Alternative Modes Of Action Research Articles

Novel Pyrazino[1,2-a]indole-1,3(2H,4H)-dione Derivatives Targeting the Replication of Flaviviridae Viruses: Structural and Mechanistic Insights.

Infections with Flaviviridae viruses, such as hepatitis C (HCV), dengue (DENV), and yellow fever (YFV) viruses, are major public health problems worldwide. In the case of HCV, treatment is associated with drug resistance and high costs, while there is no clinically approved therapy for DENV and YFV. Consequently, there is still a need for new chemotherapies with alternative modes of action. We have previously identified novel 2-hydroxypyrazino[1,2-a]indole-1,3(2H,4H)-diones as metal-chelating inhibitors targeting HCV RNA replication. Here, by utilizing a structure-based approach, we rationally designed a second series of compounds by introducing various substituents at the indole core structure and at the imidic nitrogen, to improve specificity against the RNA-dependent RNA polymerase (RdRp). The resulting derivatives were evaluated for their potency against HCV genotype 1b, DENV2, and YFV-17D using stable replicon cell lines. The most favorable substitution was nitro at position 6 of the indole ring (compound 36), conferring EC50 1.6 μM against HCV 1b and 2.57 μΜ against HCV 1a, with a high selectivity index. Compound 52, carrying the acetohydroxamic acid functionality (-CH2CONHOH) on the imidic nitrogen, and compound 78, the methyl-substituted molecule at the position 4 indolediketopiperazine counterpart, were the most effective against DENV and YFV, respectively. Interestingly, compound 36 had a high genetic barrier to resistance and only one resistance mutation was detected, T181I in NS5B, suggesting that the compound target HCV RdRp is in accordance with our predicted model.

Climate-smart Pest Management Strategies: Under Changing Climatic Scenarios

In the face of changing climatic conditions, it's crucial to acknowledge their far-reaching impacts on humans, animals, and agricultural systems worldwide, where negative consequences often overshadow any positive outcomes. With global warming and climate change, previously minor insect pests are now poised to wreak havoc, leading to widespread pest outbreaks. As a result, the effectiveness of various pest control measures, including host-plant resistance, natural enemies, transgenics, bio-pesticides, and synthetic chemicals, may undergo significant shifts. Growers and researchers are actively devising Integrated Pest Management (IPM) strategies to minimize environmental harm while maximizing crop yields and economic benefits. Numerous studies highlight the necessity of reevaluating pest management practices and IPM strategies to adapt to novel environmental conditions and enhance the resilience of diverse agroecosystems to weather variability. This involves initiatives such as breeding climate-resilient crops, adjusting crop calendars, employing GIS-based risk mapping for crop pests, and exploring novel pesticides with alternative modes of action, informed by predictive modeling data. Thus, this chapter explores the potential of these techniques for climate-smart insect pest management.

Comparison of transcriptomic profiles between HFPO-DA and prototypical PPARα, PPARγ, and cytotoxic agents in mouse, rat, and pooled human hepatocytes.

Like many per- or polyfluorinated alkyl substances (PFAS), toxicity studies with HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate), a short-chain PFAS used in the manufacture of some types of fluorinated polymers, indicate that the liver is the primary target of toxicity in rodents following oral exposure. Although the current weight of evidence supports the PPARα mode of action (MOA) for liver effects in HFPO-DA-exposed mice, alternate MOAs have also been hypothesized including PPARγ or cytotoxicity. To further evaluate the MOA for HFPO-DA in rodent liver, transcriptomic analyses were conducted on samples from primary mouse, rat, and pooled human hepatocytes treated for 12, 24, or 72 h with various concentrations of HFPO-DA, or agonists of PPARα (GW7647), PPARγ (rosiglitazone), or cytotoxic agents (ie, acetaminophen or d-galactosamine). Concordance analyses of enriched pathways across chemicals within each species demonstrated the greatest concordance between HFPO-DA and PPARα agonist GW7647-treated hepatocytes compared with the other chemicals evaluated. These findings were supported by benchmark concentration modeling and predicted upstream regulator results. In addition, transcriptomic analyses across species demonstrated a greater transcriptomic response in rodent hepatocytes treated with HFPO-DA or agonists of PPARα or PPARγ, indicating rodent hepatocytes are more sensitive to HFPO-DA or PPARα/γ agonist treatment. These results are consistent with previously published transcriptomic analyses and further support that liver effects in HFPO-DA-exposed rodents are mediated through rodent-specific PPARα signaling mechanisms as part of the MOA for PPARα activator-induced rodent hepatocarcinogenesis. Thus, effects observed in mouse liver are not appropriate endpoints for toxicity value development for HFPO-DA in human health risk assessment.

