Selectivity Index Research Articles

Investigating the effect of ligand structure on the anticancer properties of several new Co(II) complexes of vitaminB3-based phosphoramides

Nicotinamide, known as Vitamin-B3, has shown promising potential in improving various medical conditions. Carbacylamidophosphates (CAPh) are versatile phosphoramide ligands with a wide range of applications in both biochemistry and chemistry. Herein, to obtain compounds with enhanced anticancer activity and study the effect of the structure on this activity, four new Co(II) complexes of vitaminB3-based CAPh ligands with the formula of CoCl2[3-NC5H4CONHPO(NC5H10)2]2(C1), CoCl2[3-NC5H4CONHPO(NC5H9CH3)2]2(C2), CoCl2[3-NC5H4CONHPO(NC6H12)2]2(C3), and CoCl2[3-NC5H4CONHPO(NC4H10)2]2(C4) were designed and synthesized. FT-IR, UV–Vis, Atomic Absorption (AAS),1H, 13C, and 31PNMR, and Mass spectroscopies beside CHN and Molar conductivity methods were utilized to characterize the synthesized compounds. Using MTT-assay and Flow Cytometry, the anticancer effects of these complexes were studied on three distinct cell lines, including one normal cell line (MCF10A) and two cancer cell lines (MDA-MB-231, MCF-7). Results showed that our ligands could form complexes by coordinating with cobalt, which, not only have a very strong killing effect on cancer cells but also have a higher level of safety for normal cells and are more cost-efficient than Cisplatin. C3 was the most effective complex at inhibiting the growth of MCF-7 and MDA-MB-231 cells which exhibited a remarkable 97.5 % reduction in cancer cell growth and a Selectivity Index up to > 37. This is an impressive 93 and 54 times more selective and safer than commonly used drugs like Cisplatin and Doxorubicin, respectively.Flow Cytometry analysis shows complex-induced breast cancer cell apoptosis.The ligands’ amine structure and ring size can directly impact the complexes’ anticancer effect and safety for normal cells.

Design, synthesis, and anti-mycobacterial evaluation of 1,8-naphthyridine-3-carbonitrile analogues.

Twenty-eight compounds, viz., 1,8-naphthyridine-3-carbonitrile (ANC and ANA) derivatives, were designed and synthesized through a molecular hybridization approach. The structures of these compounds were analyzed and confirmed using 1H NMR, 13C NMR, LCMS, and elemental analyses. The synthesized compounds were evaluated by in vitro testing for their effectiveness against tuberculosis using the MABA assay, targeting the Mycobacterium tuberculosis H37Rv strain. Their minimum inhibitory concentration (MIC) was determined, showing that the tested compounds' MIC values ranged from 6.25 to ≤50 μg mL-1. Among the derivatives studied, ANA-12 demonstrated prominent anti-tuberculosis activity with a MIC of 6.25 μg mL-1. Compounds ANC-2, ANA-1, ANA 6-8, and ANA-10 displayed moderate to good anti-tuberculosis activity with MIC values of 12.5 μg mL-1. Compounds with MIC ≤ 12.5 μg mL-1 were screened against human embryonic kidney cells to assess their potential cytotoxicity. Interestingly, these compounds showed less toxicity towards normal cells, with a selectivity index value ≥ 11. To further evaluate the binding pattern in the active site of enoyl-ACP reductase (InhA) from Mtb (PDB-4TZK), a molecular docking analysis of compound ANA-12 was performed using the glide module of Schrodinger software. The stability, confirmation, and intermolecular interactions of the cocrystal ligand and the highly active compound ANA-12 on the chosen target protein were investigated through molecular dynamics simulations lasting 100 ns. In silico predictions were utilized to assess the ADMET properties of the final compounds. A suitable single crystal was developed and analyzed for compound ANA-5 to gain a deeper understanding of the compounds' structures.

