Selectivity Index Research Articles

Anthelmintic activity of 1,10-phenanthroline-5,6-dione-based metallodrugs

Parasitic worm infections impose a significant public health burden, affecting over 2 billion people, particularly in low-income regions. The limited efficacy of current treatments highlights the urgent need for new anthelmintic agents. This study investigates the potential antiparasitic activity of 1,10-phenanthroline-5,6-dione (phendione) and its metal complexes, [Cu(phendione)3](ClO4)2.8H2O and [Ag(phendione)2](ClO4), against Schistosoma mansoni, the causative agent of intestinal schistosomiasis, and Angiostrongylus cantonensis, responsible for eosinophilic meningitis in humans. Additionally, the compounds were tested on Caenorhabditis elegans, a model organism for drug discovery. All compounds exhibited strong antiparasitic activity, with Cu-phendione showing the greatest potency (EC50 = 2.3 µM for S. mansoni and 6.4 µM for A. cantonensis). Ag-phendione also demonstrated significant activity, achieving EC₅₀ values of 6.5 µM against S. mansoni and 12.7 µM against A. cantonensis. The lethal dose (LD50) values in C. elegans were over 40 times higher, indicating selective antiparasitic effects. Cytotoxicity assays using Vero cells revealed a low toxicity profile and a high selectivity index. Given the promising biological properties of phendione and its metal complexes, these findings contribute to the growing body of research seeking to address the urgent need for new anthelmintic therapies.

Multiple mechanisms of action of a triazole-derived salt against Leishmania amazonensis: apoptosis-like death and autophagy.

Current chemotherapy for leishmaniasis faces significant limitations due to high toxicity, prolonged treatment regimens, and increasing parasite resistance, highlighting the urgent need for innovative treatment strategies. This study aimed to evaluate the in vitro activity of 1,2,3-triazole derivatives against promastigotes and amastigotes of Leishmania amazonensis, as well as their cytotoxicity in murine macrophages. Additionally, we investigated the mechanism of parasite death through different biochemical and cellular indicators of cell death parameters. Our results underscored the importance of the salt form, as the neutral form showed no inhibition of parasite growth. In contrast, the triazole-derived salt demonstrated promising selective index (SI = 34.28) and antileishmanial activity (IC50 = 0.13 μM and IC50 = 2.06 μM against promastigote and amastigote forms, respectively), proving more active than miltefosine, the standard drug. Regarding the mode of action of the triazole-derived salt, this compound induced significant mitochondrial alterations in the parasite, characterized by an increase in mitochondrial membrane potential (ΔΨm), elevated levels of total and mitochondrial Reactive Oxygen Species (ROS), and lipid body accumulation in the cytoplasm. Treatment with triazole-derived salt also produced several ultrastructural, biochemical, and cellular changes in the promastigote forms, such as the occurrence of apoptosis-like death, including cell shrinkage and reduction in length, as well as exposure of phosphatidylserine in the outer leaflet of the plasma membrane and marked cell cycle interruption, in addition to DNA fragmentation. Despite MDC positive and the presence of membrane-bound vacuoles resembling autophagosomal structures observed by TEM analysis, autophagy is not a predominant process, with severe mitochondrial damage emerging as the primary event leading to parasite death. These findings demonstrate the promising antileishmanial potential of the triazole-derived salt, with its effect on multiple targets in parasite cells. Moreover, the association of the active compound with miltefosine showed an additive effect in treating L. amazonensis-infected macrophages. Altogether, these results highlight the therapeutic potential of the evaluated salt and support further studies to assess its in vivo efficacy in a murine model of cutaneous leishmaniasis.

Reactivity of 2-((3-Cyano-4-(4-fluorophenyl)-6-(naphthalen-2-yl)pyridin-2-yl)oxy)acetohydrazide Toward some Reagents for Preparing a Promising Anticancer Agents and Molecular Docking Study.

