Promising Activity Research Articles

Chemical Profiling and Enzyme Inhibitory Activities of Essential Oil Isolated from Pistacia khinjuk Leaves: Insights On GC-MS Analysis and Skin Aging-Relevant Enzymes.

Pistacia khinjuk is a species of flowering plants belonging to family Anacardiaceae, with promising pharmacological activities like antioxidants, anti-inflammatory, antiviral, and antimicrobial. This study aimed to investigate the GC-MS chemical composition of essential oil isolated from Pistacia khinjuk leaves and its inhibitory properties against aging-relevant enzymes such a collagenase and elastase. The isolated oil showed predominance of β-cadinene (15.34 %), γ-amorphene (8.50 %), α-cadinol (8.14 %), τ-cadinol (7.57 %), (E)-β-caryophyllene (5.77 %), α-pinene (4.70 %), phytol (4.57 %), α-muurolene (3.30 %), (+)-epi-bicyclosesquiphellandrene (3.21 %), and cubenene (3.16 %). Further, it showed remarkable inhibitory activities against collagenase and elastase with IC50 values of 15.61±0.69 and 41.12±2.09 μg/mL, respectively compared to epigallocatechin gallate (IC50=29.52±1.3 μg/mL and 26.86±1.37 μg/mL). as a conclusion, the leaf oil is recommended for topical cosmetic preparations to retard skin aging symptoms such as wrinkles. However, the bioavailability assessment and toxicological profile should be considered in the future studies.

A Review on the Mechanism and Structure-activity Relationship of Resveratrol Heteroaryl Analogues.

Resveratrol is one of the most interesting naturally-occurring nonflavonoid phenolic compounds with various biological activities, such as anticancer, neuroprotection, antibacterial, and anti-inflammatory. However, there is no clinical usage of resveratrol due to either its poor activity or poor pharmacokinetic properties. Heteroarenes-modified resveratrol is one pathway to improve its biological activities and bioavailability, and form more modification sites. In this review, we present the progress of heteroaryl analogues of resveratrol with promising biological activities in the latest five years, ranging from the synthesis to the structure-activity relationship and mechanism of actions. Finally, introducing heteroarenes into resveratrol is an effective strategy, which focuses on the selectivity of structure-activity relationship in vivo.

A new framework for novel analogues of pazopanib as potent and selective human carbonic anhydrase inhibitors: Design, repurposing rational, synthesis, crystallographic, in vivo and in vitro biological assessments

Herein, we describe the design and synthesis of novel aryl pyrimidine benzenesulfonamides APBSs 5a-n, 6a-c, 7a-b, and 8 as pazopanib analogues to explore new potent and selective inhibitors for the CA IX. All APBSs were examined in vitro for their promising inhibition activity against a small panel of hCAs (isoforms I, II, IX, and XII). The X-ray crystal structure of CA I in adduct with a representative APBS analogue was solved. APBS-5m, endowed with the best hCA IX inhibitory efficacy and selectivity, was evaluated for antiproliferative activity against a small panel of different cancer cell lines, SK-MEL-173, MDA-MB-231, A549, HCT-116, and HeLa, and it demonstrated one-digit IC50 values range from 2.93 μM (MDA-MB-231) to 5.86 μM (A549). Furthermore, compound APBS-5m was evaluated for its influence on hypoxia-inducible factor (HIF-1α) production, apoptosis induction, and colony formation in MDA-MB-231 cancer cells. The in vivo efficacy of APBS-5m as an antitumor agent was additionally investigated in an animal model of Solid Ehrlich Carcinoma (SEC). In order to offer perceptions into the conveyed hCA IX inhibitory efficacy and selectivity in silico, a molecular docking investigation was also carried out.

Shining light on carbon dots: Toward enhanced antibacterial activity for biofilm disruption.