Ursolic acid acetate and iso-mukaadial acetate bind to Plasmodium falciparum Hsp90, abrogating its chaperone function in vitro

Plasmodium falciparum is the most lethal malaria parasite. Increasing incidences of drug resistance of P. falciparum have prompted the need for discovering new and effective antimalarial compounds with an alternative mode of action. Heat shock protein 90 (PfHsp90) facilitates protein folding and is a promising antimalarial drug target. We have previously reported that iso-mukaadial acetate (IMA) and ursolic acid acetate (UAA) exhibit antimalarial activity. We investigated the abilities of IMA and UAA to bind PfHsp90 by molecular docking and dynamics simulations. The in silico predictions were validated by biochemical assays conducted on recombinant PfHsp90. The interaction between the ligands and PfHsp90 was evaluated using ultraviolet-visible spectroscopy (UV-vis), Fourier transform infrared (FTIR), and surface plasmon resonance (SPR) analysis. The results obtained by docking calculations and MD dynamics simulation predicted that UAA and IMA preferentially bound to PfHsp90 via the N-terminal domain, with UAA binding more stable than IMA. UV-vis-based data suggest that PfHsp90 harbors buried aromatic amino acids, which were exposed in the presence of either IMA or UAA. In addition, data obtained using FTIR suggested that IMA and UAA destabilized the secondary structure of PfHsp90. Of the two compounds, UAA bound to PfHsp90 within the micromolar range based on surface plasmon resonance (SPR)-based binding assay. Furthermore, both compounds disrupted the holdase chaperone function of PfHsp90 as the chaperone failed to suppress heat-induced aggregation of the model proteins, malate dehydrogenase (MDH), luciferase, and citrate synthase in vitro. In addition, both compounds lowered the ATPase activity of PfHsp90. The molecular dynamics simulation analysis indicated that the docked complexes were mostly stable for 100 ns, validating the data obtained through the biochemical assays. Altogether, this study expands the repository of antiplasmodial compounds that have PfHsp90 among their possible targets.

Naphthoquinone Derivatives from Angustimassarina populi CF-097565 Display Anti-Tumour Activity in 3D Cultures of Breast Cancer Cells.

Cancer is one of the leading causes of death worldwide, with breast cancer being the second cause of cancer-related mortality among women. Natural Products (NPs) are one of the main sources for drug discovery. During a screening campaign focused on the identification of extracts from Fundación MEDINA's library inhibiting the proliferation of cancer cell lines, a significant bioactivity was observed in extracts from cultures of the fungus Angustimassarina populi CF-097565. Bioassay-guided fractionation of this extract led to the identification and isolation of herbarin (1), 1-hydroxydehydroherbarin (4) plus other three naphthoquinone derivatives of which 3 and 5 are new natural products and 2 is herein described from a natural source for the first time. Four of these compounds (1, 3, 4 and 5) confirmed a specific cytotoxic effect against the human breast cancer cell line MCF-7. To evaluate the therapeutic potential of the compounds isolated, their efficacy was validated in 3D cultures, a cancer model of higher functionality. Additionally, an in-depth study was carried out to test the effect of the compounds in terms of cell mortality, sphere disaggregation, shrinkage, and morphology. The cell profile of the compounds was also compared to that of known cytotoxic compounds with the aim to distinguish the drug mode of action (MoA). The profiles of 1, 3 and 4 showed more biosimilarity between them, different to 5, and even more different to other known cytotoxic agents, suggesting an alternative MoA responsible for their cytotoxicity in 3D cultures.