This study aims to synthesize a novel series of nicotinonitriles incorporating pyrazole, oxadiazole, isoindoline, thiadiazole, and thiazolidinone moieties (compounds 4-11). The synthesis utilizes 2-((3-cyano-4-(4-fluorophenyl)-6-(naphthalen-2-yl)pyridin-2-yloxy)acetohydrazide (3) as a key starting material to enhance potential anticancer activity. The molecular structures of compounds 4-11 were elucidated using various spectroscopic techniques and elemental analysis. The synthesized compounds were screened for cytotoxic activity against human cancer cell lines, including MCF-7 (human Caucasian breast adenocarcinoma), MDA-MB-231 (breast ductal carcinoma), and PC-3 (prostate cancer), using an MTT assay with doxorubicin as a reference drug. Among the tested compounds, 4, 6b, and 7 exhibited the most promising cytotoxic activity, with IC50 values ranging from 22.5 to 91.3 μM. The safety profile of these compounds was further evaluated using noncancerous human skin fibroblast cells (BJ-1). Notably, 6b and 7 demonstrated high selectivity indices (SI >3) against cancer cells, indicating preferential cytotoxicity, whereas compound 4 lacked selectivity. Docking studies, consistent with experimental data, further supported the potential anticancer properties of compounds 4, 6b, and 7. Given their significant inhibitory effects on cancer cell lines with minimal to no impact on normal cells, compounds 6b and 7 are strong candidates for further drug development as potential anticancer agents.

Exploring the anticancer potential of extracts and compounds from the heartwood of Cotinus coggygria Scop. wild growing in Serbia.

Cotinus coggygria has a long history of use in traditional medicine in Europe and Asia. The aim of study was to explore the cytotoxicity of extracts (EE-ethanol, MME-methylene chloride/methanol, and WE-water) and compounds (butin, butein, fisetin, sulfuretin, taxifolin, eriodictyol, fustin, cotinignan A, sulfuretin auronol, 3-O-methylepifustin, 3-O-methylfustin, and sitosterol-3-O-β-D-glucoside) isolated from C. coggygria. Mechanisms of anticancer effects of three extracts, butin, butein, and sulfuretin were examined. Compounds were isolated from the EE using silica gel column chromatography and semipreparative HPLC. Structure elucidation was performed using NMR spectroscopy. Cytotoxicity was evaluated using MTT assay. The effects on cell cycle and cell death were investigated by flow cytometry. The antimigration effects were examined by scratch assay, while expression of the MMP2, MMP9, and VEGFA were measured by quantitative real time PCR. The antioxidant effects were examined by flow cytometry. 3-O-methylepifustin, epitaxifolin, and sulfuretin auronol were found for the first time in C. coggygria. The extracts and compounds showed selective cytotoxicity against HeLa, MDA-MB-231, HL-60, K562, A375, PC-3, and DU 145 cells. HeLa cells were the most sensitive to the cytotoxicity of MME (IC50 value of 47.45µg/mL), while leukemia K562 and HL-60 cells were the most sensitive to the MME and EE (IC50 values in the range from 31.04 to 44.57µg/mL). Butein exerted strong cytotoxicity on HeLa, K562, and MDA-MB-231 cells (IC50 values of 8.66 µM, 13.91 µM, and 22.36 µM). EE, butin, butein, sulfuretin, and fisetin were highly selective against leukemia K562 cells when compared with normal fibroblasts MRC-5 (selectivity index: 4.01, 5.15, 6.17, 7.05, > 4.41, respectively). Butein and fisetin showed high selectivity in the cytotoxic activity against HeLa cells when compared with MRC-5 cells (selectivity index: 9.91 and > 6.61). Three extracts, butin, butein, and sulfuretin, initiated apoptosis in HeLa cells by activating caspase-8 and caspase-9. The extracts, butin, butein, and sulfuretin inhibited HeLa cell migration. EE, MME, butein, and sulfuretin exerted cytoprotective effects in normal fibroblasts. This research might suggest promising anticancer effects and underscores the need for additional research on C. coggygria extracts and compounds to assess their potential in cancer prevention and therapy.

Paeonol Inhibits the Replication of Bovine Herpesvirus Type 1 In Vitro Through Regulating the PI3K/AKT Pathway.