In spite of tremendous efforts dedicated to addressing bacterial infections and biofilm formation, the post-antibiotic ear continues to witness a gap between the established materials and an easily accessible yet biocompatible antibacterial reagent. Here we show carbon dots (CDs) synthesized via a single hydrothermal process can afford promising antibacterial activity that can be further enhanced by exposure to light. By using citric acid and polyethyleneimine as the precursors, the photoluminescence CDs can be produced within a one-pot, one-step hydrothermal reaction in only 2 h. The CDs demonstrate robust antibacterial properties against both Gram-positive and Gram-negative bacteria and, notably, a considerable enhancement of antibacterial effect can be observed upon photo-irradiation. Mechanistic insights reveal that the CDs generate singlet oxygen (1O2) when exposed to light, leading to an augmented reactive oxygen species level. The approach for disruption of biofilms and inhibition of biofilm formation by using the CDs has also been established. Our findings present a potential solution to combat antibacterial resistance and offer a path to reduce dependence on traditional antibiotics.

Anti-proliferative, antimicrobial, DFT calculations, and molecular docking 3D scaffold based on sodium alginate, chitosan, neomycin sulfate and hydroxyapatite

3D multifunctional scaffold has been designed based on Cs/SA/NS/NPHA. Nanoparticles hydroxyapatite (NPHA) was prepared via precipitation method of sodium dihydrogen phosphate in presence calcium chloride. Different ratios of Chitosan (CS)/Sodium Alginate (SA) were used to prepare Cs/SA scaffolds in presence of CaCl2 as a cross linker. NPHA was incorporated in CS/SA scaffold and neomycin sulfate (NS) was added as an antimicrobial agent. The structure and surface morphology of the scaffolds were investigated via infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscope (SEM) and thermal gravimetric analysis (TGA) techniques. Additionally, Antimicrobial activity of the scaffold has evaluated against Gram- negative and Gram- positive bacteria. The result showed promising antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans. Furthermore, cytotoxicity against MG63 osteosarcoma cell and fibroblast normal cell line has investigated. The result showed anti-proliferative against MG63. DFT calculations and molecular docking were used to study the reactivity of the compounds. The results exhibited that Cs/SA/NS/NPHA is potent expected to be used in bone tissue regeneration.

Targeting Cysteine Proteases and their Inhibitors to Combat Trypanosomiasis.

Trypanosomiasis, caused by protozoan parasites of the Trypanosoma genus, remains a significant health burden in several regions of the world. Cysteine proteases play a crucial role in the pathogenesis of Trypanosoma parasites and have emerged as potential therapeutic targets for the development of novel antiparasitic drugs. This review article aims to provide a comprehensive overview of the role of cysteine proteases in trypanosomiasis and their potential as therapeutic targets. We discuss the biological significance of cysteine proteases in Trypanosoma parasites and their involvement in essential processes, such as host immune evasion, cell invasion, and nutrient acquisition. A comprehensive literature search was conducted to identify relevant studies and research articles on the role of cysteine proteases and their inhibitors in trypanosomiasis. The selected studies were critically analyzed to extract key findings and provide a comprehensive overview of the topic. Cysteine proteases, such as cruzipain, TbCatB and TbCatL, have been identified as promising therapeutic targets due to their essential roles in Trypanosoma pathogenesis. Several small molecule inhibitors and peptidomimetics have been developed to target these proteases and have shown promising activity in preclinical studies. Targeting cysteine proteases and their inhibitors holds great potential for the development of novel antiparasitic drugs against trypanosomiasis. The identification of potent and selective cysteine protease inhibitors could significantly contribute to the combat against trypanosomiasis and improve the prospects for the treatment of this neglected tropical disease.

Mechanisms of inhibition of advanced glycation product (AGE) and α-glucosidase by Heliotropium bacciferum: Spectroscopic and molecular docking analysis