Hdp-101, an Anti-BCMA Antibody-Drug Conjugate with a Novel Payload Amanitin in Patients with Relapsed Multiple Myeloma, Initial Findings of the First in Human Study

Introduction Several antibody-drug conjugates (ADCs) are currently being evaluated in clinical trials in a variety of malignancies. The vast majority of these are based on a few toxic compounds, largely limited to microtubule- or DNA-targeting toxins which impact proliferating cells and have limited efficacy in diseases with a low proliferative fraction such as multiple myeloma. Thus, new compounds with alternative modes of action and the ability to actively induce cell death in non-proliferating tumor cells could enhance the therapeutic potential of ADCs. We are currently developing amanitin based ADCs. Amanitin specifically inhibits RNA polymerase II thereby inhibiting the cellular transcription process at very low concentrations irrespective of the proliferation status of the target cell. Subsequently tumor cells enter apoptosis and are eliminated. HDP-101 an Amanitin based antibody drug conjugate HDP-101 is a new ADC targeting BCMA carrying a synthetic version of amanitin as a payload. In vitro cytotoxic potency of HDP-101 was demonstrated on BCMA-positive myeloma cell lines, as well as on non-proliferating primary CD138+ cells isolated from patients with refractory myeloma The cytotoxic effects of HDP-101 were seen even in non-proliferating myeloma cells with low BCMA density. Toxicity was observed neither in non-BCMA expressing control cells nor in myeloma cells exposed to an amanitin-loaded non-target control antibody. In murine xenograft models of human myeloma, HDP-101 caused dose-dependent tumor regression including complete remissions after a single dose in subcutaneous and as well as in disseminated models. Safety profiling in Cynomolgus monkeys revealed a good therapeutic index after repeated dosing. Our non-clinical studies concluded that this amanitin-based ADC is a novel promising approach in the therapy of multiple myeloma to overcome drug resistance and improve patient outcome. HDP-101-01 Clinical study HDP-101-01 is a first-in-human, open label, non-randomized, multicenter, phase 1/2a trial with HDP-101 in patients with myeloma whose disease has progressed. The aim of the Phase 1 dose escalation part is to determine the Maximum Tolerated Dose and/or establish the Recommended Phase 2 Dose. The primary objective of the phase 2 dose expansion phase is to assess the preliminary anti-tumor activity of HDP-101. An adaptive Bayesian logistic regression model with overdose control principle is used to guide the dose escalation steps. An Interim Analysis is planned after each cohort is completed. The design of the study ensures a safe and adaptive dose escalation to reach a potential clinical benefit in a patient who have limited or no therapeutic options. HDP-101-01 Study progress The study started enrollment in February, 2022. As of 10th of July, 2023, eight (2 female and 6 male) patients were dosed in 3 consecutive dose cohorts. The median age of the patients was 70 years, ranging between 50 and 80. All 8 patients were heavily pre-treated and multidrug-resistant. The median previous lines of treatment were 7 (5 to 15). Table 1 HDP-101-01 Results Seven of 8 patients were evaluable for dose limiting toxicities (DLTs) in the first 3 treatment cohorts. The initial 3 cohorts were well tolerated, without any DLTs, there were no signs of liver and kidney toxicity, no infusion reaction was detected. No reports of keratopathy or visual acuity loss were observed. Free payload was not detected in any of the available pharmacokinetic samples. Based on the limited data, the PK of HDP-101 was in line with our expectation based on the preclinical observations, exposure to HDP-101 is dose proportional. Anti-drug antibody (ADA) was not detected and there's no sign of immunogenicity. Objective responses were not reported in these initial cohorts however in Cohort #3 (60μg/Kg) there was one patient ongoing after 8 cycles of treatment with SD. This patient had a slow decrease in M-protein levels. Image 1 The initial dose cohorts showed good tolerability in late stage relapsed and/or refractory multiple myeloma patients. The study continues to enroll patients to higher dose cohorts at selected sites in the US, Germany, Poland and Hungary. Currently the study is enrolling patients in Cohort #4 at the dose of 80μg/Kg. Additional updates will be provided at the 2023 ASH Annual Meeting.

Genetic validation of PfFKBP35 as an antimalarial drug target

Plasmodium falciparum accounts for the majority of over 600,000 malaria-associated deaths annually. Parasites resistant to nearly all antimalarials have emerged and the need for drugs with alternative modes of action is thus undoubted. The FK506-binding protein PfFKBP35 has gained attention as a promising drug target due to its high affinity to the macrolide compound FK506 (tacrolimus). Whilst there is considerable interest in targeting PfFKBP35 with small molecules, a genetic validation of this factor as a drug target is missing and its function in parasite biology remains elusive. Here, we show that limiting PfFKBP35 levels are lethal to P. falciparum and result in a delayed death-like phenotype that is characterized by defective ribosome homeostasis and stalled protein synthesis. Our data furthermore suggest that FK506, unlike the action of this drug in model organisms, exerts its antiproliferative activity in a PfFKBP35-independent manner and, using cellular thermal shift assays, we identify putative FK506-targets beyond PfFKBP35. In addition to revealing first insights into the function of PfFKBP35, our results show that FKBP-binding drugs can adopt non-canonical modes of action – with major implications for the development of FK506-derived molecules active against Plasmodium parasites and other eukaryotic pathogens.

