Discovery of novel, orally bioavailable phenylacetamide derivatives as multikinase inhibitors and in vivo efficacy study in hepatocellular carcinoma animal models.

Hepatocellular carcinoma (HCC) is considered as one of the leading causes of death in liver disease patients. Several signal transduction pathways are involved in HCC pathogenesis. Multikinase inhibitors (MKIs) show beneficial effects for HCC and the FDA approved a few MKIs including sorafenib, lenvatinib for HCC treatments. Here, a novel series of phenylacetamide derivatives were designed, synthesized and evaluated as multikinase inhibitors. Several compounds showed nanomolar IC50 values against FLT1, FLT3, FLT4, KDR, PDGFRα, PDGFRß. The compounds were tested against human hepatocellular carcinoma (HCC), human colon adenocarcinoma and human gastric carcinoma cell lines. With favorable pharmacokinetics profiles, compound 12 and compound 14 were selected for in vivo efficacy studies in Hep3B mice models and demonstrated efficacious than sorafenib.

Quinazolinone-Hydrazine Cyanoacetamide Hybrids as Potent Multitarget-Directed Druggable Therapeutics against Alzheimer's Disease: Design, Synthesis, and Biochemical, In Silico, and Mechanistic Analyses.

The discovery of effective multitarget-directed ligands (MTDLs) against multifactorial Alzheimer's disease (AD) remnants has been focused in an incessant drug discovery pursuit. In this perception, the current study explores the rational design, synthesis, and evaluation of 26 quinazolinone-hydrazine cyanoacetamide hybrids 7(a-j), 8(a-j), and 9(a-f) as MTDLs against AD. These new compounds were synthesized in four-step processes using simple phthalimide as the starting material without any major workup procedures and were characterized by different spectroscopic techniques. In Ellman's assay, the most potent analogues 7i, 8j, and 9d were identified as selective and mixed-type inhibitors of hAChE. Furthermore, biophysical and computational assessments revealed that the analogues 7i, 8j, and 9d were bound to both the catalytic active site and peripheral anionic site of hAChE with high affinity. The molecular dynamics simulation analysis highlighted the conformational changes of hAChE upon binding of 7i, 8j, and 9d and also the stability of resulting biomolecular systems all over 100 ns simulations. In addition to antioxidant activity, the most active congeners were found to protect substantially SK-N-SH cells from oxidative damage. Decisively, the most active analogues 7i, 8j, and 9d were assessed as potent Aß1-42 fibril modulators and protective agents against Aß1-42-induced toxicity in SH-SY5Y cells. Additionally, glioblastoma C6 cell-based assays also demonstrated the use of the most active congeners 7i, 8j, and 9d as protective agents against Aß1-42-induced toxicity. Overall, this multifunctional capacity of quinazolinone-hydrazine cyanoacetamide hybrids demonstrated the noteworthy potential of these hybrids to develop as effectual MTDLs against AD. However, further pharmacokinetics, toxicology, and behavioral studies are warranted.

Exploring 2-mercapto-N-arylacetamide analogs as promising anti-melanogenic agents: in vitro and in vivo evaluation.

Based on the hypothesis that the 2-mercaptoacetamide moiety chelates the copper ions of tyrosinase, 2-mercapto-N-arylacetamide (2-MAA) analogs were designed and synthesized as potential tyrosinase inhibitors. Four 2-MAA analogs showed low IC50 values ranging from 0.95 to 2.0 µM against mushroom tyrosinase, which was 12-26 times lower than that of kojic acid (IC50 value = 24.3 µM). However, according to a copper ion chelation experiment performed, the 2-MAA analogs did not participate in chelation with copper ions. To identify the mode of inhibition of the 2-MAA analogs, kinetic studies were performed, and the results were supported by docking results. In addition, docking simulation results suggested that the 2-MAA analogs strongly inhibited tyrosinase activity because of the hydrogen bonding of the amide NH group and the hydrophobic interaction of the aryl ring instead of chelation with copper ions. In experiments using B16F10 cells, 2-MAA analogs were shown to inhibit melanin production by inhibiting cellular tyrosinase activity. Western blotting showed that in addition to directly inhibiting tyrosinase activity, analog 7 also has an anti-melanogenic effect by inhibiting the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase. The 2-MAA analogs showed no appreciable cytotoxicity against HaCaT and B16F10 cells, making them suitable for dermal applications. In a depigmentation experiment using zebrafish embryos, analogs 1 and 2 showed more potent depigmentation effects than kojic acid even at 1000 times lower concentration than that of kojic acid. These results suggest that the 2-MAA analogs are promising anti-melanogenic agents that can inhibit most tyrosinases in various species.

