New Mechanism Of Action Research Articles

Recent Advances and Outlook of Benzopyran Derivatives in the Discovery of Agricultural Chemicals.

Scaffold structures, new mechanisms of action, and targets present enormous challenges in the discovery of novel pesticides. The discovery of new scaffolds is the basis for the continuous development of modern agrochemicals. Identification of a good scaffold such as triazole, carbamate, methoxy acrylate, pyrazolamide, pyrido-pyrimidinone mesoionic, and bisamide often leads to the development of a new series of pesticides. In addition, pesticides with the same target, including the inhibitors of succinate dehydrogenase (SDH), oxysterol-binding-protein, and p-hydroxyphenyl pyruvate dioxygenase (HPPD), may have the same or similar scaffold structure. Recent years have witnessed significant progress in the discovery of new pesticides using natural products as scaffolds or bridges. In recent years, there have been increasing reports on the application of natural benzopyran compounds in the discovery of new pesticides, especially osthole and coumarin. A systematic and comprehensive review of benzopyran active compounds in the discovery of new agricultural chemicals is helpful to promote the discussion and development of benzopyran active compounds. Therefore, this work systematically reviewed the research and application of benzopyran derivatives in the discovery of agricultural chemicals, summarized the antiviral, herbicidal, antibacterial, fungicidal, insecticidal, nematicidal and acaricidal activities of benzopyran active compounds, and discussed the structural-activity relationship and mechanism of action. In addition, some active fragments were recommended to further optimize the chemical structure of benzopyran active compounds based on reference information.

Development of Penicillin-Based Carbonic Anhydrase Inhibitors Targeting Multidrug-Resistant Neisseria gonorrhoeae.

The development of antibacterial drugs with new mechanisms of action is crucial in combating the rise of antibiotic-resistant infections. Bacterial carbonic anhydrases (CAs, EC 4.2.1.1) have been validated as promising antibacterial targets against pathogens such as Helicobacter pylori, Neisseria gonorrhoeae, and vancomycin-resistant enterococci. A multitarget strategy is proposed to design penicillin-based CA inhibitor hybrids for tackling resistance by targeting multiple bacterial pathways, thereby resensitizing drug-resistant strains to clinical antibiotics. The sulfonamide derivatives potently inhibited the CAs from N. gonorrhoeae and Escherichia coli with KI values in the range of 7.1-617.2 nM. Computational simulations with the main penicillin-binding protein (PBP) of N. gonorrhoeae indicated that these hybrid derivatives maintained the mechanism of action of the lead β-lactams. A subset of derivatives showed potent PBP-related antigonococcal effects against multidrug-resistant N. gonorrhoeae strains, with several compounds significantly outperforming both the lead β-lactam and CA inhibitor drugs (MIC values in the range 0.25 to 0.5 μg/mL).

(Heteroarylmethyl)benzoic Acids as a New Class of Bacterial Cystathionine γ-Lyase Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling.

Antibiotic resistance is one of the most serious global health threats. Therefore, there is a need to develop antimicrobial agents with new mechanisms of action. Targeting of bacterial cystathionine γ-lyase (bCSE), an enzyme essential for bacterial survival, is a promising approach to overcome antibiotic resistance. Here, we described a series of (heteroarylmethyl)benzoic acid derivatives and evaluated their ability to inhibit bCSE or its human ortholog hCSE using known bCSE inhibitor NL2 as a lead compound. Derivatives bearing the 6-bromoindole group proved to be the most active, with IC50 values in the midmicromolar range, and highly selective for bCSE over hCSE. Furthermore, none of these compounds showed significant toxicity to HEK293T cells. The obtained data were rationalized by ligand-based and structure-based molecular modeling analyses. The most active compounds were also found to be an effective adjunct to several widely used antibacterial agents against clinically relevant antibiotic-resistant strains of such bacteria as Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The most potent compounds, 3h and 3i, also showed a promising in vitro absorption, distribution, metabolism, and excretion (ADME) profile. Finally, compound 3i manifested potentiating activity in pneumonia, sepsis, and infected-wound in vivo models.

Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors.

Although vaccination remains the prevalent prophylactic means for controlling Influenza A virus (IAV) infections, novel structural antivirus small-molecule drugs with new mechanisms of action for treating IAV are highly desirable. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring oxime, which might target the hemagglutinin (HA)-mediated IAV entry into the host cells. SAR analysis revealed that the size and linker of the macrocycles play an important role in improving potency. Particularly, as a 14-membered macrocyclic oxime, 37 exhibited potent inhibitory activity against IAV H1N1 with an EC50 value of 23 nM and low cytotoxicity, which alleviated cytopathic effects and protected cell survival obviously after H1N1 infection. Furthermore, 37 showed significant synergistic activity with neuraminidase inhibitor oseltamivir in vitro.

Development of Noninvasive Method for the Automated Analysis of Nine Steroid Hormones in Human Saliva by Online Coupling of In-Tube Solid-Phase Microextraction with Liquid Chromatography–Tandem Mass Spectrometry

Accurate measurement of steroid hormones is crucial to elucidate new mechanisms of action and diagnose steroid metabolism-related diseases. This study presents a simple, sensitive, and automated analytical method for nine representative steroid hormones. The method involves on-line coupling of in-tube solid-phase microextraction (IT-SPME) with liquid chromatography–tandem mass spectrometry (LC–MS/MS). The steroid hormones were extracted and enriched on a Supel-Q PLOT capillary column using IT-SPME. Subsequently, they were separated and detected within 6 min using a Discovery HS F5-3 column and positive ion mode multiple reaction monitoring system via LC–MS/MS. Calibration curves of these compounds using each stable isotope-labeled internal standard (IS) showed linearity with correlation coefficients greater than 0.9990 in the range of 0.01–40 ng/mL, with limits of detection (S/N = 3) of 0.7–21 pg/mL. Moreover, intra- and inter-day variations were lower than 8.1 and 15% (n = 6), respectively. The recoveries of these compounds from saliva samples were in the range of 82–114%. The developed IT-SPME/LC–MS/MS method of steroid hormones is a highly sensitive, specific, and non-invasive analytical method that allows extraction and enrichment with no organic solvents, and enables direct automated online analysis by simply ultrafiltrating a small sample of saliva.

Advanced UPLC-MS/MS Method for the Quantification of SIPI6398 in Rat Plasma and Its Pharmacokinetic Characterization.

SIPI6398 is a novel anti-schizophrenia agent with a new mechanism of action and demonstrates better target selectivity and safety compared to its competitors. However, few in vivo studies on the pharmacokinetics and bioavailability of SIPI6398 have been performed. A rapid and simple ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) approach was developed for accurate quantification of SIPI6398 in rat plasma. A simple protein precipitation of acetonitrile-methanol (9 : 1, v/v) was used to treat plasma. Chromatography was performed on a UPLC HSS T3 column (50 mm × 2.1 mm, 1.8 μm) at a flow rate of 0.4 ml/min. The mobile phase consisted of acetonitrile-water (with 0.1% formic acid) and gradient elution was used, and the elution time was 4 minutes. Quantitative analysis was performed using electrospray ionization (ESI) in positive ion detection mode with multiple reaction monitoring (MRM) mode. To evaluate the pharmacokinetics and bioavailability, SIPI6398 was administered to rats in two different ways: oral (4 mg/kg) and intravenous (2 mg/kg) administration. The calibration curve for the UPLC-MS/MS approach shows excellent linearity in the range of 1-2000 ng/mL with an r value above 0.99. The precision, accuracy, recovery, matrix effect, and stability results all meet the criteria established for biological analytical methods. The UPLC-MS/MS method was successfully applied it to pharmacokinetics study of SIPI6398. The bioavailability of SIPI6398 was calculated to be 13.2%. These studies have the potential to contribute towards a more comprehensive comprehension of the pharmacokinetics and bioavailability of SIPI6398.