Diabetes mellitus is characterized by hyperglycemia that makes insulin more prone to glycation and form advanced glycation end products (AGEs). Here, we report the effect of glyoxal (GO) on the formation of AGEs using human insulin as model protein and their structural modifications. The present investigation also reports the anti-AGE potential of Heliotropium bacciferum (Leaf) extracts. The phytochemical analysis of H. bacciferum revealed that free phenolic extract contains higher amount of total phenolic (3901.58 ± 17.06 mg GAE/100 g) and total flavonoid content (30.41 ± 0.32 mg QE/100 g) when compared to bound phenolic extract. Naringin and caffeic acid were identified as the major phenolic ingredients by UPLC-PAD method. Furthermore, bound phenolics extract showed significantly higher DPPH and superoxide radicals scavenging activity (IC50 17.53 ± 0.36 μg/mL and 0.306 ± 0.038 mg/ mL, respectively) (p ≤ 0.05). Besides, the bound phenolics extract also showed significant (p ≤ 0.05) chelating power (IC50 0.063) compared to free phenolic extract. In addition, bound phenolic extract could efficiently trap GO under physiological conditions. Spectroscopic investigation of GO-modified insulin illustrated changes in the tertiary structure of insulin and formation of AGEs. On the other hand, no significant alteration in secondary structure was observed by far UV-CD measurement. Furthermore, H. bacciferum extract inhibited α-glucosidase activity and AGEs formation implicated in diabetes. Molecular docking analysis depicted that GO bind with human insulin in both chains and forms a stable complex with TYR A: 14, LEU A:13, ASN B:3, SER A:12 amino acid residues with binding energy of – 2.53 kcal/mol. However, caffeic acid binds to ASN A:18 and GLU A:17 residues of insulin with lower binding energy of −4.67 kcal/mol, suggesting its higher affinity towards human insulin compared to GO. Our finding showed promising activity of H. bacciferum against AGEs and its complications. The major phenolics like caffeic acid, naringin and their derivatives could be exploited for the drug development for management of AGEs in diabetes.

Novel inhaled andrographolide for treatment of lung cancer: In vitro assessment

Andrographolide is a plant-based compound that showed promising activity against lung cancer. However, the compound's poor water solubility and low bioavailability limit its oral administration. Inhaled drug delivery of andrographolide is highly favourable as it delivers active ingredients directly into the affected lungs. In the current study, we compared in vitro aerosol performance, anti-cancer activity and storages stability of two (2) inhalable andrographolide formulations. Formulation 1 was prepared using precipitation and spray drying techniques, while Formulation 2 was prepared via direct spray drying technique. Drug morphology and physicochemical properties were confirmed using scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis. In vitro aerosol dispersion profile was evaluated using the next-generation impactor (NGI). Formulation 1 consisted of elongated crystals while Formulation 2 was made up of amorphous spherical particles. Both formulations had an inhalable fraction (<5 μm) of more than 40 %, making them suitable for pulmonary drug delivery. The formulations also showed an IC25 of less than 100 μg/mL against the human lung carcinoma cells (A549). Formulation 1 and 2 was stable in a vacuum condition at 30 °C for up to 6 and 3 months, respectively. Novel inhalable andrographolide dry powders were successfully produced with a good aerosol profile, potent anti-cancer activity and adequate storage stability, which deserve further in vivo investigations.

Synthesis, characterization, biological potency, and molecular docking of Co2+, Ni2+ and Cu2+ complexes of a benzoyl isothiocyanate based ligand

The primary objective of the present study was to produce metal complexes of H4DAP ligand (N,N'-((pyridine-2,6-diylbis(azanediyl))bis(carbonothioyl))dibenzamide) derived from 2,6-diaminopyridine and benzoyl isothiocyanate with either ML or M2L stoichiometry. There are three distinct coordination complexes obtained with the formulas [Co(H2DAP)]·H2O, [Ni2(H2DAP)Cl2(H2O)2]·H2O, and [Cu(H4DAP)Cl2]·3H2O. The confirmation of the structures of all derivatives was achieved through the utilization of several analytical techniques, including FT-IR, UV–Vis, NMR, GC–MS, PXRD, SEM, TEM analysis, and QM calculations. Aiming to analyze various noncovalent interactions, topological methods such as QTAIM, NCI, ELF, and LOL were performed. Furthermore, the capacity of metal–ligand binding was examined by fluorescence emission spectroscopy. An in vitro investigation showed that the viability of MDA-MB-231 and HepG-2 cells was lower when exposed to the manufactured Cu2+ complex, in comparison to the normal cis-platin medication. The compounds were further evaluated for their in vitro antibacterial activity. The Ni2+ complex has shown promising activity against all tested pathogens, comparable to the reference drugs Gentamycin and Ketoconazole. Furthermore, a computational docking investigation was conducted to further examine the orientation, interaction, and conformation of the recently created compounds on the active site of the Bcl-2 protein.

