Selective Agents Research Articles

Antiviral effects of the fused tricyclic derivatives of indoline and imidazolidinone on ZIKV infection and RdRp activities of ZIKV and DENV

The prevalence and ravages of Zika virus (ZIKV) seriously endanger human health, especially causing significant neurological defects in both neonates as pediatric microcephaly and adults as Guillain–Barré syndrome. In this work, we studied anti-ZIKV effects of the fused tricyclic derivatives of indoline and imidazolidinone and discovered that some of them are valuable leads for drug discovery of anti-ZIKV agents. The current results show that certain compounds are broad-spectrum inhibitors of ZIKV- and dengue virus (DENV)-infection while distinctive compounds are selective ZIKV inhibitors or selective DENV inhibitors. Compounds of 12, 17 and 28 are more active against Asian ZIKV SZ-VIV01 strain than African ZIKV MR766 strain. It is valued that silylation makes six TBS compounds of 4-nitrophenyl hydrazine series and phenyl hydrazine series more active against ZIKV infection than their phenols. Time-of-addition and withdrawal studies indicate that compound 12 majorly acts on post-infection of RNA synthesis stage of ZIKV life cycle. Moreover, compounds of 12, 17 and 18 are anti-ZIKV agents with the inhibitory activities to ZIKV NS5 RdRp while 12 doesn't inhibit DENV infection even though it is a DENV RdRp inhibitor, 17 is an active agent against DENV infection but is only a weak DENV NS5 RdRp inhibitor, and 28 is inactive against DENV infection and not a DENV NS5 RdRp inhibitor. As a result, a compound's antiviral difference between ZIKV and DENV is not always related to anti-RdRp difference between ZIKV RdRp and DENV RdRp, and structural features of a compound play important roles in executing antiviral and anti-RdRp functions. Further discovery of highly potent broad-spectrum or selective agents against infection by ZIKV and DENV will be facilitated.

Regulation of c-Kit gene transcription selectively by bisacridine derivative through promoter dual i-motif structures

Backgroundc-Kit protein is a signal transduction protein involved in multiple signal pathways, which play an important role in a variety of cellular events such as cell proliferation, apoptosis and differentiation. Special DNA secondary structures on the promoter of c-Kit gene, including G-quadruplex and i-motif structures, could act as “molecular switch” for gene transcriptional regulation, which are potentially important target for development of new anti-cancer drugs. MethodsWe screened and evaluated the effect of compounds on c-Kit through several experiments, including SPR, FRET, CD, MST, NMR, dual-luciferase reporter assay, Western blot, qPCR, immunofluorescence, MTT assay, colony formation, cell scrape, cell apoptosis, cell cycle analysis, and transwell assay. ResultsAfter extensive screening, we found that bisacridine derivative B05 had selective binding and stabilization to dual i-motif structures on c-Kit gene promoter, which could down-regulate c-Kit gene transcription and translation, resulting in inhibition of cell proliferation and metastasis. B05 exhibited potent anti-tumor activity on HGC-27 cells, and strongly suppressed tumor growth in HGC-27 xenograft mice model. ConclusionsB05 could interact with c-Kit promoter dual i-motif structures with excellent selectivity, which make it possible for selective regulation of gene transcription and translation. B05 could be further developed for selective anti-cancer agent targeting c-Kit promoter i-motifs. General significancei-Motifs on different proto-oncogene promoters are diversified, and especially binding of dual i-motifs on the same promoter simultaneously could significantly down-regulate gene transcription with decreased dosage, and therefore increasing the selectivity. This new strategy shed bight light on development of selective DNA-targeting ligands.