Genetic validation of PfFKBP35 as an antimalarial drug target.

Plasmodium falciparum accounts for the majority of over 600,000 malaria-associated deaths annually. Parasites resistant to nearly all antimalarials have emerged and the need for drugs with alternative modes of action is thus undoubted. The FK506-binding protein PfFKBP35 has gained attention as a promising drug target due to its high affinity to the macrolide compound FK506 (tacrolimus). Whilst there is considerable interest in targeting PfFKBP35 with small molecules, a genetic validation of this factor as a drug target is missing and its function in parasite biology remains elusive. Here, we show that limiting PfFKBP35 levels are lethal to P. falciparum and result in a delayed death-like phenotype that is characterized by defective ribosome homeostasis and stalled protein synthesis. Our data furthermore suggest that FK506, unlike the action of this drug in model organisms, exerts its antiproliferative activity in a PfFKBP35-independent manner and, using cellular thermal shift assays, we identify putative FK506-targets beyond PfFKBP35. In addition to revealing first insights into the function of PfFKBP35, our results show that FKBP-binding drugs can adopt non-canonical modes of action - with major implications for the development of FK506-derived molecules active against Plasmodium parasites and other eukaryotic pathogens.

Exploring chemical control of 2,4-D–resistant wild radish (Raphanus raphanistrum) with auxin-related compounds

AbstractSynthetic auxin herbicides were developed and commercialized 60 yr before their mode of action was definitively elucidated. Although evolution of resistance to auxinic herbicides proceeded more slowly than for some other herbicide chemistries, it has become a major problem in the dicotyledonous weeds of many cropping areas of the world. With the molecular characterization of the auxin perception and signaling pathway in the mid-2000s came a greater understanding of how auxinic herbicides work, and how resistance may develop in weeds subjected to repeated selection with these herbicides. In wild radish (Raphanus raphanistrum L.) populations in southern Australia, resistance to multiple herbicides, including synthetic auxins such as 2,4-D, has reduced the number of chemical control options available. The aim of this study was to determine whether compounds involved in auxin biosynthesis, transport, and signaling are able to synergize with 2,4-D and increase its ability to control 2,4-D–resistant R. raphanistrum populations. Although some mild synergism was observed with a few compounds (abscisic acid, cyclanilide, tryptamine), the response was not large or consistent enough to warrant further study. Similarly, alternative auxinic herbicides applied pre- or postemergence were no more effective than 2,4-D. Therefore, while use of auxinic herbicides continues to increase due to the adoption of transgenic resistant crops, nonchemical control techniques will become more important, and chemical control of 2,4-D–resistant R. raphanistrum should be undertaken with alternative modes of action, using mixtures and good stewardship to delay the development of resistance for as long as possible.

Harnessing Transition Metal Scaffolds for Targeted Antibacterial Therapy.

Antimicrobial resistance, caused by persistent adaptation and growing resistance of pathogenic bacteria to overprescribed antibiotics, poses one of the most serious and urgent threats to global public health. The limited pipeline of experimental antibiotics in development further exacerbates this looming crisis and new drugs with alternative modes of action are needed to tackle evolving pathogenic adaptation. Transition metal complexes can replenish this diminishing stockpile of drug candidates by providing compounds with unique properties that are not easily accessible using pure organic scaffolds. We spotlight four emerging strategies to harness these unique properties to develop new targeted antibacterial agents.

Harnessing Transition Metal Scaffolds for Targeted Antibacterial Therapy

AbstractAntimicrobial resistance, caused by persistent adaptation and growing resistance of pathogenic bacteria to overprescribed antibiotics, poses one of the most serious and urgent threats to global public health. The limited pipeline of experimental antibiotics in development further exacerbates this looming crisis and new drugs with alternative modes of action are needed to tackle evolving pathogenic adaptation. Transition metal complexes can replenish this diminishing stockpile of drug candidates by providing compounds with unique properties that are not easily accessible using pure organic scaffolds. We spotlight four emerging strategies to harness these unique properties to develop new targeted antibacterial agents.