Novel compounds with dual inhibition activity against SARS-CoV-2 critical enzymes RdRp and human TMPRSS2

COVID-19 caused major worldwide problems. The spread of variants and limited treatment encouraged the design of novel anti-SARS-CoV-2 compounds. A series of compounds RH1-23 were designed to dually target RNA-dependent RNA polymerase (RdRp) and transmembrane serine protease 2 (TMPRSS2). Compared to remdesivir, in vitro screening indicated the highest selectivity and potent activity of RH11–13 with half maximum inhibitory concentration (IC50) 3.9, 5.7, and 19.72 nM, respectively. RH11–12 showed superior inhibition activity against TMPRSS2 and RdRP with IC50 (1.7 and 4.2), and (6.1 and 4.42) nM, respectively. WaterMap analysis and molecular dynamics studies demonstrated the superior enzyme binding activity of RH11 and RH12. On Vero-E6 cells, RH11 and RH12 significantly inhibited the viral replication with 66 % and 63.2 %, and viral adsorption with 44 % and 65 %, alongside virucidal effect with 51.40 % and 90.5 %, respectively. Furthermore, the potent activity of RH12 was tested on TMPRSS2-expressing cells (Calu-3) compared to camostat. RH12 exhibited selectivity index (26.05) similar to camostat (28.01) and comparable to its SI on Vero-E6 cells (22.6). RH12 demonstrated also a significant inhibition of the viral adsorption on Calu-3 cells with 60 % inhibition at 30 nM. The designed compounds exhibited good physiochemical properties. These findings indicate a broad-spectrum antiviral efficacy of the designed compounds, particularly RH12, with a promise for further development.

Synthesis, COX-2 inhibition, anti-inflammatory activity, molecular docking, and histopathological studies of new pyridazine derivatives

Five new pyridazine scaffolds were synthesized and assessed for their inhibitory potential against both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) compared with indomethacin and celecoxib. The majority of the synthesized compounds demonstrated a definite preference for COX-2 over COX-1 inhibition. Compounds 4c and 6b exhibited enhanced potency towards COX-2 enzyme with IC50 values of 0.26 and 0.18 µM, respectively, compared to celecoxib with IC50 = 0.35 µM. The selectivity index (SI) of compound 6b was 6.33, more than that of indomethacin (SI = 0.50), indicating the most predominant COX-2 inhibitory activity. Consequently, the in vivo anti-inflammatory activity of compound 6b was comparable to that of indomethacin and celecoxib and no ulcerative effect was detected upon the oral administration of compound 6b, as indicated by the histopathological examination. Moreover, compound 6b decreased serum plasma PEG2 and IL-1β. To rationalize the selectivity and potency of COX-2 inhibition, a molecular docking study of compound 6b into the COX-2 active site was carried out. The COX-2 inhibition and selectivity of compound 6b can be attributed to its ability to enter the side pocket of the COX-2 enzyme and interact with the essential amino acid His90. Together, these findings suggested that compound 6b is a promising lead for the possible design of COX-2 inhibitors that could be employed as safe and effective anti-inflammatory drugs.

Discovery of antimalarial drugs from secondary metabolites in actinomycetes culture library