Tumor killing by a dietary curcumin mono-carbonyl analog that works as a selective ROS generator via TrxR inhibition

In comparison with normal cells, cancer cells feature intrinsic oxidative stress, thereby being more vulnerable to further production of reactive oxygen species (ROS) by pro-oxidative anticancer agents (PAAs). However, PAAs also inevitably generate ROS in normal cells, resulting in their narrow therapeutic window and toxic side effects that greatly limit their clinical application. To develop PAAs that generate ROS selectively in cancer cells over in normal cells, we rationally designed three series of 21 dietary curcumin 5-carbon mono-carbonyl analogs differentiated by either placement of the cyclohexanone, piperidone, and methylpiperidone linkers, or introduction of electron-withdrawing trifluoromethyl and electron-donating methoxyl groups on its two aromatic rings in the ortho, meta, or para position to the linkers. From the designed molecules, 2c, characterized of the presence of the meta-CF3-substituted mode and the piperidone linker, was identified as a potent selective ROS-generating agent, allowing its ability to kill selectively human non-small cell lung cancer NCI–H460 (IC50 = 0.44 μM) over human normal lung MRC-5 cells with a selectivity index of 32.0. Additionally, it was more potent and selective than the conventional chemotherapeutic agents (5-fluorouracil and camptothecin) did. Mechanistical investigation reveals that by means of its Michael acceptor unit and structure characteristics as described above, 2c could covalently modify the Sec-498 residue of intracellular thioredoxin reductase (TrxR) to generate ROS selectively, resulting in ROS-dependent apoptosis and ferroptosis of NCI–H460 cells. Noticeably, 2c inhibited significantly the growth of NCI–H460 cell xenograft tumor in nude mice without obvious toxicity to liver and kidney. Together, this work highlights a practical strategy of targeting TrxR overexpressed in cancer cells to develop PAAs capable of generating ROS selectively, as evidenced by the example of 2c.

Novel Thiopyrano[2,3-d]thiazole-pyrazole Hybrids as Potential Nonsulfonamide Human Carbonic Anhydrase IX and XII Inhibitors: Design, Synthesis, and Biochemical Studies.

In recent years, molecular hybridization strategies have developed into a potent strategy for drug discovery. A series of novel thiopyrano[2,3-d]thiazoles linked to the pyrazole moiety was designed and developed as anticancer agents by a molecular hybridization. Target compounds were synthesized and characterized by spectroscopic tools as well as X-ray crystallography analysis as in the case of thiopyrano[2,3-d]thiazole derivative 5a. The MTT assay was used to demonstrate the in vitro efficacy of compounds 5a-g and 7a-j on MCF-7 and HePG-2. The results showed that some cycloadducts such as bromophenyl-4-thioxo-2-thiazolidinone 3e, 4-methylphenyl derivative of thiopyrano[2,3-d]thiazole 5d, and 6-substituted-thiopyrano[2,3-d]thiazoles 7e-j displayed good to excellent IC50 in the range of 10.08 ± 1.5 to 25.95 ± 2.8 μg/mL against the MCF-7 cell line and from 7.83 ±2.1 to 13.37 ± 1.2 μg/mL against the HePG-2 cell line. To explore the enzymatic tests for isozymes hCAIX and hCAXII, the most promising eight compounds 3e, 5d, and 7e-j with IC50 ranging from 7.83 ± 2.1 to 25.95 ± 2.8 μM were chosen. Compound 7e exhibited an IC50 (0.067 ± 0.003 μM) similar to that of the standard drug AZA against CAIX (0.059 ± 0.003 μM)). For CAXII, the compound 7i had an IC50 equal to 0.123 ± 0.007 μM compared to that of AZA (0.083 ± 0.005 μM). In addition, using flow cytometry, cell cycle analysis and apoptosis studies in HePG-2 were performed for the two potent anticancer and selective carbonic anhydrase agents (7e and 7i). An enzymatic assay of these two compounds against caspase-9 was also examined. Interestingly, the molecular docking studies revealed that compounds 7e and 7i successfully embedded themselves in the active pockets of the CAIX and CAXII enzymes through different interactions. Overall, the novel thiopyrano[2,3-d]thiazole-pyrazole hybrids (7e and 7i) were suggested to be potent and selective inhibitors of CAIX and CAXII.