The bovine herpesvirus type I (BHV-1) is a significant pathogen that poses a threat to the healthy development of the cattle industry and has a global prevalence. Paeonol is a phenolic constituent extracted from the dried root bark of peony in the buttercup family. Although paeonol has anti-inflammatory and antioxidant effects, its antiviral capacity remains unclear. Here, we conducted a cytotoxicity assay to screen the safe concentration of the paeonol using bovine turbinate (BT) cells as a model. Antiviral studies showed that paeonol inhibited BHV-1 gB gene and VP8 protein expression, and reduced cytopathic effect and viral titer. Furthermore, paeonolalso demonstrated a potent effect on BHV-1 replication with an EC50of 18.54μg/mL and a Selectivity Index (SI) of 28.64. Mechanistic analysis revealed that the PI3K/AKT pathway might be involved in the antiviral mechanism of paeonol. Molecular docking combined with western blot assay further confirmed that paeonol was able to bind stably to the active sites of PI3K and AKT proteins, and significantly inhibited the activation of PI3K/AKT pathway. Interestingly, 740Y-P (a PI3K/AKT pathway agonist) significantly attenuated the anti-BHV-1 effect of paeonol. The above experiments are the first to confirm the inhibitory effect of paeonol on BHV-1 replication, which not only adds evidence to the biological function of paeonol as an antiviral agent, but also lays the foundation for the prevention and control of this disease and the development of feed additives.

Design, Synthesis, and Molecular Docking Studies of Indolo[3,2-c]Quinolines as Topoisomerase Inhibitors.

The tetracyclic indoloquinoline ring system has attracted considerable interest in the recent past due to its broad spectrum of biological activities and its binding to various types of nucleic acids. This study aims to elucidate their interactions with DNA and their effects on topoisomerases (TOPO) I and II. Several compounds derived from 6-amino-11H-indolo[3,2-c]quinoline with diverse groups on the quinoline ring have been successfully synthesized according to a previously established protocol where all the synthesized indolo[3,2-c]quinoline derivatives were evaluated in vitro against A549, HCT-116, BALB/3T3, and MV4-11 cell lines using MTT (3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyl- tetrazolium bromide) assay. These derivatives were then screened for their topo I and II inhibitory activities. The tested compounds were more effective at killing MV4-11 leukemia cells than the standard cancer drug cisplatin, as shown by the fact that their IC50 values were less than 0.9 μM. On the other hand, cisplatin revealed an IC50 value of 2.36 μM. Moreover, they exhibited inhibitory activity against both Topoisomerase (Topo) I and II. The most potent compound, 5g, demonstrated a suppressive impact on topoisomerase I, with an IC50 value of 2.9 μM compared to the positive control Camptothecin (IC50 1.64 μM) and compound 8 displayed remarkable topoisomerase II inhibitory activity with an IC50 of 6.82 μM compared to the positive control Doxorubicin (IC50 6.49 μM). The cell cycle study for compounds 5g and 8 revealed that cell cycle arrest occurred at the G1/S and S phases, respectively. Compounds 5g and 8 showed a high selectivity index, which suggests that they could be used to develop low-toxicity chemotherapeutic agents. The results of this study demonstrate that compounds 5g and 8 can be considered promising candidates for further anti-cancer drug development, which might be related to inhibiting TOPO I and TOPO II activities.

Mechanistic Approach into 1,2,3-triazoles-based IIIM(S)-RS98 Mediated Apoptosis in Lung Cancer Cells.

Lung cancer is a major public health problem across the globe, since it is the second most frequent cancer and the leading cause of cancer fatalities. This necessitates careful assessment of current therapies for lung cancer and discovery of novel drug candidates. 1,2,3 triazole compounds have emerged as an important class of prospective chemotherapeutic drugs for the treatment of lung cancer, with promising anti-lung cancer activity shown via a variety of pathways. They may interact with a various enzymes and receptors in cancer cells, causing cell cycle arrest and the activation of apoptosis. The present study aims to investigate the cytotoxic potential of institutional molecule based on 1,2,3 triazole [IIIM(S)-RS98] on multiple cancer cell lines. The compound was found to be most active on A549 cells and displayed the selectivity index as 8.16 in normal cells (e.g. HEK293). The in vitro findings revealed that IIIM(S)-RS98 induced apoptosis, loss of mitochondrial membrane potential, enhanced ROS and nitric oxide levels, and arrest cells in the G1 phase of the cell cycle. It inhibits the cell migration and clonogenic potential of A549 cells. Additionally, the downregulation of PI3K and p-Akt pathway leads to the activation of pro-apoptotic proteins Bax, downregulation of bcl2, activation of caspase 9, cleaved caspase 3, and cleaved parp1 expression and finally contribute towards apoptosis. Furthermore, molecular docking analysis indicated the interactions of IIIM(S)-RS98 with the apoptotic target proteins. The results demonstrated the potential of IIIM(S)-RS98 in the therapy of lung cancer.