BackgroundNatural products play a key role as potential sources of biologically active substances for the discovery of new drugs. This study aimed to identify secondary metabolites from actinomycete library extracts that are potent against the asexual stages of Plasmodiumfalciparum (P.falciparum).MethodsSecondary metabolites from actinomycete library extracts were isolated from culture supernatants by ethyl acetate extraction. Comprehensive screening was performed to identify novel antimalarial compounds from the actinomycete library extracts (n = 28). The antimalarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) lines of P.falciparum. The cytotoxicity was then evaluated in primary adult mouse brain (AMB) cells.ResultsOut of the 28 actinomycete extracts, 17 showed parasite growth inhibition > 50% at a concentration of 50 µg/mL, nine were identified with an IC50 value < 10 µg/mL, and seven suppressed the parasite significantly with an IC50 value < 5 µg/mL. The extracts from Streptomycesaureus strains HUT6003 (Extract ID number: 2), S.antibioticus HUT6035 (8), and Streptomyces sp. strains GK3 (26) and GK7 (27), were found to have the most potent antimalarial activity with IC50 values of 0.39, 0.09, 0.97, and 0.36 µg/mL (against 3D7), and 0.26, 0.22, 0.72, and 0.21 µg/mL (against Dd2), respectively. Among them, Streptomycesantibioticus strain HUT6035 (8) showed the highest antimalarial activity with an IC50 value of 0.09 µg/mL against 3D7 and 0.22 µg/mL against Dd2, and a selective index (SI) of 188 and 73.7, respectively.ConclusionSecondary metabolites obtained from the actinomycete extracts showed promising antimalarial activity in vitro against 3D7 and Dd2 cell lines of P.falciparum with minimal toxicity. Therefore, secondary metabolites obtained from actinomycete extracts represent an excellent starting point for the development of antimalarial drug leads.

New potent EV-A71 antivirals targeting capsid

The enterovirus is a genus of single-stranded, highly diverse positive-sense RNA viruses, including Human Enterovirus A-D and Human Rhinovirus A-C species. They are responsible for numerous diseases and some infections can progress to life-threatening complications, particularly in children or immunocompromised patients. To date, there is no treatment against enteroviruses on the market, except for polioviruses (vaccine) and EV-A71 (vaccine in China). Following a decrease in enterovirus infections during and shortly after the (SARS-Cov2) lockdown, enterovirus outbreaks were once again detected, notably in young children. This reemergence highlights on the need to develop broad-spectrum treatment against enteroviruses. Over the last year, our research team has identified a new class of small-molecule inhibitors showing anti-EV activity. Targeting the well-known hydrophobic pocket in the viral capsid, these compounds show micromolar activity against EV-A71 and a high selectivity index (SI) (5h: EC50, MRC-5 = 0.57 μM, CC50, MRC-5 >20 μM, SI > 35; EC50, RD = 4.38 μM, CC50, RD > 40 μM, SI > 9; 6c: EC50, MRC-5 = 0.29 μM, CC50, MRC-5 >20 μM, SI > 69; EC50, RD = 1.66 μM, CC50, RD > 40 μM, SI > 24; Reference: Vapendavir EC50, MRC-5 = 0.36 μM, CC50, MRC-5 > 20 μM, EC50, RD = 0.53 μM, CC50, RD > 40 μM, SI > 63). The binding mode of these compounds in complex with enterovirus capsids was analyzed and showed a series of conserved interactions. Consequently, 6c and its derivatives are promising candidates for the treatment of enterovirus infections.

Synthesis, characterization, in vitro and in silico assessment of novel diclofenac derivative metal complexes

A novel hydrazone ligand was synthesized by condensing diclofenac hydrazide with salicylaldehyde. This ligand was then used to create complexes with cobalt(II), nickel(II), copper(II), gadolinium(III), lanthanum(III), and silver(I). Structural characterization of these compounds was achieved through various techniques, including nuclear magnetic resonance spectroscopy, infrared spectroscopy, ultraviolet-visible spectroscopy, mass spectrometry, elemental analysis, thermal analysis, magnetic susceptibility measurements, electron spin resonance spectroscopy, X-ray diffraction, and conductivity measurements. The inhibitory effects of the synthesized compounds on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, critical targets for anti-inflammatory drugs, were assessed. Notably, the cobalt(II) and silver(I) complexes exhibited high selectivity for inhibiting COX-2, with selectivity indices of 118.75 and 105.00, respectively. The antitumor potential of the compounds was evaluated against MCF-7 (breast cancer) and HepG-2 (liver cancer) cell lines. The copper(II) and gadolinium(III) complexes demonstrated the highest efficacy, significantly inhibiting the growth of both cancer cell lines with half-maximal inhibitory concentration (IC50) values as low as 0.37 µM and 0.58 µM (MCF-7) and 0.35 µM and 0.67 µM (HepG-2), respectively. These complexes outperformed the original ligand in inhibiting cancer cell growth. In silico studies, using the SwissADME web tool and AutoDocke Vina, corroborated the experimental findings and provided insights into the compounds' physicochemical properties, pharmacokinetics, drug-likeness, and potential binding interactions with COX-1, COX-2, and the target proteins in the cancer cell lines.