Comparison of Two Culture-Based Detection Systems for the Isolation of Arcobacter butzleri, Arcobacter cryaerophilus, and Arcobacter skirrowii in Raw Ground Poultry

Arcobacters are emerging pathogens that have been underestimated due to a lack of a standardized isolation method. The aim of this research was to evaluate the ability to isolate Arcobacter butzleri, Arcobacter cryaerophilus, and Arcobacter skirrowii using two Arcobacter-specific culture detection systems: (i) the Houf broth and modified charcoal cefoperazone deoxycholate agar supplemented with cefoperazone, amphotericin B, and teicoplanin (HB/mCCDA+CAT), and (ii) the Nguyen-Restaino-Juárez Arcobacter enrichment broth and chromogenic agar (NRJ-B/M). Both detection systems were evaluated for productivity ratio, sensitivity, and specificity. As a result, the productivity ratio for both plating agars were >90%, which indicates that the selective agents used in the two plating agars did not inhibit Arcobacter growth. Moreover, sensitivity evaluations using artificially inoculated retail ground poultry (n = 780) determined that both detection systems were able to isolate A. butlzeri with >95% sensitivity at the 0.1 and 1.0–2.0 CFU/g detection level. The sensitivity in A. cryaerophilus isolation was higher for NRJ-B/M (78.0% at 0.1 CFU/g; 95.1% at 1.0–2.0 CFU/g) when compared with HB/mCCDA+CAT (34.1% at 0.1 CFU/g; 51.2% at 1.0–2.0 CFU/g). Both detection systems resulted in <50% sensitivity when isolating A. skirrowii at 0.1 and 1.0–2.0 CFU/g; however, the sensitivity for NRJ-B/M was significantly higher than HB/mCCDA+CAT. At the detection level of 5.0 CFU/g, both detection systems were able to isolate A. skirrowii with 100% sensitivity. Specificity comparisons using uninoculated ground poultry samples (n = 40) indicated the growth of background microbiota were significantly inhibited or could be easily differentiated on NRJ-B/M (90.0%, specificity) when compared with HB/mCCDA+CAT (30.0%, specificity). Overall, these results show that the NRJ-B/M detection system is a more sensitive and specific detection system when isolating Arcobacter spp. from ground chicken.

LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials.

Histone lysine-specific demethylase 1 (LSD1/KDM1A) was first identified in 2004 as an epigenetic enzyme able to demethylate specific lysine residues of histone H3, namely H3K4me1/2 and H3K9me1/2, using FAD as the cofactor. It is ubiquitously overexpressed in many types of cancers (breast, gastric, prostate, hepatocellular, and esophageal cancer, acute myeloid leukemia, and others) leading to block of differentiation and increase of proliferation, migration and invasiveness at cellular level. LSD1 inhibitors can be grouped in covalent and non-covalent agents. Each group includes some hybrid compounds, able to inhibit LSD1 in addition to other target(s) at the same time (dual or multitargeting compounds). To date, 9 LSD1 inhibitors have entered clinical trials, for hematological and/or solid cancers. Seven of them (tranylcypromine, iadademstat (ORY-1001), bomedemstat (IMG-7289), GSK-2879552, INCB059872, JBI-802, and Phenelzine) covalently bind the FAD cofactor, and two are non-covalent LSD1 inhibitors [pulrodemstat (CC-90011) and seclidemstat (SP-2577)]. Another TCP-based LSD1/MAO-B dual inhibitor, vafidemstat (ORY-2001), is in clinical trial for Alzheimer's diseases and personality disorders. The present review summarizes the structure and functions of LSD1, its pathological implications in cancer and non-cancer diseases, and the identification of LSD1 covalent and non-covalent inhibitors with different chemical scaffolds, including those involved in clinical trials, highlighting their potential as potent and selective anticancer agents.