Agomelatine-loaded nanostructured lipid carriers alleviate neuropathic pain in rats by Nrf2/HO-1 signalling pathway.

Neuropathic pain arises from impairments or malfunctions within the nervous system, resulting in atypical transmission and interpretation of pain signals. In the present study, we examined the neuroprotective effects of agomelatine (AGM) and agomelatine-loaded nanostructured lipid carriers (AGM-NLCs) in neuropathic animal models induced by chronic constriction injury (CCI) of the sciatic nerve. Male Sprague Dawley rats were divided into seven experimental groups to compare the effects of AGM and AGM-NLCs, which were administered at 20 mg/kg for 14 consecutive days after CCI. Our finding demonstrated that CCI triggered the onset of analgesia in these animals, corroborated by mechanical allodynia and thermal hyperalgesia. Furthermore, CCI induced an elevation in inflammatory mediators such as interleukin (IL)-1ß and inducible nitric oxide synthase (iNOS), and downregulated heme oxygenase-1 (HO-1) and nuclear factor E2-related factor (Nrf2). Treatment with AGM and AGM-NLCs reversed inflammatory cascades and elevated antioxidant enzyme levels, leading to a reduction in paw withdrawal latency and threshold in rats. To further investigate the effect of AGM and AGM-NLCs, all-trans retinoic acid (ATRA) was administered, which antagonizes Nrf2. ATRA substantially downregulated Nrf2 expression and exacerbated thermal hyperalgesia, whereas Nrf2 and HO-1 expressions were significantly upregulated after AGM-NLCs administration. Overall, the results demonstrated that AGM-NLCs offer promising antinociceptive and anti-inflammatory properties in alleviating neuropathic pain symptoms, which can be attributed to improved drug delivery and therapeutic outcomes compared with AGM alone.

Discovery of new acetamide derivatives of 5-indole-1,3,4-oxadiazol-2-thiol as inhibitors of HIV-1 Tat-mediated viral transcription.

Human immunodeficiency virus-1 (HIV-1) encodes a transcriptional factor called Tat, which is critical for viral transcription. Tat-mediated transcription is highly ordered apart from the cellular manner; therefore, it is considered a target for developing anti-HIV-1 drugs. However, drugs targeting Tat-mediated viral transcription are not yet available. Our high-throughput screen of a compound library employing a dual-reporter assay identified a 1,3,4-oxadiazole scaffold against Tat and HIV-1 infection. Furthermore, a serial structure-activity relation (SAR) study performed with biological assays found 1,3,4-oxadiazole derivatives (9 and 13) containing indole and acetamide that exhibited potent inhibitory effects on HIV-1 infectivity, with half-maximal effective concentrations (EC50) of 0.17 (9) and 0.24 µM (13), respectively. The prominent derivatives specifically interfered with the viral transcriptional step without targeting other infection step(s) and efficiently inhibited the HIV-1 replication cycle in the T cell lines and peripheral blood mononuclear cells infected with HIV-1. Additionally, compared to the wild type, the compounds exhibited similar potency against anti-retroviral drug-resistant HIV-1 strains. In a series of mode-of-action studies, the compounds inhibited the ejection of histone H3 for facilitating viral transcription on the long-terminal repeat (LTR) promoter. Furthermore, SAHA (a histone deacetylase inhibitor) treatment abolished the compound potency, revealing that the compounds can possibly target Tat-regulated epigenetic modulation of LTR to inhibit viral transcription. Overall, our screening identified novel 1,3,4-oxadiazole compounds that inhibited HIV-1 Tat, and subsequent SAR-based optimization led to the derivatives 9 and 13 development that could be a promising scaffold for developing a new class of therapeutic agents for HIV-1 infection.

The characteristics of frozen-thawed rooster sperm using various intracellular cryoprotectants.