Synthesis, Crystal Structure, Hirshfeld, DFT, Molecular Docking, Dynamics Studies, and Anti-cancer Activity of 1-Substituted-2-(4-(diethylamino)-2-hydroxyphenyl)- 1H-benzo[d]imidazole-5-ethyl carboxylates

In our present work, a novel series of 1-substituted-2-2-(4-(diethylamino)-2-hydroxyphenyl)- 1H-benzo[d]imidazole-5-ethyl carboxylates were synthesized by an efficient “one-pot” nitro reductive cyclization method using sodium dithionite is reported as potential anticancer agents. IR, 1H & 13C NMR and Mass spectral data confirmed the synthesized compounds' structure. Compound 6a and 6j were confirmed by their single crystal XRD studies. The Hirshfeld surfaces computational method was applied to visualize and analyse the intermolecular interactions within the crystal structure. All the synthesized compounds were assessed for in vitro anticancer activity towards human lung adenocarcinoma A549 cells and breast cancer MCF-7 cell lines. Compound 6j showed a promising activity with an IC50 value 42.7 μg/mL and 89.63 μg/mL against A549 and MCF-7 cell lines respectively. The potent compounds were assessed for cytotoxicity study on human embryonic kidney HEK 293 cell line and found to be non-toxic. Also, apoptosis study indicated compound 6j induced early apoptosis in the A549 lung adenocarcinoma and MCF-7 breast cancer cells. Molecular docking and dynamic simulation studies were carried out on human estrogen receptor protein (PDB: 3ERT).

Discovery of N,N'-diarylurea molecules with activity against multidrug-resistant Staphylococcus aureus.

The emergence and global spread of methicillin-resistant Staphylococcus aureus (MRSA) pose a serious threat to public health, underscoring the urgent need for novel antibacterial interventions. Here, we screened 18 newly synthesized N,N'-diarylurea derivatives to identify compounds with activity against MRSA. Our investigations led to the discovery of a small molecule, SCB-24, which exhibited promising antimicrobial activity against MRSA USA300. Notably, SCB-24 demonstrated high activity even in the presence of 10% fetal bovine serum and showed excellent selectivity for bacterial over mammalian cells. SCB-24 also showed potent activity against various MRSA strains, including those resistant to second- and third-line antibiotics. Importantly, the efficacy of SCB-24 was inferior to that of vancomycin in MRSA-infected Galleria mellonella larvae. Overall, our findings suggest that SCB-24 has great potential as a new therapeutic for multidrug-resistant S. aureus infections.

A pivotal phase 2 single-arm study of glecirasib (JAB-21822) in patients with NSCLC harboring KRAS G12C mutation.

468214 Background: KRAS G12C mutation occurs in approximately 4% of non-small cell lung cancers (NSCLC) in China. Glecirasib (Jacobio, Beijing, PRC) is a potent and highly selective covalent oral inhibitor of KRAS G12C. Methods: This phase 2 single-arm study (NCT05009329) of glecirasib was conducted in China at 43 sites, enrolling participants with locally advanced or metastatic KRAS G12C mutated NSCLC. Subjects must have received prior platinum-based therapy and an immune checkpoint inhibitor (ICI) as well as appropriate targeted agents for any actionable mutations per local standards. Primary study objective is overall response rate (ORR) assessed by independent review committee (IRC). The secondary study objectives include duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Here we report topline results from this pivotal study. Results: A total of 119 patients with NSCLC harboring KRAS G12C mutation were enrolled and treated with single agent glecirasib at 800mg daily (median follow up 10.4 months). The median age was 62 years, 79% was male and 21% was female, and 80.7% had ECOG PS 1. The prior lines of therapy include 1-3, with 94.1% (112/119) patients having received prior platinum-based therapy and ICI. Confirmed ORR was 47.9% (56/117; 95% CI, 38.5%-57.3%) and confirmed DCR was 86.3% (101/117; 95% CI, 78.7%-92%) assessed by IRC. Median PFS per IRC was 8.2 months (95% CI, 5.5 – 13.1), and median OS was 13.6 months (95% CI, 10.9 – NE). Median DOR has not been reached (95% CI, 7.2 – NE ). Overall, treatment-related adverse events (TRAEs) of any grade were observed in 97.5% of subjects. Most common TRAEs [≥15%] were anemia (56.3%), blood bilirubin increased (48.7%), alanine aminotransferase increased (35.3%), aspartate aminotransferase increased (35.3%), hypertriglyceridemia (28.6%) and γ-Glutamyl transferase increased (15.1%). Grade 3 and 4 TRAEs were observed in 39.5%. No grade 5 TRAEs occurred. Most of patients can stay on the treatment and 5.0% patients discontinued the treatment due to TRAE. In contrast to other FDA approved KRAS G12C inhibitor, Gleciasib has 6.7% of nausea, 7.6% vomiting, 3.4% diarrhea in which only one grade 3 nausea is reported. Conclusion: The pivotal phase 2 study of Glecirasib has met the primary endpoints and demonstrates impressive ORR and PFS with promising clinical activity for patients with KRAS G12C mutated advanced NSCLC. Glecirasib is well tolerated, with an extremely low gastrointestinal toxicity profile, which may improve patient compliance with oral therapy. Clinical trial information: NCT05009329 .