The Role of a Neoadjuvant RET Inhibitor in Medullary Thyroid Cancer

The Role of a Neoadjuvant <i>RET</i> Inhibitor in Medullary Thyroid Cancer

Oncolytic NDV-AMHA1 Strain Effective Against Glioblastoma Cancer Cells

Glioblastoma multiforme (GBM) is one of the most life-threatening types of cancer that is difficult to treat. The search for effective yet safe therapy is progressing and non-conventional therapies such as using viruses as a smart and selective agent against cancer are promising. The aim of the study was the presence of a reliable method to use Newcastle disease virus (NDV) as an oncolytic agent against GBM, which attempted to propagate the NDV in laboratory experiments. Ahmed Majeed Hamza Al-Shammari-1 (AMHA1) attenuated strain of NDV was propagated in chicken embryos. The virus's tittered in Vero-slamed cells to determine the infective dose. MTT cell viability assay was used to investigate the killing effects of NDV on Ahmed-Majeed-Glioblastoma-Multiforme-2005 (AMGM5) human glioblastoma cancer cells derived from Iraqi patients. The infected cells' morphology was studied to measure the cytolytic effect of the NDV in cancer cells. Results showed that After 24 to 72 hours of inoculation, all of the chicken embryos died when the AMHA1 Iraqi NDV strain was injected. Cell viability assay showed that the NDV-AMHA1 strain has cytotoxicity at MOI of 0.1, 0.5, and 1 for 72 hours of exposure to cancer cells. The morphological analysis showed that NDV induces cell death in the infected cells with both necrotic and apoptotic features. In conclusion, the study focuses on the propagation of the oncolytic NDV as a biological agent capable of overcoming treatment resistance through infecting and replicating inside cancer.

Evaluation on Antimicrobial Activity of The Lichen Pleurosticta acetabulum

In this study, the ethanol extract of the lichen Pleurosticta acetabulum (Neck.) Elix &amp;amp; Lumbsch (Parmeliaceae) was investigated for their antimicrobial activity against various microorganisms by the disc diffusion method. Mycobacterium smegmatis CCM 2067, Micrococcus luteus CCM 169, Staphylococcus aureus ATCC 6538P, Proteus vulgaris ATCC 8427, Pseudomonas aeruginosa ATCC 27853, Listeria monocytogenes ATCC 15313, Klebsiella pneumoniae UC57, Bacillus cereus ATCC 7064, Escherichia coli ATCC 10536, Rhodotorula rubra DSM 70403, Candida albicans ATCC 10231 and Kluyveromyces fragilis ATCC 8608 were used as test microorgams. We have found that the ethanol extract of the lichen has a potential antimicrobial effect against all tested microorganisms, forming inhibition zones between 12.6-22.4 mm, as compared with the standard antibiotics. Notably, the extract has a strong effect against Escherichia coli and Staphylococcus aureus, especially Candida albicans. In conclusion, P. acetabulum may assist in the discovery of new antimicrobial agents that can serve as selective agents or in the preparation of new combined therapeutic drugs. However, the effect of this lichen species on more pathogenic organisms should be investigated and further and detailed pharmacological and toxicological studies should be conducted.

Truncated ring-A amaryllidaceae alkaloid modulates the host cell integrated stress response, exhibiting antiviral activity to HSV-1 and SARSCoV-2

The total synthesis of four novel mono-methoxy and hydroxyl substituted ring-A dihydronarciclasine derivatives enabled identification of the 7-hydroxyl derivative as a potent and selective antiviral agent targeting SARSCoV-2 and HSV-1. The concentration of this small molecule that inhibited HSV-1 infection by 50% (IC50), determined by using induced pluripotent stem cells (iPCS)-derived brain organ organoids generated from two iPCS lines, was estimated to be 0.504 µM and 0.209 µM. No significant reduction in organoid viability was observed at concentrations up to 50 mM. Genomic expression analyses revealed a significant effect on host-cell innate immunity, revealing activation of the integrated stress response via PERK kinase upregulation, phosphorylation of eukaryotic initiation factor 2α (eIF2α) and type I IFN, as factors potentiating multiple host-defense mechanisms against viral infection. Following infection of mouse eyes with HSV-1, treatment with the compound dramatically reduced HSV-1 shedding in vivo.

A Mini Review of Novel Topoisomerase II Inhibitors as Future Anticancer Agents.

Several reviews of inhibitors of topoisomerase II have been published, covering research before 2018. Therefore, this review is focused primarily on more recent publications with relevant points from the earlier literature. Topoisomerase II is an established target for anticancer drugs, which are further subdivided into poisons and catalytic inhibitors. While most of the topoisomerase II-based drugs in clinical use are mostly topoisomerase II poisons, their mechanism of action has posed severe concern due to DNA damaging potential, including the development of multi-drug resistance. As a result, we are beginning to see a gradual paradigm shift towards non-DNA damaging agents, such as the lesser studied topoisomerase II catalytic inhibitors. In addition, this review describes some novel selective catalytic topoisomerase II inhibitors. The ultimate goal is to bring researchers up to speed by curating and delineating new scaffolds as the leads for the optimization and development of new potent, safe, and selective agents for the treatment of cancer.