Cryopreservation of rooster semen is essential for conserving genetic resources, genetic improvement, and increasing productivity. However, the nature of avian sperm presents a global issue in ensuring superior frozen semen for artificial insemination. Thus, the present study aimed to evaluate the impact of using dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), and ethylene glycol (EG) as cryoprotectants on post-thawed sperm motility, quality, antioxidant indicators, and fertilizing capacity. Twice a week, fresh semen ejaculates were collected from 15 adult roosters and immediately evaluated to constitute a pool from clean and qualified samples. The pooled semen was further diluted at a ratio of 1:2 (v/v) with an extender and then subjected to a freezing protocol in a liquid nitrogen vapor after adding a cryoprotectant solution containing 6% of either DMA, DMSO, or EG, respectively. After thawing, characteristics of sperm motion, quality, antioxidants, and fertilizing ability were evaluated and compared to fresh and cooled semen as controls. The results demonstrated that semen cooling negatively affected some parameters of sperm motility, quality, antioxidant biomarkers, and fertility. In comparison to the DMSO and EG groups, employing DMA considerably (P < 0.05) raised the percentages of sperm progressive motility, viability, plasma membrane intactness, and DNA integrity. The DMA group showed a significant increase in the catalase and glutathione reduced antioxidant enzyme activity and a reduction in nitric oxide and lipid peroxidation. After artificial insemination, the DMA and DMSO groups exhibited considerably (P < 0.05) better rates of hatchability and fertility than the EG group. It is concluded that freezing extenders containing 6% DMA is better than DMSO or EG to improve the post thaw semen quality and fertility in chickens.

Design, Synthesis, and Herbicidal Activities of N-(5-(3,5-Methoxyphenyl)-(thiazole-2-yl))phenoxyacetamide Derivatives.

Thiazole and phenoxyacetic acid are key moieties in many natural and synthetic biologically active agents. A series of N-(5-(3,5-methoxyphenyl)-(thiazole-2-yl))phenoxyacetamide derivatives 6an-6bd were designed and synthesized, and their structures were confirmed by NMR and HRMS. Most of derivatives exhibited superior inhibition of Echinochloa crusgalli (E.c.) and Lactuca sativa (L.s.) seed germination by the Petri dish bioassay. Indeed, herbicidal bioassays indicated that 6an (2-(2,4-dichlorophenoxy)-N-(5-(3,5-dimethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide) had the best inhibition against L.s. (IC50 = 42.7 g/ha, 375 g/ha at field experiments). 6an also had no harmful effect on Zea mays at 2- to 4-fold field usage. Moreover, transcriptomics and metabolomics analysis showed that 6an significantly influenced cell metabolism, including galactose metabolism and ascorbate and aldarate metabolism. These discoveries highlight that 6an shows promise to be developed as a potential herbicide.

Agomelatine Is Unable to Attenuate Kainic Acid-Induced Deficits in Early Life Communicative Behavior.

Early life seizures are associated with a variety of behavioral comorbidities. Among the most prevalent of these are deficits in communication. Auditory communicative behaviors in mice, known as ultrasonic vocalizations (USVs), can be used to assess potential treatments. Agomelatine is a melatonin agonist that effectively reduces behavioral comorbidities of seizures in adults; however, its ability to attenuate seizure-induced communicative deficits in neonates is unknown. To address this, we administered C57 mice either saline or kainic acid (KA) on postnatal day (PD) 10. The mice then received either agomelatine or saline 1-h post-status epilepticus. On PD 11, we assessed the quantity of USVs produced, the duration, peak frequency, fundamental frequency, and amplitude of the vocalizations, as well as the call type utilization. We found that KA increased vocal production and reduced USV variability relative to controls. KA also increased USV duration and amplitude and significantly altered the types of calls produced. Agomelatine did not attenuate any of the deficits. Our study is the first to assess agomelatine's efficacy to correct USVs and thus provides an important point of context to the literature, indicating that despite its high therapeutic efficacy to attenuate other behavioral comorbidities of seizures, agomelatine's ability to correct neonatal communicative deficits is limited.

SPH7854, a gut-limited RORγt antagonist, ameliorates TNBS-induced experimental colitis in rat.

