activity indicated that andropanilide D significantly reduced the secretion of TNF-α, IL-6 and IL-1β and downregulated the protein expression of COX-2 and iNOS in LPS-induced RAW264.7 macrophages in a concentration-dependent manner based on Western blot and ELISA experiments. In conclusion, andropanilide D possesses potential medicinal value for the treatment of inflammation and further expands the material basis of the anti-inflammatory effect of A. paniculata.

Anti-Inflammatory Flavonoids from Agrimonia pilosa Ledeb: Focusing on Activity-Guided Isolation.

To elucidate the anti-inflammatory properties and constituents of Agrimonia pilosa Ledeb. (A. pilosa), a comprehensive investigation was conducted employing activity-guided isolation. The anti-inflammatory effects were evaluated through an in vitro nitric oxide (NO) assay on lipopolysaccharide (LPS)-treated RAW 264.7 macrophage cells. Seven bio-active compounds with anti-inflammatory properties were successfully isolated from the butanol fraction and identified as follows: quercetin-7-O-β-d-rhamnoside (1), apigenin-7-O-β-d-glucopyranoside (2), kaempferol-7-O-β-d-glucopyranoside (3), quercetin (4), kaempferol (5), apigenin (6), and apigenin-7-O-β-d-glucuronide-6″-butylester (7). All isolated compounds showed strong NO inhibitory activity with IC50 values ranging from 1.4 to 31 µM. Compound 6 demonstrated the most potent NO inhibition. Compound 7, a rare flavonoid, was discerned as a novel anti-inflammatory agent, ascertained through its inaugural demonstration of nitric oxide inhibition. Subsequently, a comprehensive structure-activity relationship (SAR) analysis was conducted employing eight flavonoids derived from A. pilosa. The outcomes elucidated that flavones exhibit superior NO inhibitory effects compared to flavonols, and the aglycone form manifests greater potency in NO inhibition than the glycone counterpart. These results highlight A. pilosa as a promising source of effective anti-inflammatory agents and indicate its potential as a health-beneficial dietary supplement and therapeutic material.

Furofuranoid-Type Lignans and Related Phenolics from Anisacanthus virgularis (Salisb.) Nees with Promising Anticholinesterase and Anti-Ageing Properties: A Study Supported by Molecular Modelling.

Lignan phytomolecules demonstrate promising anti-Alzheimer activity by alleviating dementia and preserving nerve cells. The purpose of this work is to characterize the lignans of Anisacanthus virgularis and explore their potential anti-acetylcholinesterase and anti-ageing effects. Phytochemical investigation of A. virgularis aerial parts afforded a new furofuranoid-type lignan (1), four known structural analogues, namely pinoresinol (2), epipinoresinol (3), phillyrin (4), and pinoresinol 4-O-β-d-glucoside (5), in addition to p-methoxy-trans-methyl cinnamate (6) and 1H-indole-3-carboxaldehyde (7). The structures were established from thorough spectroscopic analyses and comparisons with the literature. Assessment of the anticholinesterase activity of the lignans 1-5 displayed noticeable enzyme inhibition of 1 (IC50 = 85.03 ± 4.26 nM) and 5 (64.47 ± 2.75 nM) but lower activity of compounds 2-4 as compared to the reference drug donepezil. These findings were further emphasized by molecular docking of 1 and 5 with acetylcholinesterase (AChE). Rapid overlay chemical similarity (ROCS) and structure-activity relationships (SAR) analysis highlighted and rationalized the anti-AD capability of these compounds. Telomerase activation testing of the same isolates revealed 1.64-, 1.66-, and 1.72-fold activations in cells treated with compounds 1, 5, and 4, respectively, compared to untreated cells. Our findings may pave the way for further investigations into the development of anti-Alzheimer and/or anti-ageing drugs from furofuranoid-type lignans.

Novel Evodiamine-Based Sulfonamide Derivatives as Potent Insecticide Candidates Targeting Insect Ryanodine Receptors.