Synthesis and biological evaluation of O4′-benzyl-hispidol derivatives and analogs as dual monoamine oxidase-B inhibitors and anti-neuroinflammatory agents

Design, synthesis, and biological evaluation of two series of O4′-benzyl-hispidol derivatives and the analogous corresponding O3′-benzyl derivatives aiming to develop selective monoamine oxidase-B inhibitors endowed with anti-neuroinflammatory activity is reported herein. The first O4′-benzyl-hispidol derivatives series afforded several more potentially active and MAO-B inhibitors than the O3′-benzyl derivatives series. The most potential compound 2e of O4′-benzyl derivatives elicited sub-micromolar MAO-B IC50 of 0.38 µM with a selectivity index >264 whereas most potential compound 3b of O3′-benzyl derivatives showed only 0.95 MAO-B IC50 and a selectivity index >105. Advancement of the most active compounds showing sub-micromolar activities to further cellular evaluations of viability and induced production of pro-neuroinflammatory mediators confirmed compound 2e as a potential lead compound inhibiting the production of the neuroinflammatory mediator nitric oxide significantly by microglial BV2 cells at 3 µM concentration without significant cytotoxicity up to 30 µM. In silico molecular docking study predicted plausible binding modes with MAO enzymes and provided insights at the molecular level. Overall, this report presents compound 2e as a potential lead compound to develop potential multifunctional compounds.

Hybrids of 4-aminosalicylic acid with dual anti-mycobacterial and anti-inflammatory activities: Synthesis, biological evaluation, in silico investigation and structure-activity relationships exploration

Studies point toward a beneficial effect of NSAIDs as an adjunctive tuberculosis treatment. To discover new antitubercular compounds with anti-inflammatory activity and favorable safety profiles, three new series of non-carboxylic 4-aminosalicylic acid hybrids bearing various hydrazides (3 and 5), heterocyclic scaffolds (6–15), hydrazones (16a–d) and carboxylic analogues bearing 1,2,3-triazoles (19 and 20), were synthesized. The synthesized hybrids were evaluated for their antimycobacterial activity against H37Rv using MABA assay. Among them, compounds 8, 16a–c, 19 and 20 exhibited MIC values (9.90–37.62 µM) with good selectivity index. 16b and 20 were the most potent with MIC 9.90 and 11.40 µM, respectively. Based on an in silico docking study at COX-2 active site, 11 compounds 13a, 13b, 14a–g, 16a and 16b were selected for testing their COX-2 inhibition. The most active compounds, 13a, 16a and 16b were further tested for COX-1 and 5-LOX inhibition. Also, their COX-2 selectivity indices (SI) were determined. 16a and 16b showed the highest potency and selectivity against COX-2 IC50 = 0.31, 1.26 µg/mL, respectively, and 5-LOX with IC50 = 5.49, 25.44 µg/mL, respectively. Computational docking simulations and in Silico ADME/pharmacokinetic studies for the most active hybrids were performed and discussed. Thus structure-activity relationships were explored. In conclusion, compounds 16a and 16b represent a good starting point for the development of new potential drugs of dual antitubercular and anti-inflammatory activities.

The Imidazacridine Derivative LPSF/AC-05 Induces Apoptosis, Cell Cycle Arrest, and Topoisomerase II Inhibition in Breast Cancer, Leukemia, and Lymphoma.