Data sets of human and mouse protein kinase inhibitors with curated activity data including covalent inhibitors.

Generation of high-quality data sets of protein kinase inhibitors (PKIs). Publicly available PKIs with reliable activity data were curated. PKIs with very weak activity were classified as inactive. Analogue series and PKIs containing reactive groups (warheads) enabling covalent inhibition were systematically identified. A total of 155,579 human and 3057 mouse PKIs were obtained. Human PKIs were active 440 kinases and included 13,949 covalent PKIs. The collection of qualifying PKIs and corresponding inactive compounds is made available as an open access deposition. Potential limitations include activity data incompleteness and assay variance. The data set can be used to investigate PKIs with alternative modes of action and calibrate computational methods.

Novel starting points for fragment-based drug design against mycobacterial thioredoxin reductase identified using crystallographic fragment screening.

The increasing number of people dying from tuberculosis and the existence of extensively drug-resistant strains has led to an urgent need for new antituberculotic drugs with alternative modes of action. As part of the thioredoxin system, thioredoxin reductase (TrxR) is essential for the survival of Mycobacterium tuberculosis (Mtb) and shows substantial differences from human TrxR, making it a promising and most likely selective target. As a model organism for Mtb, crystals of Mycobacterium smegmatis TrxR that diffracted to high resolution were used in crystallographic fragment screening to discover binding fragments and new binding sites. The application of the 96 structurally diverse fragments from the F2X-Entry Screen revealed 56 new starting points for fragment-based drug design of new TrxR inhibitors. Over 200 crystal structures were analyzed using FragMAXapp, which includes processing and refinement by largely automated software pipelines and hit identification via the multi-data-set analysis approach PanDDA. The fragments are bound to 11 binding sites, of which four are positioned at binding pockets or important interaction sites and therefore show high potential for possible inhibition of TrxR.

Ex vivo and in vitro antiplasmodial activity and toxicity of Caesalpinia decapetala (Roth) Alston (Fabaceae)

Ethnopharmacological relevanceMalaria is among the most prevalent and devastating parasitic diseases globally with most cases reported in Sub-Saharan Africa. One of the major reasons for the high malaria prevalence is the ever-increasing emergence of resistant strains of malaria-causing parasites to the currently used antimalarial drugs. This, therefore, calls for the search for antimalarial compounds with alternative modes of action. Plants used in traditional medicine for the treatment of malaria offer possible sources of such compounds. Caesalpinia decapetala has been used traditionally for the treatment of various diseases including malaria. However, the antiplasmodial activity of the plant has never been reported. Aim of the studyTo determine the ex vivo and in vitro antiplasmodial activities of the extracts of the roots, stem bark and leaves of Caesalpinia decapetala. MethodologyThe roots, stem bark and leaves of Caesalpinia decapetala (Roth) Alston (Caesalpiniaceae) were collected and air-dried under a shade then extracted consecutively with dichloromethane and methanol (1:1 (v/v) (4 × 0.8 L). The extracts were tested for antiplasmodial activities against four strains of Plasmodium falciparum (W2, DD2, 3D7, and D6) and fresh P. falciparum field isolates using the SYBR green I assay. The mean fifty percent inhibition concentration (IC50) was determined for each assay. An acute oral toxicity test was done based on the Organization for Economic Cooperation and Development (OECD 425) guidelines using Swiss albino mice. ResultsThe leaves and stem bark extracts showed good antiplasmodial activities with IC50 values of 4.54 and 4.86 μg/mL, respectively, when tested against the fresh field isolates ex vivo. Similarly, the roots extract showed an IC50 value of 6.49 μg/mL when tested against field isolates ex vivo. The roots extract showed the highest antiplasmodial activities among the samples when tested against W2 (IC50 = 6.12 μg/mL), DD2 (IC50 = 8.17 μg/mL), and D6 (IC50 = 16.02 μg/mL) strains of P. falciparum whereas the leaves showed the highest activity (IC50 = 9.3 μg/mL) when tested against the 3D7 strain of P. falciparum. No mortality was observed for the mice treated with 2000 mg/kg of the leaves and stem bark extracts. The mouse treated with 2000 mg/kg of the roots extracts regained weight by day 12 of the observation period. ConclusionCaesalpinia decapetala has the potential to suppress the growth of P. falciparum thereby contributing to combating the recurrent emergence of antimalarial drug resistance.