Pests represent an important impediment to efficient agricultural production and pose a threat to global food security. On the basis of our prior research focused on identifying insecticidal leads targeting insect ryanodine receptors (RyRs), we aimed to identify evodiamine scaffold-based novel insecticides. Thus, a variety of evodiamine-based derivatives were designed, synthesized, and assessed for their insecticidal activity against the larvae of Mythimna separata (M. separata) and Plutella xylostella (P. xylostella). The preliminary bioassay results revealed that more than half of the target compounds exhibited superior activity compared to evodiamine, matrine, and rotenone against M. separata. Among these, compound 21m displayed the most potent larvicidal efficiency, with a remarkable mortality rate of 93.3% at 2.5 mg/L, a substantial improvement over evodiamine (10.0% at 10 mg/L), matrine (10.0% at 200 mg/L), and rotenone (30.0% at 200 mg/L). In the case of P. xylostella, compounds 21m and 21o displayed heightened larvicidal activity, boasting LC50 values of 9.37 × 10-2 and 0.13 mg/L, respectively, surpassing that of evodiamine (13.41 mg/L), matrine (291.78 mg/L), and rotenone (18.39 mg/L). A structure-activity relationship analysis unveiled that evodiamine-based derivatives featuring a cyclopropyl sulfonyl group at the nitrogen atom of the B ring and a fluorine atom in the E ring exhibited more potent larvicidal effects. This finding was substantiated by calcium imaging experiments and molecular docking, which suggested that 21m could target insect RyRs, including resistant mutant RyRs of P. xylostella (G4946E and I4790M), with higher affinity than chlorantraniliprole (CHL). Additionally, cytotoxicity assays highlighted that the potent compounds 21i, 21m, and 21o displayed favorable selectivity and low toxicity toward nontarget organisms. Consequently, compound 21m emerges as a promising candidate for further development as an insecticide targeting insect RyRs.

Synthesis of Acrylopimaric Acid Triazole Derivatives and Their Antioomycete Activity against Phytophthora capsici.

To develop new antioomycete agents against plant pathogens, two series of acrylopimaric acid triazole derivatives from rosin were synthesized. The in vitro antioomycete activity of these derivatives was evaluated and screened against Pseudoperonospora cubensisi, Plasmopara viticola, Phytophthora sojae, Phytophthora infestans, and Phytophthora capsici. Compound 5m showed the highest antioomycete activity against P. capsici, with a half-maximal effective concentration (EC50) value that was lower than that of the positive control metalaxyl (1.391 and 1.815 mg/L, respectively). Compound 5m demonstrated satisfactory protective and curative efficacy against P. capsici in pepper in in vivo antioomycete activity studies. Physiological and biochemical testing showed that the action mechanism of compound 5m on P. capsici involved altering the morphology and ultrastructure of the mycelium, increasing cell membrane permeability, inducing dysfunction of the nucleus and mitochondria, and ultimately causing cell necrosis. In addition, the analysis of three-dimensional quantitative structure-activity relationship (3D-QSAR) revealed the significance of the molecular structure and charge distribution in the interaction between compound 5m and its target. Collectively, these findings indicate that compound 5m has the potential as an antioomycete candidate.

In-situ construction of nitrogen-doped porous carbon nanosheets supported well-dispersed Fe3O4 nanoparticles for efficient purification of antibiotic wastewater via peroxydisulfate activation