Cancer is the major cause of morbidity and mortality worldwide. Current treatments for both solid and hematological tumors are associated with severe adverse effects and drug resistance, necessitating the development of novel selective antineoplastic drugs. The present study describes the antitumor activity of the imidazacridine derivative 5-acridin-9-ylmethylidene-2-thioxoimidazolidin-4-one (LPSF/AC05) in breast cancer, leuke-mia, and lymphoma cells. Cytotoxicity assays were performed in PBMC and in breast cancer, leukemia, and lymphoma cell lines using the MTT method. Changes in cell cycle progression and apoptosis were assessed using flow cytometry. Moreover, topoisomerase II inhibition as-says were performed. LPSF/AC05 exhibited cytotoxicity in six of the nine cell lines tested. The best results for leukemia and lymphoma were observed in the Toledo, Jurkat, and Raji cell lines (IC50 = 27.18, 31.04, and 33.36 M, respectively). For breast cancer, the best re-sults were observed in the triple-negative cell line MDA-MB-231 (IC50 = 27.54 μM). The compound showed excellent selectivity, with no toxicity to normal human cells (IC50 > 100M; selectivity index > 3). Cell death was primarily induced by apoptosis in all cell lines. Furthermore, LPSF/AC05 treatmentinduced cell cycle arrest at the G0/G1 phase in leuke-mia/lymphoma and at the G2/M phase in breast cancer. Finally, topoisomerase II was inhibited. These results indicate the potential ap-plication of LPSF/AC05 in cancer therapy.

Synthesis of Nitrostyrylthiazolidine-2,4-dione Derivatives Displaying Antileishmanial Potential.

A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2-5 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure-activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC50 = 7 µM) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC50 = 101 and 121 µM, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC50 = 3.3 µM, CC50 = 85 and 30 µM, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH7.4 = 16 µM), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold.

The interactive effects of medicinal dyes with conventional antimicrobials against skin pathogens.

This study aimed to explore potential synergistic effects of medicinal dyes with antimicrobials against pathogens responsible for skin infections. Antimicrobial testing was conducted using minimum inhibitory concentrations and minimum bactericidal/fungicidal concentration assays. The fractional inhibitory index (ΣFIC) of combinations was calculated, and isobolograms were constructed on selected combinations. Toxicity studies were conducted using the brine-shrimp lethality assay. Combination (1:1 ratio) studies noted that 26% of dye-antibiotic combinations were synergistic against the Gram-positive strains, 15% against the Gram-negative strains, and 14% against the yeasts. The Mercurochrome: Betadine® combination noted synergy at ratios against all the Staphylococcus aureus strains with ΣFIC values ranging from 0.05 to 0.48. The combination of Gentian violet with Gentamycin noted a 15-fold decrease in toxicity, and a selectivity index of 977.50 against the Escherichia coli (DSM 22314) strain. Time-kill studies were conducted on the combinations with the highest safe selectivity index (SI) value and lowest safe SI value i.e. Gentian violet with Gentamycin and Malachite green with Neomycin. Both combinations demonstrated better antimicrobial activity in comparison to the independent values and the controls. This study highlights the potential for medicinal dye combinations as a treatment for skin infections.

Nanostructured gadolinium(III) micelles: Synthesis, characterization, cytotoxic activities, and MRI applications in vivo