Avermectins Inhibit Replication of Parvovirus B19 by Disrupting the Interaction Between Importin α and Non-Structural Protein 1

Human parvovirus B19 (B19V) is a major human pathogen in which the ssDNA genome is replicated within the nucleus of infected human erythroid progenitor cells (EPCs) through a process involving both cellular and viral proteins, including the non-structural protein (NS)1. We previously characterized the interaction between NS1 classical nuclear localization signal (cNLS: GACHAKKPRIT-182) and host cell importin (IMP)α and proposed it as a potential target for antiviral drug development. Here, we further extend on such findings. First, we demonstrate that NS1 nuclear localization is required for viral production since introducing the K177T substitution in a cloned, infectious viral genome resulted in a non-viable virus. Secondly, we demonstrate that the antiparasitic drug ivermectin (IVM), known to inhibit the IMPα/β dependent nuclear import pathway, could impair the NS1-NLS:IMPα interaction and suppress viral replication in UT7/EpoS1 cells in a dose-dependent manner. We also show that a panel of structurally related avermectins (AVMs) can dissociate the NS1-NLS:IMPα complex with half-maximal inhibitory concentrations in the nanomolar range. Among them, Eprinomectin emerged as the most selective inhibitor of B19V replication, with a selectivity index of c. 5.0. However, when tested in EPCs generated from peripheral blood mononuclear cells, which constitute a cellular population close to the natural target cells in bone marrow, the inhibitory effect of IVM and Eprinomectin was demonstrated to a lesser extent, and both compounds exhibited high toxicity, thus highlighting the need for more specific inhibitors of the NS1-NLS:IMPα interaction.

Enhanced Anticancer Selectivity of Cyclometalated Imidazole/Pyrazole-Imine IridiumIII Complexes Through the Switch from Cationic to Zwitterionic Forms.

Cyclometalated iridiumIII complexes have shown promising anticancer properties, with variations in charge and ligand substitution significantly influencing their biological activity. However, zwitterionic iridiumIII complexes remain scarcely explored. Herein, we report a series of zwitterionic cyclometalated imidazole/pyrazole-imine iridiumIII complexes and compare their biological activity to analogous cationic complexes with sulfonate counteranions. X-ray crystallography confirmed the structural differences between the cationic and zwitterionic forms. These complexes exhibited cytotoxicity against A549, HeLa, and HepG2 cancer cells, with IC50 values ranging from 14.35 to 69.12 μM. While cationic complexes showed higher cytotoxicity, zwitterionic complexes demonstrated enhanced selectivity for A549 cancer cells over BEAS-2B normal cells (selectivity index: 3.72-5.90 for zwitterionic forms vs 1.16-1.44 for cationic forms). This selectivity is attributed to distinct cellular uptake mechanisms: zwitterionic complexes use an energy-dependent pathway in cancer cells and an energy-independent pathway in normal cells, leading to differences in cellular accumulation and redox activity. Mechanistic studies revealed that both complex types induce ROS generation and mitochondrial membrane depolarization (MMP), with apoptosis as the primary cell death pathway.

Novel α-mangostin derivatives as promising antiviral agents: Isolation, synthesis, and evaluation against chikungunya virus.