HDAC inhibitors activate lipid peroxidation and ferroptosis in gastric cancer

Gastric cancer remains among the deadliest neoplasms worldwide, with limited therapeutic options. Since efficacies of targeted therapies are unsatisfactory, drugs with broader mechanisms of action rather than a single oncogene inhibition are needed. Preclinical studies have identified histone deacetylases (HDAC) as potential therapeutic targets in gastric cancer. However, the mechanism(s) of action of HDAC inhibitors (HDACi) are only partially understood. This is particularly true with regard to ferroptosis as an emerging concept of cell death.In a panel of gastric cancer cell lines with different molecular characteristics, tumor cell inhibitory effects of different HDACi were studied. Lipid peroxidation levels were measured and proteome analysis was performed for the in-depth characterization of molecular alterations upon HDAC inhibition. HDACi effects on important ferroptosis genes were validated on the mRNA and protein level.Upon HDACi treatment, lipid peroxidation was found increased in all cell lines. Class I HDACi (VK1, entinostat) showed the same toxicity profile as the pan-HDACi vorinostat. Proteome analysis revealed significant and concordant alterations in the expression of proteins related to ferroptosis induction. Key enzymes like ACSL4, POR or SLC7A11 showed distinct alterations in their expression patterns, providing an explanation for the increased lipid peroxidation. Results were also confirmed in primary human gastric cancer tissue cultures as a relevant ex vivo model.We identify the induction of ferroptosis as new mechanism of action of class I HDACi in gastric cancer. Notably, these findings were independent of the genetic background of the cell lines, thus introducing HDAC inhibition as a more general therapeutic principle.

Inhibition Mechanism of SARS-CoV-2 Infection by a Cholesterol Derivative, Nat-20(S)-yne.

The coronavirus disease 2019 (COVID-19) is caused by the etiological agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19, with the recurrent epidemics of new variants of SARS-CoV-2, remains a global public health problem, and new antivirals are still required. Some cholesterol derivatives, such as 25-hydroxycholesterol, are known to have antiviral activity against a wide range of enveloped and non-enveloped viruses, including SARS-CoV-2. At the entry step of SARS-CoV-2 infection, the viral envelope fuses with the host membrane dependent of viral spike (S) glycoproteins. From the screening of cholesterol derivatives, we found a new compound 26,27-dinorcholest-5-en-24-yne-3β,20-diol (Nat-20(S)-yne) that inhibited the SARS-CoV-2 S protein-dependent membrane fusion in a syncytium formation assay. Nat-20(S)-yne exhibited the inhibitory activities of SARS-CoV-2 pseudovirus entry and intact SARS-CoV-2 infection in a dose-dependent manner. Among the variants of SARS-CoV-2, inhibition of infection by Nat-20(S)-yne was stronger in delta and Wuhan strains, which predominantly invade into cells via fusion at the plasma membrane, than in omicron strains. The interaction between receptor-binding domain of S proteins and host receptor ACE2 was not affected by Nat-20(S)-yne. Unlike 25-hydroxycholesterol, which regulates various steps of cholesterol metabolism, Nat-20(S)-yne inhibited only de novo cholesterol biosynthesis. As a result, plasma membrane cholesterol content was substantially decreased in Nat-20(S)-yne-treated cells, leading to inhibition of SARS-CoV-2 infection. Nat-20(S)-yne having a new mechanism of action may be a potential therapeutic candidate for COVID-19.

Identification of active main metabolites of anti-infective inhibitors of the macrophage infectivity potentiator protein by liquid chromatography using mass detection.