Gadolinium-based contrast agents (GBCAs) are used in around 40 % of MRI procedures. Despite initial perceptions of minimal risk, their long-term use has emphasized the need to reduce toxicity and develop more efficient GBCAs with extended blood retention. Advancements in nanomaterials have led to improved GBCAs, enhancing MRI diagnostics. This study synthesizes and characterizes nanostructured gadolinium(III) micelles as superior MRI contrast agents. The complexes, [Gd(L)2], where L is a ligand of the N-alkyl-N-methylglucamine surfactant series (L8, L10 or L12, L10), form nanostructured micelles in aqueous solution. Gd(L8)2 and Gd(L10)2 relaxivities remained stable across concentrations. Compared to Gd-DTPA, Gd(III) micelles showed enhanced T1-weighted MRI contrast. Gd(L12)2 micelles exhibited cytotoxicity against B16F10 melanoma cells (IC50 42.5 ± 2.2 μM) and L292L929 fibroblasts (IC50 52.0 ± 2.5 μM), with a selectivity index of 1.2. In vivo application in mice brain T2-weighted images suggests nanostructured Gd(III) micelles are promising MRI contrast agents for targeting healthy organs or tumors.

DNA G-quadruplexes in the genome of Trypanosoma cruzi as potential therapeutic targets for Chagas disease: Dithienylethene ligands as effective antiparasitic agents

Chagas disease is caused by the parasite Trypanosoma cruzi and affects over 7 million people worldwide. The two actual treatments, Benznidazole (Bzn) and Nifurtimox, cause serious side effects due to their high toxicity leading to treatment abandonment by the patients. In this work, we propose DNA G-quadruplexes (G4) as potential therapeutic targets for this infectious disease. We have found 174 PQS per 100,000 nucleotides in the genome of T. cruzi and confirmed G4 formation of three frequent motifs. We synthesized a family of 14 quadruplex ligands based in the dithienylethene (DTE) scaffold and demonstrated their binding to these identified G4 sequences. Several DTE derivatives exhibited micromolar activity against epimastigotes of four different strains of T. cruzi, in the same concentration range as Bzn. Compounds L3 and L4 presented remarkable activity against trypomastigotes, the active form in blood, of T. cruzi SOL strain (IC50 = 1.5–3.3 μM, SI = 25–40.9), being around 40 times more active than Bzn and displaying much better selectivity indexes.

High throughput virtual screening and validation of Plant-Based EGFR L858R kinase inhibitors against Non-Small cell lung Cancer: An integrated approach Utilizing GC–MS, network Pharmacology, Docking, and molecular dynamics

Lung cancer ranks as the 2nd most common cancer globally. It’s the most prevalent cancer in men and the 2nd most common in women. The prominent events in EGFR-mutated non-small-cell lung cancer (NSCLC) include the emergence of the L858R mutation within EGFR exon 21. Despite the promising efficacy of EGFR inhibitors in managing lung cancer, the development of acquired resistance poses a significant hurdle. In the current investigation, we focused on the screening of two phytochemicals, namely Dehydrocostus lactone and Mokkolactone, derived from the Saussurea lappa plant, as potential inhibitors targeting EGFR L858R mutant lung cancer. The chloroform and ethanol extract of the plant demonstrated anti-proliferative activity through the Resazurin chemosensitivity assay, exhibiting an IC50 value of 37.90 ± 0.29 µg/ml with selectivity index 2.4. Through a GC–MS study, we identified 11 phytochemicals for further insilico analysis. These compounds underwent ADMET assessment followed by drug likeliness analysis before being subjected to molecular docking against EGFR L858R, identified through protein–protein interaction network analysis. All phytochemicals exhibited binding energy scores ranging from −6.9 to −8.1 kcal/mol. Dehydrocostus lactone and Mokkolactone were specifically identified for their binding profile. Findings from 100 ns molecular dynamics simulations demonstrated their enhanced stability compared to the reference ligand DJK. This was evident in the root mean square deviation (RMSD) values, ranging from 0.23 ± 0.01 nm to 0.30 ± 0.05 nm, the radius of gyration values, from 1.71 ± 0.01 nm to 1.72 ± 0.01 nm, and the solvent accessible surface area values, from 155.39 ± 2.40 nm2 to 159.32 ± 2.14 nm2. Additionally, favourable characteristics were observed in terms of hydrogen bonding, principal component analysis, and free energy landscape analysis. Examination of their electronic structure via density functional theory revealed efficient properties, with the highest occupied molecular orbital-least unoccupied molecular orbital energy gap values ranging from −3.984 eV to −6.547 eV. Further, in vivo analysis is required to gain a more comprehensive understanding and efficacy of these identified phytochemicals against lung cancer.