Potential Anti-SARS-CoV-2 Effects of Gossypol and AT-101: Molecular Docking Study Against Angiotensin Converting Enzyme 2

This study explores the potential anti-SARS-CoV-2 effects of gossypol (GP) and its AT-101 derivative through in silico molecular docking simulations. GP and AT-101 are natural and modified compounds, respectively, with promising biological activities. Using Autodock Vina software, molecular docking simulations were performed to assess the binding interactions between GP, AT-101, and the receptor binding domain of angiotensin-converting enzyme 2 (ACE2) which plays a vital role in facilitating viral entry into host cells. The docking results revealed that GP and AT-101 exhibited favorable interactions with ACE2, suggesting their potential as anti-SARS-CoV-2 agents. GP formed seven hydrogen bonds with ACE2, while AT-101 formed eight, indicating more stable binding and superior interaction. However, it is important to acknowledge that these findings are based on in silico modeling and further research is required to validate the antiviral properties of l and AT-101 in vitro and in vivo. Moreover, the long-term safety and efficacy of these compounds for COVID-19 treatment warrant further investigation through clinical trials. In conclusion, this in silico study provides preliminary evidence of the potential anti-SARS-CoV-2 effects of GP and AT-101 by demonstrating their ability to interact with ACE2. However, it is important to acknowledge that these findings are based on in silico modeling and further research is required to validate the antiviral properties of GP and AT-101 in vitro and in vivo.

Biogenic Synthesis of Selenium and Copper Oxide Nanoparticles and Inhibitory Effect against Multi-Drug Resistant Biofilm-Forming Bacterial Pathogens.

Antimicrobial resistance (AMR), caused by microbial infections, has become a major contributor to morbid rates of mortality worldwide and a serious threat to public health. The exponential increase in resistant pathogen strains including Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) poses significant hurdles in the health sector due to their greater resistance to traditional treatments and medicines. Efforts to tackle infectious diseases caused by resistant microbes have prompted the development of novel antibacterial agents. Herein, we present selenium and copper oxide monometallic nanoparticles (Se-MMNPs and CuO-MMNPs), characterized using various techniques and evaluated for their antibacterial potential via disc diffusion, determination of minimum inhibitory concentration (MIC), antibiofilm, and killing kinetic action. Dynamic light scattering (DLS), scanning electron microscopy (SEM/EDX), and X-ray diffraction (XRD) techniques confirmed the size-distribution, spherical-shape, stability, elemental composition, and structural aspects of the synthesized nanoparticles. The MIC values of Se-MMNPs and CuO-MMNPs against S. aureus and E. coli were determined to be 125 μg/mL and 100 μg/mL, respectively. Time-kill kinetics studies revealed that CuO-MMNPs efficiently mitigate the growth of S. aureus and E. coli within 3 and 3.5 h while Se-MMNPs took 4 and 5 h, respectively. Moreover, CuO-MMNPs demonstrated better inhibition compared to Se-MMNPs. Overall, the proposed materials exhibited promising antibacterial activity against S. aureus and E. coli pathogens.