Design, Biological Evaluation, and Computer-Aided Analysis of Dihydrothiazepines as Selective Antichlamydial Agents.

Chlamydia trachomatis (CT) causes the most prevalent sexually transmitted bacterial disease in the United States. The lack of drug selectivity is one of the main challenges of the current antichlamydial pharmacotherapy. The metabolic needs of CT are controlled, among others, by cylindrical proteases and their chaperones (e.g., ClpX). It has been shown that dihydrothiazepines can disrupt CT-ClpXP. Based on this precedent, we synthesized a dihydrothiazepine library and characterized its antichlamydial activity using a modified semi-high-throughput screening assay. Then, we demonstrated their ability to inhibit ClpX ATPase activity in vitro, supporting ClpX as a target. Further, our lead compound displayed a promising selectivity profile against CT, acceptable cytotoxicity, no mutagenic potential, and good in vitro stability. A two-dimensional quantitative structure-activity relationship (2D QSAR) model was generated as a support tool in the identification of more potent antichlamydial molecules. This study suggests dihydrothiazepines are a promising starting point for the development of new and selective antichlamydial drugs.

Genome-phenotype-environment associations identify signatures of selection in a panmictic population of threespine stickleback.

Adaptive genetic divergence occurs when selection imposed by the environment causes the genomic component of the phenotype to differentiate. However, genomic signatures of natural selection are usually identified without information on which trait is responding to selection by which selective agent(s). Here, we integrate whole-genome sequencing with phenomics and measures of putative selective agents to assess the extent of adaptive divergence in threespine stickleback occupying the highly heterogeneous lake Mývatn, NE Iceland. We find negligible genome wide divergence, yet multiple traits (body size, gill raker structure and defence traits) were divergent along known ecological gradients (temperature, predatory bird densities and water depth). SNP based heritability of all measured traits was high (h2 =0.42-0.65), indicating adaptive potential for all traits. Environment-association analyses further identified thousands of loci putatively involved in selection, related to genes linked to, for instance, neuron development and protein phosphorylation. Finally, we found that loci linked to water depth were concurrently associated with pelvic spine length variation - supporting the conclusion that divergence in pelvic spine length occurred in the face of gene flow. Our results suggest that whilst there is substantial genetic variation in the traits measured, phenotypic divergence of Mývatn stickleback is mostly weakly associated with environmental gradients, potentially as a result of substantial gene flow. Our study illustrates the value of integrative studies that combine genomic assays of multivariate trait variation with landscape genomics.

Mapping the diffusion pattern of 1O2 along DNA duplex by guanine photooxidation with an appended biphenyl photosensitizer

To realize nucleic acid-targeting photodynamic therapy, a photosensitizer should be attached at the optimal position on a complementary oligonucleotide, where a guanine photooxidation is maximized. Here we show the photooxidation of 22 DNA duplexes with varied lengths between a 1O2-generating biphenyl photosensitizer attached at a midchain thymine in a strand and the single guanine reactant in the other strand. The best photooxidation efficiencies are achieved at 9, 10, and 21 base intervals, which coincides with the pitch of 10.5 base pairs per turn in a DNA duplex. The low efficiencies for near and far guanines are due to quenching of the biphenyl by guanine and dilution of 1O2 by diffusion, respectively. The 1O2-diffusion mapping along DNA duplex provides clues to the development of efficient and selective photosensitizer agents for nucleic acid-targeting photodynamic therapy, as well as an experimental demonstration of diffusion of a particle along cylindrical surface in molecular level.

Designing Tailored Thiosemicarbazones with Bespoke Properties: The Styrene Moiety Imparts Potent Activity, Inhibits Heme Center Oxidation, and Results in a Novel "Stealth Zinc(II) Complex".