Due to increasing antibiotic resistance, the development of anti-infectives with new mechanisms of action is crucial. Virulence factors such as the "macrophage infectivity potentiator" (Mip) protein, which catalyzes the folding of proline-containing proteins by means of their cis-trans isomerase (PPIase) activity, have come into focus as a potential new target. Since the inhibition of Mip by small molecules has been shown to lead to reduced virulence and survival in vitro, especially of Gram-negative bacteria such as Burkholderia pseudomallei (Bp), Neisseria meningitidis (Nm), and Neisseria gonorrhoeae (Ng), or Coxiella burnetii (Cb), among many others, a library of Mip inhibitors was developed. As drug metabolism has a significant impact on the overall therapeutic outcome, this report describes the biotransformation of the most potent Mip inhibitors. Therefore, the anti-infectives were treated using human liver microsomes in vitro. Liquid chromatography with tandem mass spectrometry (LC/MS-MS) methods were applied to identify the metabolites and quantify the metabolic degradation of the hit compounds. Active metabolites, N-oxides, were found, leading to new opportunities for further drug development.

Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3-Benzylmenadione Revealed by High-Content Imaging.

Chagas disease, or American trypanosomiasis, is a neglected tropical disease which is a top priority target of the World Health Organization. The disease, endemic mainly in Latin America, is caused by the protozoan Trypanosoma cruzi and has spread around the globe due to human migration. There are multiple transmission routes, including vectorial, congenital, oral, and iatrogenic. Less than 1% of patients have access to treatment, relying on two old redox-active drugs that show poor pharmacokinetics and severe adverse effects. Hence, the priorities for the next steps of R&D include (i) the discovery of novel drugs/chemical classes, (ii) filling the pipeline with drug candidates that have new mechanisms of action, and (iii) the pressing need for more research and access to new chemical entities. In the present work, we first identified a hit (4a) with a potent anti-T. cruzi activity from a library of 3-benzylmenadiones. We then designed a synthetic strategy to build a library of 49 3-(4-monoamino)benzylmenadione derivatives via reductive amination to obtain diazacyclic benz(o)ylmenadiones. Among them, we identified by high content imaging an anti-amastigote "early lead" 11b (henceforth called cruzidione) revealing optimized pharmacokinetic properties and enhanced specificity. Studies in a yeast model revealed that a cruzidione metabolite, the 3-benzoylmenadione (cruzidione oxide), enters redox cycling with the NADH-dehydrogenase, generating reactive oxygen species, as hypothesized for the early hit (4a).

Activation of the RIG-I/MAVS Signaling Pathway during Human Adenovirus Type 3 Infection Impairs the Pro-Inflammatory Response Induced by Secondary Infection with Staphylococcus aureus.

The exacerbation of pneumonia in children with human adenovirus type 3 (HAdV-3E) is secondary to a Staphylococcus aureus (S. aureus) infection. The influence of host-pathogen interactions on disease progression remains unclear. It is important to note that S. aureus infections following an HAdV-3E infection are frequently observed in clinical settings, yet the underlying susceptibility mechanisms are not fully understood. This study utilized an A549 cell model to investigate secondary infection with S. aureus following an HAdV-3E infection. The findings suggest that HAdV-3E exacerbates the S. aureus infection by intensifying lung epithelial cell damage. The results highlight the role of HAdV-3E in enhancing the interferon signaling pathway through RIG-I (DDX58), resulting in the increased expression of interferon-stimulating factors like MX1, RSAD2, and USP18. The increase in interferon-stimulating factors inhibits the NF-κB and MAPK/P38 pro-inflammatory signaling pathways. These findings reveal new mechanisms of action for HAdV-3E and S. aureus in secondary infections, enhancing our comprehension of pathogenesis.