Investigations into fruit and vegetable processing residues (FVPRs) offer huge opportunities to discover novel therapeutics against many diseases. In this study, detailed investigation of Garcinia mangostana fruit peel extract led to the isolation and identification of ten known compounds (1-10). Further, a new series of α-mangostin derived sulphonyl piperzines, aryl alkynes and 1,2,3-triazole derivatives were synthesized using Huisgen 1,3-dipolar cyclo-addition reaction ("click" chemistry). Both isolated compounds and synthetic derivatives were evaluated for their anti-chikungunya activity (CHIKV). Isolated compounds, gartanin (1), mangostenone-F (4), 1-isomangostin (5), mangostenone-D (6), epicatechin (7) and derivatives 14, 15c, 15d, 15e, 15f, 17d, 17f, and 18h exerted anti-CHIKV activity. Compounds 17d, 17f and 18h manifested higher antiviral activity (>2 log reduction in virus titer) with a selectivity index (SI)>50. The compounds with higher antiviral activity were evaluated further with various assays, time of addition assay, entry and entry bypass assay and were also subjected to molecular docking with viral proteins. The results revealed that 17d, 17f and 18h affect multiple stages of virus life cycle through probable interaction with envelope proteins and nsP3 macrodomain of CHIKV. Overall, this study provides evidence for anti-CHIKV activity of natural xanthones from Garcinia mangostana L and their derivatives which could be further investigated for development of therapeutics against chikungunya.

Activity Evaluation and Mode of Action of ICA Against Toxoplasma gondii In Vitro

Toxoplasmosis is a significant zoonotic parasitic disease. Currently, there is no effective vaccine available to prevent human infection, and treatment primarily relies on chemotherapy. However, the lack of specific therapeutic agents and the limitations of existing drugs highlight the urgent need for novel, safe, and effective anti-Toxoplasma gondii (T. gondii) medications. In this study, we evaluated the toxicity of ICA (N-(pyridin-2-yl)-4-(pyridine-2-yl)thiazol-2-amine) to host cells and assessed its inhibitory and anti-proliferative effects on T. gondii tachyzoites. We further investigated the impact of ICA on the ultrastructure of T. gondii using transmission electron microscopy (TEM). Additionally, we measured alterations in mitochondrial membrane potential, superoxide levels, and ATP levels in T. gondii to assess the effect of ICA on mitochondrial function. Our findings demonstrated that ICA exhibits a safe and effective inhibitory effect on T. gondii, with a selectivity index (SI) of 258.25. Notably, ICA demonstrated a more potent anti-proliferative effect than pyrimethamine (PYR). Ultrastructural observations revealed that ICA induces mitochondrial swelling and membrane rupture in T. gondii. Further investigations confirmed that ICA leads to mitochondrial dysfunction in T. gondii. In conclusion, our results suggest that ICA possesses the potential to serve as a lead compound for the development of novel anti-T. gondii therapies.

Design, Synthesis, Docking Studies, and Investigation of Dual EGFR/VEGFR-2 Inhibitory Potentials of New Pyrazole and Pyrazolopyridine Derivatives.

The anticancer potential of certain newly synthesized pyrazole and pyrazolopyridine derivatives has been estimated. NCI 60 cancer cells cytotoxic screening pointed out compounds 3e and 3f as the highest cytotoxic agents with % mean growth inhibition of 67.69% and 87.34%, respectively. The five dose outcomes outlined 3f as the most potent cytotoxic agent with promising MG-MID GI50 = 3.3 µM when compared to erlotinib (MG-MID GI50 = 7.68 µM). In the in vitro assays, compounds 3d, 3e, 3f, and 4a demonstrated dual inhibitory potential on EGFRWT and VEGFR-2 with IC50 range of 0.066-0.184 µM and 0.102-0.418 µM, respectively. The best dual EGFR/VEGRF-2 inhibitory effect was shown by the compound 3f. Moreover, the latter compound stopped the cell cycle at the G1/S phase. Also, it greatly boosted total apoptosis, including early and late apoptosis, by 54.5- and 84.7-fold, respectively, which supposes HCT-116 cell death via inducing apoptosis. This was confirmed by the elevation of the BAX and caspase-3 levels, and the decreased BCL-2 level. Moreover, the safety of the most active compound 3f was assessed and the results showed promising selectivity of compound 3f toward HCT-116 over FHC (selectivity index [SI]: 20.84) when compared to erlotinib (SI: 3.42). Finally, compound 3f demonstrated efficient binding to both EGFR and VEGFR-2 enzymes, which could explain the sufficient inhibition level of each enzyme.