A series of quinazolin-4(3H)-one-morpholine hybrids as anti-lung-cancer agents: Synthesis, molecular docking, molecular dynamics, ADME prediction and biological activity studies.

In this study, we synthesized 15 novel quinazoline-morpholinobenzylideneamino hybrid compounds from methyl anthranilate and we assessed their cytotoxicity via invitro assays against A549 and BEAS-2B cell lines. Molecular docking studies were conducted to evaluate the protein-ligand interactions and inhibition mechanisms on nine different molecular targets, while molecular dynamics (MD) simulations were carried out to assess the stability of the best docked ligand-protein complexes. Additionally, ADME prediction was carried out to determine physicochemical parameters and drug likeness. According to the cytotoxicity assays, compound 1 (IC50 = 2.83 μM) was found to be the most active inhibitor against A549 cells. While the selectivity index (SI) of compound 1 is 29, the SI of the reference drugs paclitaxel and sorafenib, used in this study, are 2.40 and 4.92, respectively. Among the hybrid compounds, 1 has the best docking scores against VEGFR1 (-11.744 kcal/mol), VEGFR2 (-12.407 kcal/mol) and EGFR (-10.359 kcal/mol). During MD simulations, compound 1 consistently exhibited strong hydrogen bond interactions with the active sites of VEGFR1 and 2, and these interactions were maintained for more than 90% of the simulation time. Additionally, the RMSD and RMSF values of the ligand-protein complexes exhibited high stability at their minimum levels around 1-2 Å. In conclusion, these findings suggest that compound 1 may be a potent and selective inhibitor candidate for lung cancer treatment and inhibition of VEGFR2, especially.

Antiviral Activity of Kappaphycus alvarezii Seaweed against ZIKV.

Zika virus (ZIKV) is a flavivirus transmitted through the bites of infected Aedes mosquitoes. These viruses can also be transmitted through sexual contact, vertical transmission, and possibly transfusion. Most cases are asymptomatic, but symptoms can include rash, conjunctivitis, fever, and arthralgia, which are characteristic of other arboviruses. Zika infection can lead to complications such as microcephaly, miscarriage, brain abnormalities, and Guillain-Barré syndrome (GBS). The aim is to determine the inhibitory potential of the algae Kappaphycus alvarezii (K. alvarezii) on ZIKV replication. Cytotoxicity experiments were performed using Vero cells to determine the CC50, and ZIKV replication inhibition assays (ATCC® VR-1839™) were conducted to determine the EC50. The mechanism of action was also studied to assess any synergistic effect with Ribavirin. K. alvarezii demonstrated low toxicity with a CC50 of 423 μg/mL and a potent effect on ZIKV replication with an EC50 of 0.65 μg/mL and a Selectivity Index (SI) of 651, indicating the extract's safety. Virucidal effect assays were carried out to evaluate the possible mechanism of action, and the compound addition time was studied, showing the potential to delay the treatment of infected cells by up to 6 hours. A potential synergistic effect was observed when K. alvarezii extract was combined with suboptimal concentrations of Ribavirin, resulting in 99% inhibition of viral replication. Our data demonstrate the significant potential of K. alvarezii extract and highlight the need for further studies to investigate its mechanism of action. We propose this extract as a potential anti-Zika compound.

1,3,5-Triaza-7-phosphaadamantane and Cyclohexyl Groups Impart to Di-Iron(I) Complex Aqueous Solubility and Stability, and Prominent Anticancer Activity in Cellular and Animal Models.