Facile synthesis of Fe3O4@biochar@SO3H as magnetically separable Bronsted acid nanocatalyst for biodiesel production from different oil feedstocks

A novel magnetically separable Fe3O4@biochar@SO3H catalyst was developed from mesua assamica (King & prain) waste seed shells biochar for cost-effective biodiesel production using novel mesua assamica seed oil, jatropha oil, and soybean oil. The magnetic solid acid catalyst was synthesized via impregnation of biochar with Fe3O4 magnetic nanoparticles followed by sulfonation techniques. Fourier transform infrared (FT-IR) and X-ray photoelectron spectroscopy (XPS) analysis suggested the successful sulfonation and existence of –SO3H groups on catalyst surface. The synthesized magnetic acidic catalyst possesses total acidity of 3.9 mmol g−1 and –SO3H density of 1.8 mmol g−1. The field emission transmission electron microscopy (FETEM) led core-shell structured catalyst particle demonstrated a mean size of 87.4 nm and the surface area of 71.47 m2 g−1. The acidic catalyst easily afforded maximum yield of 96.8% mesua assamica biodiesel, 95.3% jatropha biodiesel, and 95.8% soybean biodiesel under optimized reaction parameters. The kinetic investigation suggested the occurrence of pseudo first order kinetics with activation energy of 32.42 kJ mol−1. The magnetically separable catalyst also displayed promising activity and stability up to 3rd cycle with more than 75% biodiesel yield.

Emetine induces oxidative stress, cell differentiation and NF-κB inhibition, suppressing AML stem/progenitor cells

Acute myeloid leukemia (AML) is a fatal malignancy of the blood and bone marrow. Leukemic stem cells (LSCs) are a rare subset of leukemic cells that promote the development and progression of AML, and eradication of LSCs is critical for effective control of this disease. Emetine is an FDA-approved antiparasitic drug with antitumor properties; however, little is known about its potential against LSCs. Herein, we explored the antileukemic potential of emetine, focusing on its effects on AML stem/progenitor cells. Emetine exhibited potent cytotoxic activity both in hematologic and solid cancer cells and induced AML cell differentiation. Emetine also inhibited AML stem/progenitor cells, as evidenced by decreased expression of CD34, CD97, CD99, and CD123 in KG-1a cells, indicating anti-AML stem/progenitor cell activities. The administration of emetine at a dosage of 10 mg/kg for two weeks showed no significant toxicity and significantly reduced xenograft leukemic growth in vivo. NF-κB activation was reduced in emetine-treated KG-1a cells, as shown by reduced phospho-NF-κB p65 (S529) and nuclear NF-κB p65. DNA fragmentation, YO-PRO-1 staining, mitochondrial depolarization and increased levels of active caspase-3 and cleaved PARP (Asp214) were detected in emetine-treated KG-1a cells. Moreover, treatment with the pancaspase inhibitor Z-VAD(OMe)-FMK partially prevented the apoptotic cell death induced by emetine. Emetine treatment also increased cellular and mitochondrial reactive oxygen species, and emetine-induced apoptosis in KG-1a cells was partially prevented by the antioxidant N-acetylcysteine, indicating that emetine induces apoptosis, at least in part, by inducing oxidative stress. Overall, these studies indicate that emetine is a novel potential anti-AML agent with promising activity against stem/progenitor cells, encouraging the development of further studies aimed at its clinical application.

Design and Synthesis of Polyheterocyclic Compounds Containing Pyrazolopyridopyrimidine Nucleus with Antimicrobial Activities.

This study reports the design, synthesis, and antibacterial evaluation of a library of novel polyheterocyclic derivatives featuring a unique fused pyrimidopyridopyrazole moiety. A cyclocondensation reaction between an amino-pyrazolopyridopyrimidine precursor and malonates afforded a series of pyrimidopyridopyrazolopyrimidine derivatives. Further diversification was achieved through nucleophilic cyclocondensation, yielding a collection of complex polyheterocyclic systems encompassing various ring structures. All synthesized compounds were rigorously characterized using spectroscopic techniques and elemental analysis. The antibacterial activity of the newly synthesized compounds was assessed against a panel of Gram-positive and Gram-negative bacteria. Notably, several compounds exhibited promising antibacterial activity, highlighting their potential as leads for the development of novel antibiotics.