Clinical management of treatment-resistant depression

Treatment-resistant depression (TRD) is acomplex disorder. Although no standardized definition has been established to date, there are promising and well-established treatment options for the condition. Looking at the current pharmacological and neuromodulatory strategies, there is an urgent need for fast-acting and well-tolerated treatment options. The search for new mechanisms of action goes beyond the monoamine hypothesis. For example, esketamine is already an established treatment method that is fast-acting and well tolerated, while psychedelics or esmethadone are currently still undergoing clinical trials. Compounds that can be used off-label, such as dextromethorphan or anti-inflammatory strategies are also presented. Pharmacological approaches that focus on the modulation of the glutamatergic system or belong to the class of psychedelics, appear to be of particular importance for current research and development. These particularly include substances that rapidly exert clinical effects and have afavorable side-effect profile.

Abstract 2058: Compound library screening to identify modulators of alternative splicing in non-small cell lung cancer (NSCLC)

Abstract Alternative splicing is a molecular mechanism that allows a single gene to encode multiple proteins. It is a complex and highly controlled process used to regulate normal gene expression but is often dysregulated in cancer. Compounds that can modulate alternative splicing are currently being explored as a potential new class of therapeutic agent in cancer. This highlights the need for a deeper understanding of the splicing process, its regulation, and its impact. The discovery of novel and specific tool compounds that modulate splicing would therefore not only be beneficial in investigating the regulation and dysregulation of splicing in cancer but could also be exploited therapeutically. To identify novel regulators of splicing, we generated a cell-based split luciferase screening assay based on alternative splicing of MCL-1 (myeloid cell leukemia-1 protein) pre-mRNA. The MCL1 gene usually produces an mRNA encoding a ‘long’ variant (MCL1L) that is an anti-apoptotic protein often highly expressed in cancers. However, in some circumstances, for example following genetic knockdown of splicing factors, a pro-apoptotic ‘short’ variant (MCL1S) is expressed as a result of exon-skipping. Here we engineered the human NSCLC cell line NCI-H1299 to express a luminescent-tagged version of the MCL1S splice variant to monitor its induction upon spliceosome modulation. Using this engineered cell line, we screened an unannotated library of 12,000 compounds selected to have low molecular weights and favorable properties for cellular uptake. The screen had an average Z’ value of 0.89 over 45 microplates, indicating high assay robustness. Hits were identified as any compound with a luminescence of greater than the average + two standard deviations of the screening dataset. The compounds were validated by repetition in the screening assay, giving 34 candidate hits that were then triaged by qPCR assay to confirm splicing modulation of MCL1. One interesting hit was found to increase mRNA and cellular protein levels of MCL1S and induced altered splicing across the transcriptome that was distinct from the splicing profiles of a diverse panel of splicing modulators, including compounds targeting SF3B1, CLK, and RBM39. In addition, treatment with this hit compound resulted in accumulation of the splicing factor SC35 in cytoplasmic granules, an unusual phenotype not seen with known splicing modulators, that could explain the distinct splicing modulation we have observed. Deconvolution and further characterization of screening hits and potentially unique new mechanisms of action could improve current understanding of alternative splicing and its regulation in NSCLC. The discovery of novel compounds to expand our current toolset of splicing modulators will be key in building the foundation for future splicing targeted drug discovery. Citation Format: Rachel Cooley, Marissa V. Powers, Adam G. Bond, Patrizia Jensen, Gary Newton, Andrea Scarpino, Juliane Braun, Christina Esdar, Paul A. Clarke. Compound library screening to identify modulators of alternative splicing in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2058.

The role of sodium – glucose cotransporter-2 inhibitors in the treatment of different phenotypes of chronic heart failure

The number of patients with chronic heart failure syndrome is steadily increasing worldwide and Ukraine is not an exception. About 50 % of patients with heart failure have preserved ejection fraction of left ventricle. Recently, there has been significant progress in the diagnosis of this phenotype of heart failure, many diagnostic scales and practice-oriented algorithms have been developed, but the issue of treatment of chronic heart failure remains open. Aim of the study. To summarize and analyze the results of large-scale randomized trials and to discuss the possible pathophysiological mechanisms underlying the “pleiotropiс” effects of sodium-glucose cotransporter-2 inhibitors. Sodium-glucose cotransporter-2 inhibitors are the first class of antidiabetic drugs that have demonstrated improved cardiovascular prognosis in patients with chronic heart failure with preserved ejection fraction regardless of the presence of diabetes mellitus. Conclusions. The necessity of prescribing sodium-glucose cotransporter-2 inhibitors in a cohort of patients with heart failure, regardless of left ventricular ejection fraction, has the highest level of evidence. The pathophysiological mechanisms underlying these effects are not fully understood. Further trials will allow us to identify new mechanisms of action and establish potential relationships between them.