Multiple lines of evidence suggest that Retinoic Acid Related Orphan Nuclear Receptor gamma t (RORγt) is a potent therapeutic target for inflammatory bowel disease (IBD). However, systemic blockade of RORγt easily leads to thymic lymphoma and aberrant liver function. Therefore, the development of gut-limited RORγt antagonists may lead to the development of innovative IBD therapeutics that improve safety and retain effectiveness. We discovered SPH7854, a potent and selective RORγt antagonist. The effect of SPH7854 on the differentiation of T helper 1 (Th1)/Th17/regulatory T (Treg) cells was evaluated in mouse and human primary cells. SPH7854 (2-(4-(ethylsulfonyl)phenyl)-N- (6-(2-methyl-2-(pyridin-2-yl) propanoyl)pyridin-3-yl)acetamide) dose-dependently inhibited interleukin-17A (IL-17A) secretion from mouse CD4 + T cells and human peripheral blood mononuclear cells (PBMC). Additionally, SPH7854 strongly suppressed Th17 cell differentiation and considerably promoted Treg cell differentiation while slightly affected Th1 cell differentiation from mouse CD4 + T cells. The pharmacokinetic (PK) studies indicated that SPH7854 was restricted to the gut: the bioavailability and maximal plasma concentration of SPH7854 after oral administration (6 mg/kg) were 1.24 ± 0.33 % and 4.92 ± 11.81 nM, respectively, in rats. Strikingly, oral administration of SPH7854 (5 mg/kg and 15 mg/kg) twice daily significantly alleviated 2, 4, 6-trinitrobenzensulfonic acid (TNBS)-induced colitis in rats. SPH7854, especially at 15 mg/kg, significantly alleviated symptoms and improved macroscopic signs and microscopic structure in rat colitis, with decreased colonic mucosal levels of IL-17A, IL-6, tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and myeloperoxidase (MPO). These evidences indicated that blockade of RORγt activity via a gut-limited antagonist may be an effective and safe therapeutic strategy for IBD treatment.

Lack of Acute Agomelatine Effect in a Model of Social Anxiety in Healthy Volunteers: A Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Agomelatine is an antidepressant drug that acts as an agonist of melatoninergic MT1/2 receptors and an antagonist of serotonergic 5-HT2C receptors. Studies suggest that agomelatine has anxiolytic properties in social anxiety, but there are no studies that assessed the effects of this compound in human experimental anxiety induced by a public speaking test. The objective of our investigation was to assess the effects of agomelatine on human experimental anxiety using the Simulation Public Speaking Test (SPST). METHODS: Agomelatine (25 mg, n = 14), citalopram (20 mg, n = 14), venlafaxine (75 mg, n = 14), or placebo (n = 14) were administered in single doses to healthy volunteers in a double-blind study. Subjective anxiety was assessed with the Visual Analogue Mood Scale. Arterial blood pressure, heart rate, and blood levels of prolactin and cortisol were also recorded, as well as plasma levels of the 3 drugs. RESULTS: The SPST induced significant subjective, physiological, and hormonal effects in all groups. The SPST also increased the anxiety and decreased mental sedation Visual Analogue Mood Scale factors during the anticipatory and performance phases of the test. Citalopram increased anxiety during the test in females, whereas agomelatine and venlafaxine were not different from placebo. CONCLUSIONS: Confirming previous results, a serotonin selective reuptake inhibitor, citalopram, caused an anxiogenic effect in the SPST only in females. Acute administration of a low dose of agomelatine failed to modify the behavioral and physiological changes caused by this test. Future studies using higher doses and repeated administration should investigate if agomelatine behavioral and physiological effects could be detected in human experimental anxiety models.

Arbidol, an antiviral drug, identified as a sodium channel blocker with anticonvulsant activity.

BACKGROUND AND PURPOSE: Sodium channel blockers (SCBs) have traditionally been utilized as anti-seizure medications by primarily targeting the inactivation process. In a drug discovery project aiming at finding potential anticonvulsants, we have identified arbidol, originally an antiviral drug, as a potent SCB. In order to evaluate its anticonvulsant potential, we have thoroughly examined its biophysical properties as well as its effects on animal seizure models. EXPERIMENTAL APPROACH: Patch clamp recording was used to investigate the electrophysiological properties of arbidol, as well as the binding and unbinding kinetics of arbidol, carbamazepine and lacosamide. Furthermore, we evaluated the anticonvulsant effects of arbidol using three different seizure models in male mice. KEY RESULTS: Arbidol effectively suppressed neuronal epileptiform activity by blocking sodium channels. Arbidol demonstrated a distinct mode of action by interacting with both the fast and slow inactivation of Nav1.2 channels compared with carbamazepine and lacosamide. A kinetic study suggested that the binding and unbinding rates might be associated with the specific characteristics of these three drugs. Arbidol targeted the classical binding site of local anaesthetics, effectively inhibited the gain-of-function effects of Nav1.2 epileptic mutations and exhibited varying degrees of anticonvulsant effects in the maximal electroshock model and subcutaneous pentylenetetrazol model but had no effect in the pilocarpine-induced status epilepticus model. CONCLUSIONS AND IMPLICATIONS: Arbidol shows promising potential as an anticonvulsant agent, providing a unique mode of action that sets it apart from existing SCBs.