A novel, potent, and selective antitumor agent, namely (E)-3-phenyl-1-(2-pyridinyl)-2-propen-1-one 4,4-dimethyl-3-thiosemicarbazone (PPP44mT), and its analogues were synthesized and characterized and displayed strikingly distinctive properties. This activity was mediated by the inclusion of a styrene moiety, which through steric and electrochemical mechanisms prevented deleterious oxy-myoglobin or oxy-hemoglobin oxidation relative to other potent thiosemicarbazones, i.e., di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) or di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT). Structure-activity relationship analysis demonstrated specific tuning of PPP44mT electrochemistry further inhibited oxy-myoglobin or oxy-hemoglobin oxidation. Both PPP44mT and its Cu(II) complexes showed conspicuous almost immediate cytotoxicity against SK-N-MC tumor cells (within 3 h). In contrast, [Zn(PPP44mT)2] demonstrated a pronounced delay in activity, taking 48 h before marked antiproliferative efficacy was apparent. As such, [Zn(PPP44mT)2] was designated as a "stealth Zn(II) complex" that overcomes the near immediate cytotoxicity of PPP44mT or its copper complexes. Upon examination of the suppression of oncogenic signaling, [Zn(PPP44mT)2] was superior at inhibiting cyclin D1 expression compared to DpC or Dp44mT.

Novel thiosemicarbazone and thiazolidin‐4‐one derivatives containing vanillin core: Synthesis, characterization, and anticancer activity studies

AbstractCancer is one of the most common and lethal disease in the world, therefore, patients need new and potent anticancer agents for treatment. In this study, starting from vanillin, 24 new compounds, which are 12 thiosemicarbazone (4a‐h, 5i‐j, 6k) and 12 thiazolidin‐4‐one (7a‐h, 8i‐j and 9k) derivatives, were synthesized and characterized by Nuclear Magnetic Resonance (NMR), High‐Resolution Mass Spectroscopy (HRMS), and Fourier‐transform Infrared (FTIR) techniques. In vitro cytotoxic effects were investigated on CCD‐1079Sk human healthy fibroblast and MDA‐MB‐231 human breast cancer cell lines. For MDA‐MB‐231, molecules showed IC50 in ranging of 88.08 ± 0.027–16.54 ± 0.031 μM (Doxorubicin: 61.70 ± 0.021 μM) and for CCD‐1079Sk, molecules showed IC50 in ranging of 192.36 ± 0.018–13.58 ± 0.035 μM (Doxorubicin:52.01 ± 0.028 μM). Compounds 6k and 7f were found most selective and potent anticancer agents compared to Doxorubicin used as a standard drug.

Rilotumumab Resistance Acquired by Intracrine Hepatocyte Growth Factor Signaling.

Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for molecularly-targeted therapeutics that otherwise have shown unprecedented successes in disease control. The hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and has been a subject of targeted drug development for nearly 30 years. To anticipate and study specific resistance mechanisms associated with targeting this pathway, we engineered resistance to the HGF-neutralizing antibody rilotumumab in glioblastoma cells harboring autocrine HGF/Met signaling, a frequent abnormality of this brain cancer in humans. We found that rilotumumab resistance was acquired through an unusual mechanism comprising dramatic HGF overproduction and misfolding, endoplasmic reticulum (ER) stress-response signaling and redirected vesicular trafficking that effectively sequestered rilotumumab and misfolded HGF from native HGF and activated Met. Amplification of MET and HGF genes, with evidence of rapidly acquired intron-less, reverse-transcribed copies in DNA, was also observed. These changes enabled persistent Met pathway activation and improved cell survival under stress conditions. Point mutations in the HGF pathway or other complementary or downstream growth regulatory cascades that are frequently associated with targeted drug resistance in other prevalent cancer types were not observed. Although resistant cells were significantly more malignant, they retained sensitivity to Met kinase inhibition and acquired sensitivity to inhibition of ER stress signaling and cholesterol biosynthesis. Defining this mechanism reveals details of a rapidly acquired yet highly-orchestrated multisystem route of resistance to a selective molecularly-targeted agent and suggests strategies for early detection and effective intervention.

Optimization of the 2-arylquinazoline-4(3H)one scaffold for a selective and potent antitrypanosomal agent: modulation of the mechanism of action through chemical functionalization.