Heterogeneous catalysts composed of transition metal oxides and carbon-based materials have displayed significant potential in persulfates activation for the elimination of diverse refractory organic pollutants. Herein, the nitrogen-doped porous carbon (N-pC) nanosheets supported well-dispersed Fe3O4 nanoparticles (Fe3O4/N-pC) were meticulously designed and fabricated. This fabrication process involved the creation of Fe3+/(CN@PDA) precursor through loading polydopamine-Fe3+ complex on graphitic carbon nitride (g-C3N4) and the following calcination process, resulting in in-situ formation of Fe3O4 nanoparticles on the N-pC nanosheets that were derived from polydopamine coated g-C3N4. The large specific surface area, coupled with accessible Fe2+/Fe3+ species, facilitated the synergy of adsorption and catalysis, enabling the rapid elimination of antibiotics via peroxydisulfate (PDS) activation. The optimal Fe3O4/N-pC catalyst demonstrated a remarkable efficacy in the degradation of tetracycline-hydrochloride (TC), reaching a quasi-first-order kinetic constant of 0.1479 min−1, which was 1.95 times that of the degradation reaction using g-C3N4 (0.0758 min−1). Mechanistic investigations revealed that both radicals (·O2-,·OH and SO4·-) and non-radical (1O2 and electron transfer) oxidation pathways were involved in TC degradation. The toxicities of degradation intermediates were assessed through a bean-sprout planting experiment and the quantitative structure-activity relationship (QSAR) analysis. This work offers some guidance on the preparation and application of heterogeneous catalysts for effectively removing organic contaminants from water.

Novel betulin derivatives as multidrug reversal agents targeting P-glycoprotein

Chemotherapy is a powerful means of cancer treatment but its efficacy is compromised by the emergence of multidrug resistance (MDR), mainly linked to the efflux transporter ABCB1/P-glycoprotein (P-gp). Based on the chemical structure of betulin, identified in our previous work as an effective modulator of the P-gp function, a series of analogs were designed, synthesized and evaluated as a source of novel inhibitors. Compounds 6g and 6i inhibited rhodamine 123 efflux in the P-gp overexpressed leukemia cells, K562/Dox, at concentrations of 0.19 µM and 0.39 µM, respectively, and increased the intracellular accumulation of doxorubicin at the submicromolar concentration of 0.098 µM. Compounds 6g and 6i were able to restore the sensitivity of K562/Dox to Dox at 0.024 µM and 0.19 µM, respectively. Structure–activity relationship analysis and molecular modeling revealed important information about the structural features conferring activity. All the active compounds fitted in a specific region involving mainly transmembrane helices (TMH) 4–6 from one homologous half and TMH 7 and 12 from the other, also showing close contacts with TMH 6 and 12. Compounds that bound preferentially to another region were inactive, regardless of their free energy of binding. It should be noted that compounds 6g and 6i were devoid of toxic effects against peripheral blood mononuclear normal cells and erythrocytes. The data obtained indicates that both compounds might be proposed as scaffolds for obtaining promising P-gp inhibitors for overcoming MDR.

Investigation into the Interaction between Penicillin-Resistant and Penicillin-Susceptible Gonococcal Penicillin-Binding Protein 2 and Target Phenolic Ligands through Molecular Docking Studies and Structure-Activity Relationship Analysis.

Gonococcal infections present a notable public health issue, and the major approach for treatment involves using β-lactam antibiotics that specifically target penicillin-binding protein 2 (PBP2) in Neisseria gonorrhoeae. This study examines the influence of flavonoids, namely, rutin, on the structural changes of PBP2 in both penicillin-resistant (FA6140) and penicillin-susceptible (FA19) strains. The research starts by clarifying the structural effects of certain mutations, such as the insertion of an aspartate residue at position 345 (Asp-345a), in the PBP2. The strain FA6140, which is resistant to penicillin, shows specific changes that lead to a decrease in penicillin binding. These mutations, namely, P551S and F504L, have a significant impact on the pace at which acylation occurs and the stability of the strain under high temperatures. Molecular docking analyses investigate the antibacterial activities of rutin and other phytocompounds, emphasising rutin's exceptional binding affinity and its potential as an inhibitor of PBP2. Quercetin and protocatechuic acid have encouraging antibacterial effectiveness, with quercetin displaying characteristics similar to those of drugs. Molecular dynamics simulations offer a detailed comprehension of the interactions between flavonoids and PBP2, highlighting rutin's exceptional antioxidant effects and strong affinity for the substrate binding site. The study's wider ramifications pertain to the pressing requirement for antiviral treatments, namely, in the context of the ongoing COVID-19 epidemic. Flavonoids have a strong affinity for binding to PBP2, indicating their potential as inhibitors to impair cell wall formation in N. gonorrhoeae. Ultimately, this study provides extensive knowledge on the interactions between proteins and ligands, the dynamics of the structure, and the ability of flavonoids to combat penicillin-resistant N. gonorrhoeae bacteria. The verified simulation outcomes establish a basis for the creation of potent inhibitors and medicinal therapies to combat infectious illnesses.