Isolation and cryopreservation of Pseudopimelodus mangurus (Siluriformes) spermatogonial cells.

Spermatogonia cryopreservation can be a strategy for future conservation actions. The neotropical Siluriformes Pseudopimelodus mangurus was already classified as vulnerable on the Red List of Threatened Species. P. mangurus spermatogonial cells were isolated, assessed, and cryopreserved. Fragments of the testis were enzymatically dissociated, purified using Percoll density gradient, and submitted to differential plating. Fractionated cells were evaluated by microscopy, ddx4 (vasa) relative expression, and alkaline phosphatase activity. Cryopreservation was conducted using ethylene glycol, glycerol, dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), and propanediol at 1 M, 1.5 M, and 2 M. Cell viability was evaluated and cell concentration was determined. Cell fractions from 20 % and 30 % Percoll gradient bands showed the highest concentrations of spermatogonia. The fraction mix showed 54 % purity and 93 % viability. After differential plating, 60 % purity and 92 % viability were obtained. Spermatogonial cells showed high alkaline phosphatase activity compared to spermatocytes and spermatids. The relative spermatogonial ddx4 expression from the Percoll density gradient was about twice as high as in samples from the testis and the differential plating. The increased ddx4 expression indicated the enrichment of spermatogonial cells by density gradient step and dead cells expressing ddx4 in differential plating, or ddx4 decreasing expression during cell culture. For this reason, cells from the Percoll gradient were chosen for cryopreservation. Propanediol at 1 M demonstrated the best condition for spermatogonial cell cryopreservation, presenting 98 % viability, while dimethylacetamide at 2 M represented the least favorable condition, with approximately 47 % viability. These findings are essential for P. mangurus spermatogonial cell cryopreservation, aiming to generate a spermatogonia cryobank for future conservation efforts.

Dual orexin receptor antagonist ameliorates sleep deprivation-induced learning and memory impairment in APP/PS1 mice.

Sleep is considered closely related to cognitive function, and cognitive impairment is the main clinical manifestation of Alzheimer's disease (AD). Sleep disturbance in AD patients is more severe than that in healthy elderly individuals. Additionally, sleep deprivation reportedly increases the activity of the hypothalamic orexin system and the risk of AD. To investigate whether intervention with the orexin system can improve sleep disturbance in AD and its impact on AD pathology. In this study, six-month-old amyloid precursor protein/presenilin 1 mice were subjected to six weeks of chronic sleep deprivation and injected intraperitoneally with almorexant, a dual orexin receptor antagonist (DORA), to investigate the effects and mechanisms of sleep deprivation and almorexant intervention on learning and memory in mice with AD. We found that sleep deprivation aggravated learning and memory impairment and increased brain ß-amyloid (Aß) deposition in mice with AD. The application of almorexant can increase the total sleep time of sleep-deprived mice and reduce cognitive impairment and Aß deposition, which is related to the improvement in Aquaporin-4 polarity. Thus, DORA may be an effective strategy for delaying the progression of AD patients by improving the sleep disturbances.

Metabolic profiling of a new synthetic cannabinoid receptor agonist, ADMB-FUBIATA, with human liver microsomes, human primary hepatocytes and human recombinant CYP450 enzymes using LC-quadrupole-orbitrap MS.

A novel synthetic cannabinoid receptor agonist (SCRA), ADMB-FUBIATA, featuring an acetamide-linked structure, has emerged on the illicit drug market. To provide dependable verification of its consumption and identify reliable biomarkers, we investigated an in vitro metabolism study of ADMB-FUBIATA incubated with human primary hepatocytes (HPHs) for the first time and correlated our findings with those from human liver microsomes (HLMs). In this work, ADMB-FUBIATA (10 µM) was incubated with HLM and HPH for 1 and 5 h, respectively, and then subjected to LC-quadrupole-orbitrap MS. A total of 25 metabolites across 8 metabolic pathways were identified after incubation with HLM and HPH, respectively. Monohydroxylation and N-dealkylation were the major metabolic pathways, and formation to ketone was first identified. In addition, the metabolism of ADMB-FUBIATA were found to be mediated by multiple CYP450 enzymes, predominantly CYP2C19, 2D6, and 3A4. This research also initially characterized the fragmentation patterns of the metabolites of ADMB-FUBIATA, elaborating on their structural relationship with ADMB-FUBIATA analogs. To effectively monitor ADMB-FUBIATA abuse, metabolites M4 and M1 were proposed as reliable biomarkers by cross-validating the HLM and HPH incubation results.