Positively-charged, chalcone-hydroxypyrone hybrid ruthenium(II)-arene complexes functionalized with ethacrynic acid: Synthesis, characterizaion, and antitumor effect

A new family of ethacrynic acid-functionalized, chalcone-hydroxypyrone hybrid ruthenium(II)-arene complexes (4a-4e) have been designed, synthesis and fully characterized by 1H and 13C NMR, ESI-MS, elemental analysis, and melting point tests. The molecular structure of 3a, one of the precursor complexes, has been determined by single-crystal X-ray diffraction. The cytotoxicity of the obtained complexes toward human cancer cell lines such as HeLa, MGC803, A549, MDA-MB-231, and MCF-7 cells have been investigated by MTT assay. Whereas complexes 4d and 4e showed significantly higher cytotoxicity than cisplatin (the positive control group) and complexes 3a-3e. Moreover, complexes 4d and 4e exhibited a certain selectivity (selectivity index: 7.33 and 7.57) toward MCF-7 cells over MCF-10a normal cells. Glutathione S-transferases (GSTs) activity assay indicate that complexes 4d and 4e exhibited higher GST inhibitory activity than ethacrynic acid (EA, the best characterized GST inhibitor), consistent with their higher cytotoxicity. Further mechanistic studies showed that 4e-induced cell apoptosis may be aroused by the production of ROS, the loss of mitochondrial membrane potential and G2/M phase cell arrest in MCF-7 cells. In addition, the in vivo antitumor effect study on the xenograft mouse models of MCF-7 cells reveal that complex 4e significantly inhibited tumor growth with a higher inhibition efficiency of 68.80 %, in comparison with the groups treated with cisplatin (59.25 %). These results highlight the strong possibility to develop positively-charged, chalcone-hydroxypyrone hybrid ruthenium(II)-arene complexes funcionalized with GST inhibitor as promising anticancer agents.

Lectin from microalgae: Non-toxic to human cells and effective against Leishmania.

New leishmanicidal products are needed for the treatment to be effective, since current drugs are toxic to healthy human/animal cells and have low efficacy against the parasite. Bioactive compounds from microalgae, such as lectins, can be explored as new anti-Leishmania candidates. This study aimed to evaluate the cytotoxic and anti-Leishmania action of the cell extract (CE) and lectin (CVU) from Chlorella vulgaris biomass. CVU purified from CE was stable within alkaline pH and temperature below 50°C. CVU showed specificity to the carbohydrate D-Galactose, which is found in the membrane of Leishmania. CE (IC50=161.4μg/mL) and CVU (IC50=66.32μg/mL) exhibited effects against the promastigotes of L. braziliensis, and scanning electron microscopy confirmed alterations the shape and size in treated parasites. CE showed a higher selectivity index than CVU on L. braziliensis promastigotes. These results demonstrate the potential of C. vulgaris as a source of active molecules that can be investigated as therapeutic candidates.

In Vitro Discovery of a Therapeutic Lead for HFMD From a Library Screen of Rocaglates/Aglains.

The lack of effective antiviral treatments for enteroviruses, including human enterovirus A71 (EV-A71), have resulted in an immense global healthcare burden associated with hand-foot-and-mouth disease (HFMD). Rocaglates and aglains belong to a family of compounds produced by Aglaia genus plants. Since the initial discovery of rocaglates in 1982, various rocaglates and aglains have been synthesized and extensively studied mainly as anticancer agents. Here, we report the discovery of a novel aglain derivative as a potential EV-A71 inhibitor. From an immunofluorescence-based phenotypic screen of a library of 296 rocaglate and aglain derivatives, we identified a lead aglain which effectively suppressed EV-A71 replication by 2.3 log fold at a non-cytotoxic concentration, with a host cell CC50 of 21.78 µM, an EV-A71 infection EC50 of 3.57 µM, and a selectivity index of 6.1. Further validation revealed inhibition of EV-A71 across multiple human cell types and a pan-enterovirus inhibitory spectrum against other enteroviruses. Subsequent mechanistic investigation revealed interference with EV-A71 intracellular post-entry events including viral RNA transcription and translation. Findings from this study have established a strong foundation for development of aglain scaffolds as much needed antiviral agents for HFMD, paving the way for future medicinal chemistry optimization and in vivo studies.