Efficacy and Bioavailability of silymarin on Plasma S100B Level in Cardiotoxicity-induced Rats

Cardiotoxicity is a cause of death by drug overdose. Silymarin, a cytoprotective agent used in this research to protect against induced-cardiotoxic effects in Albino Wister rats; exhibited signs of heart damage, such as elevated levels of S100B, troponin I, and CK-MB. Seventy albino Wister rats of both genders were divided randomly with each group having 10 rats. Silymarin-treated, cardiotoxic-induced, and control groups were treated for ten days. The bioavailability of silymarin was assessed, and evaluation of the efficacy of silymarin on the biomarker S100B and cardiac biomarkers (Troponin I, and CK-MB), also the histopathological assessments of the heart, liver, and kidney, in addition to the coefficient correlation of the studied biomarkers were analyzed. Research’s outcome indicated that the sets subjected to silymarin presented substantial differences in rat weight and food consumption, compared to a decrease in cardiotoxic clusters. S100B plasma level was increased in cardiotoxic groups, reduced in those subjected to silymarin, and eliminated by pretreatment with silymarin. Troponin I & CK-MB expressively elevated significantly in cardiotoxic prompted rats, which declined with silymarin treatment and were prohibited in pretreatment by silymarin. The shielding characteristic of silymarin detected in end organs, like the liver, kidneys, and hearts when exposed to the cardiotoxic agent clozapine was extremely significant. The consequences of the histopathological examination of this study illustrated silymarin’s cardioprotective effects. A significant positive coefficient correlation of S100B with troponin I & CK-MB was recorded. In conclusion, silymarin reduces and prevents to a larger extent the cardiotoxicity brought about by clozapine and averts heart injury. The cardioprotective efficacy of silymarin is explained by its new mechanism of action as decreasing S100B, troponin I & CK-MB levels with a strong significant correlation to each other. The cardioprotective efficacy of silymarin gives promise for monitoring the cardiotoxicity adverse drug reaction induced by drugs.

VIBRANT: spectral profiling for single-cell drug responses.

High-content cell profiling has proven invaluable for single-cell phenotyping in response to chemical perturbations. However, methods with improved throughput, information content and affordability are still needed. We present a new high-content spectral profiling method named vibrational painting (VIBRANT), integrating mid-infrared vibrational imaging, multiplexed vibrational probes and an optimized data analysis pipeline for measuring single-cell drug responses. Three infrared-active vibrational probes were designed to measure distinct essential metabolic activities in human cancer cells. More than 20,000 single-cell drug responses were collected, corresponding to 23 drug treatments. The resulting spectral profile is highly sensitive to phenotypic changes under drug perturbation. Using this property, we built a machine learning classifier to accurately predict drug mechanism of action at single-cell level with minimal batch effects. We further designed an algorithm to discover drug candidates with new mechanisms of action and evaluate drug combinations. Overall, VIBRANT has demonstrated great potential across multiple areas of phenotypic screening.

A Critical View on New and Future Antidepressants.