A novel arylpiperazine derivative (LQFM181) protects against neurotoxicity induced by 3- nitropropionic acid in in vitro and in vivo models

In the pursuit of novel antioxidant therapies for the prevention and treatment of neurodegenerative diseases, three new arylpiperazine derivatives (LQFM181, LQFM276, and LQFM277) were synthesized through a molecular hybridization approach involving piribedil and butylated hydroxytoluene lead compounds. To evaluate the antioxidant and neuroprotective activities of the arylpiperazine derivatives, we employed an integrated approach using both in vitro (SH-SY5Y cells) and in vivo (neurotoxicity induced by 3-nitropropionic acid in Swiss mice) models. In the in vitro tests, LQFM181 showed the most promising antioxidant activity at the neuronal membrane and cytoplasmic levels, and significant neuroprotective activity against the neurotoxicity induced by 3-nitropropionic acid. Hence, this compound was further subjected to in vivo evaluation, which demonstrated remarkable antioxidant capacity such as reduction of MDA and carbonyl protein levels, increased activities of succinate dehydrogenase, catalase, and superoxide dismutase. Interestingly, using the same in vivo model, LQFM181 also reduced locomotor behavior and memory dysfunction through its ability to decrease cholinesterase activity. Consequently, LQFM181 emerges as a promising candidate for further investigation into its neuroprotective potential, positioning it as a new therapeutic agent for neuroprotection.

Anti-Sporothrix activity of novel copper-itraconazole complexes.

A series of new metal complexes, [Cu(ITZ)2Cl2]·5H2O (1), [Cu(NO3)2(ITZ)2] ·3H2O·C4H10O and [Cu(ITZ)2)(PPh3)2]NO3·5H2O (3) were synthesized by a reaction of itraconazole (ITZ) with the respective copper salts under reflux. The metal complexes were characterized by elemental analyses, molar conductivity, 1H and 13C{1H} nuclear magnetic resonance, UV-Vis, infrared and EPR spectroscopies. The antifungal activity of these metal complexes was evaluated against the main sporotrichosis agents: Sporothrix brasiliensis, Sporothrix schenkii, and Sporothrix globosa. All three new compounds inhibited the growth of S. brasiliensis and S. schenckii at lower concentrations than the free azole, with complex 2 able to kill all species at 4 µM and induce more pronounced alterations in fungal cells. Complexes 2 and 3 exhibited higher selectivity and no mutagenic effect at the concentration that inhibited fungal growth and affected fungal cells. The strategy of coordinating itraconazole (ITZ) to copper was successful, since the corresponding metal complexes were more effective than the parent drug. Particularly, the promising antifungal activity of the Cu-ITZ complexes makes them potential candidates for the development of an alternative drug to treat mycoses.

LC-ESI-MS/MS-Based Comparative Metabolomic Study, Antioxidant and Antidiabetic Activities of Three Lobelia Species: Molecular Modeling and ADMET Study.

The hydroethanol (70%) extracts of three Lobelia species (L. nicotianifolia, L. sessilifolia, and L. chinensis) were analyzed using LC-ESI-MS/MS. Forty-five metabolites were identified, including different flavonoids, coumarin, polyacetylenes, and alkaloids, which were the most abundant class. By applying Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA) based on LC-ESI-MS/MS analysis, the three species were completely segregated from each other. In addition, the three Lobelia extracts were tested for their antioxidant activities using a DPPH assay and as antidiabetic agents against α-glycosidase and α-amylase enzymes. L. chinensis extract demonstrated significant antioxidant activity with an IC50 value of 1.111 mg/mL, while L. nicotianifolia showed mild suppressing activity on the α-glycosidase activity with an IC50 value of 270.8 μg/mL. A molecular simulation study was performed on the main compounds to predict their potential antidiabetic activity and pharmacokinetic properties. The molecular docking results confirmed the α-glycosidase inhibitory activity of the tested compounds, as seen in their binding mode to the key amino acid residues at the binding site compared to that of the standard drug acarbose. Furthermore, the predictive ADMET results revealed good pharmacokinetic properties of almost all of the tested compounds. The biological evaluation results demonstrated the promising activity of the tested compounds, aligned with the in silico results.