Unveiling the promising anticancer activity of palladium(II)-aryl complexes bearing diphosphine ligands: a structure-activity relationship analysis.

In continuation of our previous works on the cytotoxic properties of organopalladium compounds, in this contribution we describe the first systematic study of the anticancer activity of Pd(II)-aryl complexes. To this end, we have prepared and thoroughly characterized a wide range of palladium derivatives bearing different diphosphine, aryl and halide ligands, developing, when necessary, specific synthetic protocols. Most of the synthesized compounds showed remarkable cytotoxicity towards ovarian and breast cancer cell lines, with IC50 values often comparable to or lower than that of cisplatin. The most promising complexes ([PdI(Ph)(dppe)] and [PdI(p-CH3-Ph)(dppe)]), characterized by a diphosphine ligand with a low bite angle, exhibited, in addition to excellent cytotoxicity towards cancer cells, low activity on normal cells (MRC5 human lung fibroblasts). Specific immunofluorescence tests (cytochrome c and H2AX assays), performed to clarify the possible mechanism of action of this class of organopalladium derivatives, seemed to indicate DNA as the primary cellular target, whereas caspase 3/7 assays proved that the complex [PdI(Ph)(dppe)] was able to promote intrinsic apoptotic cell death. A detailed molecular docking analysis confirmed the importance of a diphosphine ligand with a reduced bite angle to ensure a strong DNA-complex interaction. Finally, one of the most promising complexes was tested towards patient-derived organoids, showing promising ex vivo cytotoxicity.

Structure and activity relationship analysis of xanthones from mangosteen: Identifying garcinone E as a potent dual EGFR and VEGFR2 inhibitor.

Xanthones are among the most fundamental phytochemicals in nature. The anti-cancer activities of xanthones and their derivatives have been extensively studied. Recently, we found that garcinone E (GE), an effective anti-cancer phytochemical isolated from mangosteen (Garcinia mangostanal.), showed promising anti-cancer effects in vitro and in vivo. However, little is known about its effects on epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) activity. This study aimed to identify potent dual EGFR and VEGFR2 inhibitors from mangosteen-derived xanthones using structure-activity relationship analyses. The interaction of xanthones with EGFR and VEGFR2 was analyzed using molecular docking experiments. The kinase activities of EGFR and VEGFR2 were determined using bioluminescence assays. The rat aortic ring and Matrigel plug angiogenesis assays were used to evaluate blood vessel formation ex vivo and in vivo. A breast tumor-bearing nude mouse model was established to examine the anti-tumor effects of different xanthones. Molecular docking analysis showed that GE bound tightly to EGFR and VEGFR2, with binding energies of -9.73 and -9.56kcal/mol, respectively. Kinase activity assessment showed that GE strongly inhibited both EGFR and VEGFR2 kinase activity, with IC50 values of 315.4 and 158.2nM, respectively. Moreover, GE significantly abolished the EGF- and VEGF-induced phosphorylation of EGFR and VEGFR2, respectively. GE also showed strong inhibitory effects on cancer cell growth, endothelial cell migration, invasion, and tube formation. Ex vivo and in vivo angiogenesis assays showed that GE dose-dependently suppressed blood vessel formation in the rat aorta, Matrigel plugs, and transgenic zebrafish embryos, with the lowest effective concentration of 0.25μM. Furthermore, GE (2mg/kg) strongly inhibited tumor growth and reduced tumor weight in MDA-MB-231 breast tumor-xenografted mice. GE significantly reduced microvessel density and downregulated the expression of VEGFR2, EGFR, and Ki67 in tumor tissues. The present study demonstrated that GE was the most potent dual inhibitor of EGFR and VEGFR2 among all xanthones tested. These findings may provide valuable information for the future development of novel and effective dual inhibitors of EGFR and VEGFR2.