Design, synthesis, and biological evaluation of novel 2'-deoxy-2'-spirooxetane-7-deazapurine nucleoside analogs as anti-SARS-CoV-2 agents.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an unprecedented global public health crisis and continues to pose grave threats to human health. The efficacy of current vaccines and therapeutics is likely limited for future emerging strains due to the highly mutative nature of the virus, underscoring an urgent need for the development of new, potent antiviral agents. In this study, we report the design and synthesis of a series of novel 2'-deoxy-2'-spirooxetane-7-deazapurine nucleoside analogs as potential inhibitors of SARS-CoV-2 replication. Some of these compounds demonstrate potent antiviral activity, offering a potential new weapon for therapeutic intervention against the ever-evolving SARS-CoV-2 virus. Among the tested compounds, nucleoside analog 11q exhibited the most potent antiviral activity against SARS-CoV-2 in Vero E6 cells, with IC50 values of 0.14 μM for the wild-type strain and 0.36 μM for the BA.5 strain. Notably, compound 11q exhibits up to nine times greater inhibitory activity against wild-type SARS-CoV-2 compared to Remdesivir and also possesses a superior selectivity index. These findings suggest that compound 11q is a highly promising lead candidate for future drug development aimed at combating SARS-CoV-2.

In vitro antiplasmodial activity of six plants against chloroquine-sensitive and resistant strains of Plasmodium falciparum

Introduction: The effectiveness of the first-line malaria treatment has been affected by drug resistance and adverse side effects leading to a limited number of treatment options. This calls for the search for alternative antimalarial agents. The study evaluated the in vitro antimalarial activity of six plants frequently used in herbal antimalarial products in Ghana against chloroquine-sensitive strain (3D7) and chloroquine-resistant strain (DD2) of Plasmodium falciparum. Method: Aqueous extracts were prepared from the plants by decoction and freeze-dried. A fluorescence-based SYBR Green assay was used to evaluate the antimalarial activity of the extracts against Plasmodium falciparum strains 3D7 and DD2. Also, the cytotoxic e?ects (CC50) of the plant extracts against red blood cells were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) rapid calorimetric assay technique. Results: Alstonia boonei, Cryptolepis sanguinolenta, and Azadirachta indica were the most effective mono-herbal extracts with IC50 of 8.64 ?g/mL, 6.12 ?g/mL, and 5.22 ?g/mL respectively against 3D7 lab strain and 8.47 ?g/mL, 5.12 ?g/mL and 5.22?g/mL respectively against DD2 lab strain. The aqueous extracts of Paullinia pinnata, Citrus aurantiifolia, and Tetrapleura tetraptera exhibited moderate activity against both lab strains with IC50 values of 24.72 ?g/mL, 34.89 ?g/mL and 14.94 ?g/mL respectively against 3D7 strain and 14.84 ?g/mL, 31.01 ?g/mL and14.74 ?g/mL respectively against DD2 strain. All plant extracts exhibited no cytotoxicity against RBC (?100 ?g/mL, except Cryptolepis sanguinolenta with CC50 92.7 ?g/mL). Moreover, except Paullinia pinnata, Citrus aurantiifolia and Tetrapleura tetraptera (with low selectivity index: SI < 10), all the plants displayed a good selectivity index (SI>10). Conclusion: All six frequently used antimalarial plants in monotherapy possess significant antimalarial activity against Plasmodium falciparum (3D7) and (DD2) strains. The data obtained from this study support the folkloric and frequent use of these plants in several herbal antimalarial products on the Ghanaian market.

Standardisation of <i>Perunkaya Vaippu Sarakku</i> Using Organoleptic, Physicochemical, HPTLC Fingerprinting, GC-MS, and <i>In Vitro</i> Pharmacological Studies