Predictive liver lipid biomarker signature of Acetyl-coenzyme A carboxylase inhibitor related developmental toxicity in non-pregnant female Han Wistar rats – Lipidomics biomarker discovery and validation

IntroductionAcetyl-coenzyme A carboxylase (ACCase) inhibition is an attractive herbicide target. However, issues with fetal developmental toxicity identified at the late stages of the development process can halt progression of previously promising candidates. ObjectivesTo select and verify predictive lipid biomarkers of ACCase inhibition activity in vivo using liver samples obtained from early stage 7 day repeat dose studies in non-pregnant female Han Wistar rats that could be translated to developmental toxicity endpoints discovered during late-stage studies to provide an early screening tool. MethodsLiver samples from eight rat repeat dose studies, exposed to six ACCase inhibitors from three different chemistries and one alternative mode of action (MoA) that also perturbs lipid biochemistry, were analysed using liquid chromatography – high resolution accurate mass – mass spectrometry. Multivariate and univariate data analysis methods were used for biomarker discovery and validation. ResultsA biomarker signature consisting of sixteen lipids biomarkers were selected. Verification of the signature as indicative of ACCase inhibition was established by demonstrating consistent perturbations in the biomarkers using two different ACCase inhibitor chemistries and the lack thereof with an alternate MoA. The fold change profile pattern was predictive of which test substance doses would or would not cause developmental toxicity. ConclusionA strategy for selecting and verifying a robust signature of lipid biomarkers for predicting a toxicological end point has been described and demonstrated. Differences in lipidomic profiles correlated with developmental toxicity suggesting that indicators of a molecular initiation event resulting in pup developmental toxicity can be predicted from short term, toxicity studies conducted in non-pregnant adult female Han Wistar rats.

Assessment of the mode of action underlying development of liver lesions in mice following oral exposure to HFPO-DA and relevance to humans.

HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoate) is a short-chain polyfluorinated alkyl substance (PFAS) used in the manufacture of some types of fluorinated polymers. Like many PFAS, toxicity studies with HFPO-DA indicate the liver is the primary target of toxicity in rodents following oral exposure. Due to the structural diversity of PFAS, the mode of action (MOA) can differ between PFAS for the same target tissue. There is significant evidence for involvement of peroxisome proliferator-activated receptor alpha (PPARα) activation based on molecular and histopathological responses in the liver following HFPO-DA exposure, but other MOAs have also been hypothesized based on limited evidence. The MOA underlying the liver effects in mice exposed to HFPO-DA was assessed in the context of the Key Events (KEs) outlined in the MOA framework for PPARα activator-induced rodent hepatocarcinogenesis. The first 3 KEs (ie, PPARα activation, alteration of cell growth pathways, and perturbation of cell growth/survival) are supported by several lines of evidence from both in vitro and in vivo data available for HFPO-DA. In contrast, alternate MOAs, including cytotoxicity, PPARγ and mitochondrial dysfunction are generally not supported by the scientific literature. HFPO-DA-mediated liver effects in mice are not expected in humans as only KE 1, PPARα activation, is shared across species. PPARα-mediated gene expression in humans produces only a subset (ie, lipid modulating effects) of the responses observed in rodents. As such, the adverse effects observed in rodent livers should not be used as the basis of toxicity values for HFPO-DA for purposes of human health risk assessment.

Impact of Coordination Mode and Ferrocene Functionalization on the Anticancer Activity of N-Heterocyclic Carbene Half-Sandwich Complexes.

The substitution of phenyl rings in established drugs with ferrocenyl moieties has been reported to yield compounds with improved biological activity and alternative modes of action, often involving the formation of reactive oxygen species (ROS). Translating this concept to N-heterocyclic carbene (NHC) complexes, we report here organometallics with a piano-stool structure that feature di- or tridentate ligand systems. The ligands impacted the cytotoxic activity of the NHC complexes, but the coordination modes seemed to have a limited influence, which may be related to the propensity of forming the same species in solution. In general, the stability of the complexes in an aqueous environment and their reactivity to selected biomolecules were largely dominated by the nature of the metal center. While the complexes promoted the formation of ROS, the levels did not correlate with their cytotoxic activity. However, the introduction of ferrocenyl moieties had a significant impact on the antiproliferative potency of the complexes and, in particular, some of the ferrocenyl-functionalized compounds yielded IC50 values in the low μM range.