Mining, refining, and QSAR analysing the nanoinformatics in EPA NaKnowBase.

Concerns about the safety of manufacturing and using engineered nanomaterials (ENMs) have been increasing as the technology continues to expand. Efforts have been underway to investigate the potentially harmful effects of ENMs without carrying out the challenging empirical studies. To make such investigations possible, the US EPA Office of Research and Development (ORD) developed the nanomaterial database NaKnowBase (NKB) containing the detail of hundreds of assays conducted and published by ORD scientists experimentally investigating the environmental health and safety effects of ENMs (nanoEHS). This article describes specifics of the effort to mine, refine, and analyse the NKB. Here we use a quantitative structure activity relationship (QSAR) analysis, using a random forest of decision trees to predict the in vitro cell viability effects that occur upon exposure to ENMs that are similar in composition and structure and implement a set of laboratory conditions. These predictions are confirmed using the Jaqpot cloud platform developed by the National Technical University of Athens, Greece (NTUA) where nanoEHS effects are investigated with scientists working together globally.

Application of Deep Learning for Studying NMDA Receptors.

Artificial intelligence underwent remarkable advancement in the past decade, revolutionizing our way of thinking and unlocking unprecedented opportunities across various fields, including drug development. The emergence of large pretrained models, such as ChatGPT, has even begun to demonstrate human-level performance in certain tasks.However, the difficulties of deploying and utilizing AI and pretrained model for nonexpert limited its practical use. To overcome this challenge, here we presented three highly accessible online tools based on a large pretrained model for chemistry, the Uni-Mol, for drug development against CNS diseases, including those targeting NMDA receptor: the blood-brain barrier (BBB) permeability prediction, the quantitative structure-activity relationship (QSAR) analysis system, and a versatile interface of the AI-based molecule generation model named VD-gen. We believe that these resources will effectively bridge the gap between cutting-edge AI technology and NMDAR experts, facilitating rapid and rational drug development.

Novel anthraquinone amide derivatives as potential glyoxalase-I inhibitors.

This study aimed to identify novel Glyoxalase-I (Glo-I) inhibitors with potential anticancer properties, focusing on anthraquinone amide-based derivatives. We synthesized a series of these derivatives and conducted in silico docking studies to predict their binding interactions with Glo-I. In vitro assessments were performed to evaluate the anti-Glo-I activity of the synthesized compounds. A comprehensive structure-activity relationship (SAR) analysis identified key features responsible for specific binding affinities of anthraquinone amide-based derivatives to Glo-I. Additionally, a 100 ns molecular dynamics simulation assessed the stability of the most potent compound compared to a co-crystallized ligand. Compound MQ3 demonstrated a remarkable inhibitory effect against Glo-I, with an IC50 concentration of 1.45 µM. The inhibitory potency of MQ3 may be attributed to the catechol ring, amide functional group, and anthraquinone moiety, collectively contributing to a strong binding affinity with Glo-I. Anthraquinone amide-based derivatives exhibit substantial potential as Glo-I inhibitors with prospective anticancer activity. The exceptional inhibitory efficacy of compound MQ3 indicates its potential as an effective anticancer agent. These findings underscore the significance of anthraquinone amide-based derivatives as a novel class of compounds for cancer therapy, supporting further research and advancements in targeting the Glo-I enzyme to combat cancer.

Machine Learning-Based Approach to Identify Inhibitors of Sterol-14-Alpha Demethylase: A Study on Chagas Disease.