Background: Asafoetida (Perunkayam), an oleo-gum resin derived from the roots of plants in the Ferula genus, is renowned for its efficacy as gastroprotective. It has been scientifically validated for its antioxidant, antispasmodic, neuroprotective, combating inflammation and hepatotoxicity, and various anticancer activities. However, asafoetida is not indigenous to India, and its scarcity has led to a significant price increase. Siddha, one of the oldest systems of medicine, utilises metals, herbs, and minerals to create synthetic formulations, a process known as Vaippumuraigal, to serve as alternatives to natural drugs. Aim: To standardize Perunkaya Vaippu Sarakku (PVS) using modern scientific methods. Methods: Synthetic Perunkayam was prepared and standardized through rigorous scientific procedures. Results: The prepared PVS was brownish powder, pH-4.7 and 5.73%w/w moisture. Phytochemical screening revealed the presence of alkaloids, carbohydrates, phytosterols, phenols, flavonoids, terpenoids and fixed oils. HTPLC yielded 8 fractions, Rf values ranging from 0.09-0.93. GC-MS revealed the presence of pentadecane, 2,4-di-tert-butylphenol, hexadecane, hexadecanoic and cis-vaccenic acid. PVS showed antioxidant activity compared to BHT (EC50-235.9 and 6.597μg/mL respectively). The EC50 of acetylcholine in the presence of PVS (4.782μg/ml) was higher than Acetylcholine alone (3.678μg/ml) indicating effective antispasmodic activity. Experiments on goat renal artery undeluded endothelium (en+) showed significant vasodilatory activity with an EC50 of 79.31μg/ml which was significantly (p<0.001) lower than denuded endothelium (352.4μg/ml). PVS showed significant cytotoxicity on colon-cancer (HCT-116) cell lines (IC50-116μg/ml) and low cytotoxicity on HepG2 and Vero-cell lines (IC50-538.5 and 1458μg/ml). PVS significantly (p<0.001) prevented the ethanol-induced damage in HepG-2 cell lines at 10μg/ml, inhibiting viral growth with a selectivity index of 11.26 and IC50 of 129.4μg/ml. Conclusion: PVS potently exhibited all the activities of natural asafoetida, advocated the claim of using PVS as an alternative to natural-asafoetida and standardization of the formulation confirmed the quality of PVS as per pharmacopeial standards in Siddha medicine. Major Findings: Synthetic asafoetida potently exhibited all the activities of natural asafoetida (Perunkayam) and showed the remarkable similarity and also uncovering novel compounds in synthetic alternatives.

Development of a Highly Selective Ferroptosis Inducer Targeting GPX4 with 2-Ethynylthiazole-4-carboxamide as Electrophilic Warhead.

A highly selective ferroptosis inducer with drug-like properties can significantly advance the research on inducing ferroptosis for anticancer treatment. We previously reported a highly active GPX4 inhibitor 26a, but its activity and stability need further improvement. In this work, a novel GPX4 inhibitor (R)-9i with more potent cytotoxicity (IC50 = 0.0003 μM against HT1080) and ferroptosis selectivity (selectivity index = 24933) was gained via further electrophilic warhead screening and structure-based optimization. The cellular thermal shift assay (CETSA) indicated that (R)-9i could stabilize GPX4 with a Tm value of 6.2 °C. Furthermore, (R)-9i showed strong binding affinity against GPX4 (KD = 20.4 nM). More importantly, (R)-9i has more favorable pharmacokinetic properties than 26a, which endowed (R)-9i with potential in antitumor research and as a tool drug for further study of ferroptosis. Associated with these, (R)-9i treatment significantly inhibited tumor growth in the xenograft tumor mouse model without detectable toxicity.

In vitro antiplasmodial activity and chemical composition of Combretum aculeatum, a medicinal plant from Niger.

Malaria remains a significant public health challenge in Niger, accounting for 5.6% of global malaria-related deaths. Local medicinal plants are frequently used as traditional treatments for malaria, although their efficacy and safety are often insufficiently investigated. This study aims to evaluate the antiplasmodial activity and chemical composition of eight medicinal plants from Niger. Plant extracts were tested in vitro for their ability to inhibit the uptake of [3H]-hypoxanthine in the Plasmodium falciparum NF54 chloroquine-sensitive strain. The most active extract was subjected to chemical analysis using HPLC-PDA-HRMS/MS dereplication, while major compounds were quantified via a validated HPLC-UV method. The ethyl acetate extract of Combretum aculeatum (2a) demonstrated important antiplasmodial activity, with an IC50 value of 3.1 µg/mL and a selectivity index of 24.5. C-glycosyl flavonoids were identified as the primary constituents, present at concentrations ranging from 5.7-9.8 mg of vitexin equivalent per g of extract. However, the low abundance of these compounds suggests that other constituents may contribute to the extract's antiplasmodial effects. Further investigations are required to explore possible synergies among the components of 2a and to assess its efficacy in vivo models.