Using a multigram-scalable synthesis, we obtained nine dinuclear complexes based on nonendogenous iron(I) centers and featuring variable aminocarbyne and P-ligands. One compound from the series (FEACYP) emerged for its strong cytotoxicity in vitro against four human cancer cell lines, surpassing the activity of cisplatin by 3-6 times in three cell lines, with an average selectivity index of 6.2 compared to noncancerous HEK293 cells. FEACYP demonstrated outstanding water solubility (15 g/L) and stability in physiological-like solutions. It confirmed its superior antiproliferative activity when tested in 3D spheroids of human pancreatic cancer cells and showed a capacity to inhibit thioredoxin reductase (TrxR) similar to auranofin. In vivo treatment of murine LLC carcinoma with FEACYP (8 mg kg-1 dose) led to excellent tumor growth suppression (88%) on day 15, with no signs of systemic toxicity and only limited body weight loss.

Nanofibrous Conductive Sensor for Limonene: One-Step Synthesis via Electrospinning and Molecular Imprinting.

Detecting volatile organic compounds (VOCs) emitted from different plant species and their organs can provide valuable information about plant health and environmental factors that affect them. For example, limonene emission can be a biomarker to monitor plant health and detect stress. Traditional methods for VOC detection encounter challenges, prompting the proposal of novel approaches. In this study, we proposed integrating electrospinning, molecular imprinting, and conductive nanofibers to fabricate limonene sensors. In detail, polyvinylpyrrolidone (PVP) and polyacrylic acid (PAA) served here as fiber and cavity formers, respectively, with multiwalled carbon nanotubes (MWCNT) enhancing conductivity. We developed one-step monolithic molecularly imprinted fibers, where S(-)-limonene was the target molecule, using an electrospinning technique. The functional cavities were fixed using the UV curing method, followed by a target molecule washing. This procedure enabled the creation of recognition sites for limonene within the nanofiber matrix, enhancing sensor performance and streamlining manufacturing. Humidity was crucial for sensor working, with optimal conditions at about 50% RH. The sensors rapidly responded to S(-)-limonene, reaching a plateau within 200 s. Enhancing fiber density improved sensor performance, resulting in a lower limit of detection (LOD) of 137 ppb. However, excessive fiber density decreased accessibility to active sites, thus reducing sensitivity. Remarkably, the thinnest mat on the fibrous sensors created provided the highest selectivity to limonene (Selectivity Index: 72%) compared with other VOCs, such as EtOH (used as a solvent in nanofiber development), aromatic compounds (toluene), and two other monoterpenes (α-pinene and linalool) with similar structures. These findings underscored the potential of the proposed integrated approach for selective VOC detection in applications such as precision agriculture and environmental monitoring.

Screening of ionic liquids for the solubility enhancement of quinine using COSMO-RS

Quinine has traditionally been used in medicine to treat parasitic disease malaria due to its antimalarial activities. It is sparingly soluble in water and highly soluble in organic solvents. However, these solvents are not environmentally friendly, so greener solvents need to be explored and designed. Ionic liquids (ILs) were successfully observed to be greener and capable of dissolving biologically active compounds. However, finding a potential IL from millions of possible IL combinations is challenging. This work utilizes the conductor-like screening model for real solvents (COSMO-RS) to address this issue. This study aims to determine the dissolution behavior of quinine in ILs employing the COSMO-RS. A total of 540 IL combinations of 9 cations and 60 anions were investigated. The efficacy of each IL was evaluated by predicting the activity coefficients at infinite dilution, solvation-free energy, selectivity, capacity, and performance index (P.I.). This study reveals that ILs with shorter alkyl chains, polar and non-aromatic characteristics, and smaller anions are advantageous for the solubility enhancement ofquinine.The most effective ILs, choline acetate, choline glycinate, and choline threoninate, displayed the highest selectivity, capacity, P.I., and lowest activity coefficient and solvation-free energies. The findings of the current study unlock key insights into the solubility behaviour of quinine in an aqueous solution employing ILs.