We sought to identify a potent and selective antitrypanosomal agent through modulation of the mechanism of action of a 2-arylquinazoline scaffold as an antitrypanosomal agent via chemical functionalization at the 4-position. We wished to use the: (i) susceptibility of trypanosomatids towards nitric oxide (NO) and reactive oxygen species (ROS); (ii) capacity of the 4-substituted quinazoline system to act as an antifolate agent. Three quinazolin-based moieties that differed from each other by having at the 4-position key pharmacophores targeting the induction of NO and ROS production were evaluated in vitro against Leishmania infantum and Trypanosoma cruzi parasites and their modes of action were explored. Replacement of an oxygen moiety at the 4-position of the antifolate 2-arylquinazolin-4(3H)one by hydrazinyl and 5-nitrofuryl-hydrazinyl pharmacophores enhanced antitrypanosomatid activity significantly due to promotion of an additional mechanism beyond the antifolate response such as NO or ROS production, respectively. Among the three types of chemical functionalization, the 5-nitrofuryl-hydrazinyl moiety generated the most potent compounds. Compound 3b was a potential candidate thanks to its sub-micromolar response against the promastigotes/amastigotes of L. infantum and epimastigote of T. cruzi, moderate toxicity on macrophages (J774.1), good selectivity index (∼15.1-17.6) and, importantly, non-mutagenic effects. 2-Arylquinazoline could be an attractive platform to design new anti-trypanosomatid agents with the use of key pharmacophores.

NiCo LDH nanozymes with selective antibacterial activity against Gram-negative bacteria for wound healing.

Bacterial infections have been a major threat to human health. Especially, Gram-negative (G-) bacterial infections have been an increasing problem worldwide. The overuse of antibiotics leads to an emergence of drug resistance, and thus the development of novel antimicrobial agents is important, particularly against G- bacteria. Nanozymes use reactive oxygen species (ROS) to kill bacteria, reducing the risk of bacterial resistance and providing new opportunities to meet the challenges of strain selectivity. Here, we synthesized NiCo layered double hydroxide (LDH) nanozymes, which exhibit selective antibacterial activity based on their peroxide-like (POD-like) activity. To obtain the highest antibacterial activity, the POD-like activity of NiCo LDH nanozyme was further optimized by tuning the ratio of nickel and cobalt, and Ni4Co6 LDHs showed the highest POD activity and antibacterial activity. More importantly, Ni4Co6 LDHs can achieve selective sterilization of G- bacteria due to their electrostatic adsorption and hydrophilic interactions with the bacterial cell wall. Animal experiments further indicated that the healing of G- bacteria-infected wounds was effectively promoted without damaging their normal biological tissues. In conclusion, we provide a selective antibacterial agent through a simple strategy, which provides a new direction for the application of nanozymes.

Selectively attacking tumor cells of Ru/Ir-arene complexes based on meclofenamic acid via cyclooxygenase-2 inhibition.

Breast cancer (BC) is one of the most common malignant tumors and often accompanied by inflammatory processes. Inflammation is an essential component of the tumor microenvironment, which might influence tumor proliferation and metastasis. Herein, three metal-arene complexes MA-bip-Ru, MA-bpy-Ir, and MA-bpy-Ru were prepared by tethering the non-steroidal anti-inflammatory drug meclofenamic acid (MA). Among them, MA-bip-Ru and MA-bpy-Ir showed lower cytotoxicity towards cancer cells, but MA-bpy-Ru showed significantly high selectivity and cytotoxicity towards MCF-7 cells through the autophagic pathway and exhibited no toxicity against normal HLF cells, showing potential for selective treatment of tumor cells. MA-bpy-Ru could also effectively destroy the 3D multicellular tumor spheroids, demonstrating its potential for clinical application. Besides, MA-bip-Ru, MA-bpy-Ir, and MA-bpy-Ru exhibited anti-inflammatory properties superior to MA, notably downregulating the expression of cyclooxygenase-2 (COX-2) and inhibiting the secretion of prostaglandin E2 in vitro. These findings demonstrated that MA-bpy-Ru was capable of intervening in inflammatory processes and showed the potential of MA-bpy-Ru to act as a selective anticancer agent, thus presenting a new mechanism of action for metal-arene complexes.