For the first time after many decades, many new antidepressants have been approved and many more are under various stages of development and will soon be available in the market. The new drugs present a range of new mechanisms of action with benefits in terms of speed of action, tolerability and range of treatable disorders. Neurosteroids have been recently approved and their rapid benefit may extend from postpartum depression to anxious depression and bipolar depression, dextromethorphan and bupropion combination may prove useful in major depression but also in treatment resistant depression, dextromethadone is a possible augmentation in partial antidepressant response, psychedelic drugs have the potential of long lasting benefits after a single administration, though are still experimental treatments. Botulinum has the same advantage of psychedelics of a single administration and its antidepressant effects may last for weeks or more. Further potentially interesting new antidepressant mechanisms include new drug targets, drug repurposing and genetic or epigenetic manipulations. It is therefore important that clinicians are kept up to date with new evidence so that new evidence can be rapidly translated into clinical practice.

From Plant to Chemistry: Sources of Antinociceptive Non-Opioid Active Principles for Medicinal Chemistry and Drug Design.

Pain is associated with many health problems and a reduced quality of life and has been a common reason for seeking medical attention. Several therapeutics are available on the market, although side effects, physical dependence, and abuse limit their use. As the process of pain transmission and modulation is regulated by different peripheral and central mechanisms and neurotransmitters, medicinal chemistry continues to study novel ligands and innovative approaches. Among them, natural products are known to be a rich source of lead compounds for drug discovery due to their chemical structural variety and different analgesic mechanisms. Numerous studies suggested that some chemicals from medicinal plants could be alternative options for pain relief and management. Previously, we conducted a literature search aimed at identifying natural products interacting either directly or indirectly with opioid receptors. In this review, instead, we have made an excursus including active ingredients derived from plants whose mechanism of action appears from the literature to be other than the modulation of the opioid system. These substances could, either by themselves or through synthetic and/or semi-synthetic derivatives, be investigated in order to improve their pharmacokinetic characteristics and could represent a valid alternative to the opioid approach to pain therapy. They could also be the basis for the study of new mechanisms of action in the approach to this complex and disabling pathology.

Anti-Aspergillus activities of olorofim at sub-MIC levels during early-stage growth.

Among antifungal compounds in clinical development for systemic disease, the orotomide olorofim is one of only two that target a completely new mechanism of action. Olorofim is highly potent against pathogenic Aspergillus species including cryptic species that frequently show increased resistance to current agents. In this study, our primary focus was on evaluating in detail the inhibitory activity of voriconazole and olorofim against different pathogenic Aspergillus species employing high-throughput microscopy. Compared to standardized, less-sensitive visual assessment-based methods, microscopy-assisted growth monitoring allowed us to detect sub-MIC drug concentration ranges with significant inhibitory activity at early-stage growth. This revealed that olorofim exerts growth inhibition at concentrations that are several magnitudes below those of voriconazole.

Design, synthesis, and pesticidal activities of novel pyrimidin‐4‐amine derivatives containing trifluoroethyl sulfide moiety

AbstractIn order to overcome the problem of pesticide resistance, it is necessary to discover novel pesticides with new mechanisms of action. Herein, a series of novel pyrimidin‐4‐amine derivatives containing trifluoroethyl sulfide moiety were designed and synthesized. Bioassays indicated that the title compounds synthesized possessed excellent acaricidal activity against Tetranychus urticae and fungicidal activity against Erysiphe graminis and Puccinia sorghi. Especially, the acaricidal activity of 5‐chloro‐6‐(difluoromethyl)‐N‐(2‐(2‐fluoro‐4‐methyl‐5‐((2,2,2‐trifluoroethyl)thio)phenoxy)ethyl)pyrimidin‐4‐amine (compound T4, LC50 = 0.19 mg/L) against T. urticae was close to commercial acaricide cyenopyrafen, and the fungicidal activity of 5‐chloro‐6‐(difluoromethyl)‐2‐methyl‐N‐(2‐(3‐((2,2,2‐trifluoroethyl)thio)phenoxy)ethyl)pyrimidin‐4‐amine (compound T15, EC50 = 1.32 mg/L) against P. sorghi. was superior to commercial fungicide tebuconazole. The synthesis and characterization of these compounds were given and the structure–activity relationships were discussed.