Chagas Disease, caused by the parasite Trypanosoma cruzi, remains a significant public health concern, particularly in Latin America. The current standard treatment for Chagas Disease, benznidazole, is associated with various side effects, necessitating the search for alternative therapeutic options. In this study, we aimed to identify potential therapeutics for Chagas Disease through a comprehensive computational analysis. A library of compounds derived from Cananga odorata was screened using a combination of pharmacophore modeling, structure-based screening, and quantitative structure-activity relationship (QSAR) analysis. The pharmacophore model facilitated the efficient screening of the compound library, while the structure-based screening identified hit compounds with promising inhibitory potential against the target enzyme, sterol-14-alpha demethylase. The QSAR model predicted the bioactivity of the hit compounds, revealing one compound to exhibit superior activity compared to benznidazole. Evaluation of the physicochemical, pharmacokinetic, toxicity, and medicinal chemistry properties of the hit compounds indicated their drug-like characteristics, oral bioavailability, ease of synthesis, and reduced toxicity profiles. Overall, our findings present a promising avenue for the discovery of novel therapeutics for Chagas Disease. The identified hit compounds possess favorable drug-like properties and demonstrate potent inhibitory effects against the target enzyme. Further in vitro and in vivo studies are warranted to validate their efficacy and safety profiles.

Design, synthesis and biological evaluation of rhein-piperazine-furanone hybrids as potential anticancer agents.

Novel rhein-piperazine-furanone hybrids, 5, were designed and synthesized efficiently from rhein. Cytotoxicity of all hybrids 5a-j against A549 human lung cancer cells was superior to the parent rhein and the reference cytarabine (CAR). Hybrid 5e (IC50 = 5.74 μM), the most potent compound, was 46- and 35-fold more toxic against A549 cells than rhein (IC50 = 265.59 μM) and CAR (IC50 = 202.57 μM), respectively. Moreover, hybrid 5e (IC50 = 69.28 μM) was less toxic to normal WI-38 human lung fibroblast cells with good selectivity (WI-38/A549, SI ≈ 12), being much higher than rhein (SI ≈ 1) and CAR (SI ≈ 2). Structure-activity relationship (SAR) analysis showed that cytotoxicity and selectivity against A549 lung cancer cells were greatly enhanced when methoxy-containing furanone was introduced to the hybrids (5e and 5h). Further, hybrid 5e showed better cytotoxicity against four types of human lung cancer cells (H460, A549, PC-9, and Calu-1; IC50 = 4.35-15.39 μM) than six other types of human cancer cells (SK-BR-3, SK-OV-3, 786-O, Huh-7, HCT116, and HeLa; IC50 = 13.77-60.45 μM), showing specificity. In particular, hybrid 5e showed the highest cytotoxicity (IC50 = 4.35 μM) and the highest selectivity (WI-38/H460, SI ≈ 16) against H460 human lung cancer cells. Flow cytometric analysis showed that hybrid 5e induced apoptosis in a concentration-dependent manner in H460 cells. The results show that the cytotoxicity and selectivity of rhein can be greatly enhanced by hybridization with furanone. Hybrid 5e is expected to be a leading candidate for anti-lung cancer drugs.

Designing novel anti-plasmodial quinoline-furanone hybrids: computational insights, synthesis, and biological evaluation targeting Plasmodium falciparum lactate dehydrogenase.

To combat resistance against current antimalarials, modifying key pharmacophores and exploring novel parasite-specific drug targets remained one of the key drug design strategies. The resistance to quinoline-based antimalarials arises often due to the efflux of the drug. Hence, the development of newer agents containing bulkier pharmacophores will enable medicinal chemists to counteract drug resistance. In view of this, herein we designed bulkier quinoline-furanone hybrids. Initially, virtual drug-likeness and ADMET screening were conducted to optimize physicochemical properties followed by docking of the hybrids against the Plasmodium falciparum lactate dehydrogenase (PfLDH) enzyme. The most potent hybrids that emerged from the computational screening were synthesized and screened for their bioactivity against the resistant strain of Plasmodium through Schizont Maturation Inhibition assays. Among the compounds tested, 5g and 6e demonstrated the best activity, with IC50 values similar to chloroquine (CQ), and 5g exhibited superior LDH inhibition compared to CQ. Compounds 5f, 7a, and 7f showed IC50 values comparable to CQ and moderate LDH inhibition. Structure-activity relationship (SAR) analysis revealed that halogen substitutions, particularly Br and Cl, enhanced antimalarial activity, while strong electron-withdrawing (-NO2) or -donating (-OH) groups led to diminished activity. Additionally, bulkier aromatic substitutions were favoured for antimalarial activity and LDH inhibition. The investigation successfully found potent anti-plasmodial quinoline-furanone hybrids, demonstrating promising prospects for combating malaria.