Evaluation of the mode of action and human relevance of liver tumors in male mice treated with epyrifenacil

Epyrifenacil (trademark name: Rapidicil®), a novel protoporphyrinogen oxidase (PPO)-inhibiting herbicide, induces hepatocellular adenomas and carcinomas in male CD-1 mice after 78 weeks treatment. The mode of action (MOA) of these mouse liver tumors and their relevance to humans was assessed based on the 2006 International Programme on Chemical Safety (IPCS) Human Relevance Framework. Epyrifenacil is not genotoxic and induced liver tumors via the postulated porphyria-mediated cytotoxicity MOA with the following key events: (#1) PPO inhibition; (#2) porphyrin accumulation; (#3) hepatocellular injury; with (#4) subsequent regenerative cell proliferation; and ultimately (#5) development of liver tumors. This article evaluates the weight of evidence for this MOA based on the modified Bradford Hill criteria. The MOA data were aligned with the dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specificity for a porphyria-mediated cytotoxicity MOA while excluding other alternative MOAs. Although the postulated MOA could qualitatively potentially occur in humans, we demonstrate that it is unlikely to occur in humans because of quantitative toxicodynamic and toxicokinetic differences between mice and humans. Therefore, this MOA is considered not relevant to humans, utilizing the IPCS Human Relevance Framework; consequently, a nonlinear, threshold dose response would be appropriate for human risk assessment.

Graphene materials: Armor against nosocomial infections and biofilm formation – A review

Graphene has revolutionized the field of energy and storage sectors. Out of the total number of nosocomial infections diagnosed all around the world, the majority of the cases (around 70%) are found to be due to the medical device or assistance utilized while treating the patient. Combating these diseases is vital as they cause a nuisance to the patients and medical practitioners. Coatings of graphene and its derivatives hold the key to the formation of special surfaces that can rupture microbial cells using their sharp edges, ultimately leading to nuclear and cellular fragmentation. Their incorporation as a whole or as a part in the hospital apparel and the medical device has aided medical practitioners to combat many nosocomial diseases. Graphene is found to be highly virulent with broad-spectrum antimicrobial activity against nosocomial strains and biofilm formation. Their alternate mode of action like trapping and charge transfer has also been discussed well in the present review. The various combinational forms of graphene with its conjugates as a suitable agent to combat nosocomial infections and a potential coating for newer challenges like COVID-19 infections has also been assessed in the current study. Efficiency of graphene sheets has been found to be around 89% with a reaction time as less as 3 h. Polymers with graphene seem to have a higher potency against biofilm formation. When combined with graphene oxide, silver nanoparticles provide 99% activity against nosocomial pathogens. In conclusion, this review would be a guiding light for scientists working with graphene-based coatings to unfold the potentials of this marvelous commodity to tackle the present and future pandemics to come.

Synthesis and Structure-Activity Relationship of Thioacetamide-Triazoles against Escherichia coli.

Infections due to Gram-negative bacteria are increasingly dangerous due to the spread of multi-drug resistant strains, emphasizing the urgent need for new antibiotics with alternative modes of action. We have previously identified a novel class of antibacterial agents, thioacetamide-triazoles, using an antifolate targeted screen and determined their mode of action which is dependent on activation by cysteine synthase A. Herein, we report a detailed examination of the anti-E. coli structure–activity relationship of the thioacetamide-triazoles. Analogs of the initial hit compounds were synthesized to study the contribution of the aryl, thioacetamide, and triazole sections. A clear structure–activity relationship was observed generating compounds with excellent inhibition values. Substitutions to the aryl ring were generally best tolerated, including the introduction of thiazole and pyridine heteroaryl systems. Substitutions to the central thioacetamide linker section were more nuanced; the introduction of a methyl branch to the thioacetamide linker substantially decreased antibacterial activity, but the isomeric propionamide and N-benzamide systems retained activity. Changes to the triazole portion of the molecule dramatically decreased the antibacterial activity, further indicating that 1,2,3-triazole is critical for potency. From these studies, we have identified new lead compounds with desirable in-vitro ADME properties and in-vivo pharmacokinetic properties.