Antiviral Flavonoids: A Natural Scaffold with Prospects as Phytomedicines against SARS-CoV2.

Flavonoids are vital candidates to fight against a wide range of pathogenic microbial infections. Due to their therapeutic potential, many flavonoids from the herbs of traditional medicine systems are now being evaluated as lead compounds to develop potential antimicrobial hits. The emergence of SARS-CoV-2 caused one of the deadliest pandemics that has ever been known to mankind. To date, more than 600 million confirmed cases of SARS-CoV2 infection have been reported worldwide. Situations are worse due to the unavailability of therapeutics to combat the viral disease. Thus, there is an urgent need to develop drugs against SARS-CoV2 and its emerging variants. Here, we have carried out a detailed mechanistic analysis of the antiviral efficacy of flavonoids in terms of their potential targets and structural feature required for exerting their antiviral activity. A catalog of various promising flavonoid compounds has been shown to elicit inhibitory effects against SARS-CoV and MERS-CoV proteases. However, they act in the high-micromolar regime. Thus a proper leadoptimization against the various proteases of SARS-CoV2 can lead to high-affinity SARS-CoV2 protease inhibitors. To enable lead optimization, a quantitative structure-activity relationship (QSAR) analysis has been developed for the flavonoids that have shown antiviral activity against viral proteases of SARS-CoV and MERS-CoV. High sequence similarities between coronavirus proteases enable the applicability of the developed QSAR to SARS-CoV2 proteases inhibitor screening. The detailed mechanistic analysis of the antiviral flavonoids and the developed QSAR models is a step forward toward the development of flavonoid-based therapeutics or supplements to fight against COVID-19.

In silico design of new ketorolac bioisosteres as anti-inflammatory agents

Nonsteroidal anti-inflammatory drugs (NSAIDs) are over-the-counter drugs and one of the most widely used pharmacological groups worldwide, their chronic use is limited due to their adverse effects, with gastrointestinal effects being the most relevant. Ketorolac is one of the most consumed NSAIDs worldwide, the use of which has been increasing in the treatment of acute and chronic pain; however, its use has been limited by its gastrointestinal adverse effects. Modifications in the structure of ketorolac may help the search for new chemical entity candidates for anti-inflammatory analgesic drugs with less gastric effects. Forty-two ketorolac-derived bioisosteres were designed, using in silico techniques, their physicochemical parameters (molecular weight, polar surface area, and lipophilicity) were determined with SwissADME, the Way2Drug server was used to predict the activity, a 2D quantitative structure-activity relationship (QSAR) analysis was performed to quantify the anti-inflammatory activity of the derivatives, using the ChemBL database and the R language; and the molecular modeling for the prediction of the positioning in the active site and the ligand efficiency (LE), for which the 5IKR file of the protein data bank database was used, and the molecular coupling was carried out under the parameters of AutoDock Vina. Of the 42 ketorolac derivatives, 12 molecules demonstrated good predictive oral absorption, of which only 8 molecules showed less gastro-injurious effects with Way2Drug and, under 2D QSAR analysis, 3 demonstrated excellent anti-inflammatory activity. Using the molecule modeling techniques, the LE was verified, and it was determined that molecules 32 and 34 adequately inhibited the cyclooxygenase-2 enzyme; however, the pKa of molecule 34 is not greater than that of ketorolac, molecule 32 being the one that meets with all the parameters proposed in the present study, so it would be a candidate to continue in preclinical phase studies to corroborate the findings made in this investigation.