Pyrimidine-based sulfonamides and acetamides as potent antimicrobial Agents: Synthesis, Computational Studies, and biological assessment.

A series of novel sulfonamide and acetamide derivatives of pyrimidine were synthesized and their antimicrobial activities were assessed. Based on the Microbroth dilution method, the minimum inhibitory concentration (MIC) of the synthesized compounds demonstrated moderate to good levels of antifungal and antibacterial activity. Structure-activity relationship analysis suggested that the presence of electron-withdrawing groups, such as halogens, nitrile, and nitro groups, on the pyrimidine ring contributed to the enhanced antimicrobial potency, while electron-donating substituents led to a decrease in activity. Computational studies, including density functional theory (DFT), frontier molecular orbitals (FMO), and molecular electrostatic potential (MEP) analysis, provided insights into the electronic properties and charge distribution of the compounds. Drug-likeness evaluation using ADME/Tox analysis indicated that the synthesized compounds possess favorable physicochemical properties and could be potential drug candidates. Molecular docking against the Mycobacterium TB protein tyrosine phosphatase B (MtbPtpB) revealed that the synthesized compounds exhibited strong binding affinities (-46 kcal/mol to - 61 kcal/mol) and formed stable protein-ligand complexes through hydrogen bonding and π-π stacking interactions with key residues in the active site. The observed interactions from the docking simulations were consistent with the predicted interaction sites identified in the FMO and MEP analyses. These findings suggest that the synthesized pyrimidine derivatives could serve as promising antimicrobial agents and warrant further investigation for drug development.

Design, Synthesis and Evaluation of Antifungal Activity of Pyrazoleacetamide Derivatives.

BACKGROUND: Fungal infections have posed a big challenge in the management of their treatment. Due to the resistance and toxicity of existing drug molecules in the light of pandemic infections, like COVID-19, there is an urgent need to find newer derivatives of active molecules, which can be effective in fungal infections. OBJECTIVE: In the present study, we aimed to design pyrazole derivatives using molecular modeling studies against target 1EA1 and synthesize 10 molecules of pyrazole derivatives using a multi-step synthesis approach. METHODS: Designed pyrazole derivatives were synthesized by conventional organic methods. The newly synthesized pyrazole molecules were characterized by using FT-IR, 1HNMR, 13CNMR, and LC-MS techniques. Molecular docking studies were also performed. The antifungal activity of newly synthesized compounds was assessed in vitro against Candida albicans and Aspergillus niger using the well plate method. RESULTS: Two of the compounds, OK-7 and OK-8, have been found to show significant docking interaction with target protein 1EA1. These two compounds have also been found to show significant anti-fungal activity against Candida albicans and Aspergillus nigra when compared to the standard fluconazole. The Minimum Inhibitory Concentration (MIC) value of these two compounds has been found to be 50 µg/ml. CONCLUSION: Pyrazole derivatives with -CH3, CH3O-, and -CN groups have been found to be active against tested fungi and can be further explored for their potential as promising anti-fungal agents for applications in the field of medicinal chemistry.

Chronic Caffeine Consumption, Alone or Combined with Agomelatine or Quetiapine, Reduces the Maximum EEG Peak, As Linked to Cortical Neurodegeneration, Ovarian Estrogen Receptor Alpha, and Melatonin Receptor 2.

RATIONALE: Evidence of the effects of chronic caffeine (CAFF)-containing beverages, alone or in combination with agomelatine (AGO) or quetiapine (QUET), on electroencephalography (EEG), which is relevant to cognition, epileptogenesis, and ovarian function, remains lacking. Estrogenic, adenosinergic, and melatonergic signaling is possibly linked to the dynamics of these substances. OBJECTIVES: The brain and ovarian effects of CAFF were compared with those of AGO + CAFF and QUET + CAFF. The implications of estrogenic, adenosinergic, and melatonergic signaling and the brain-ovarian crosstalk were investigated. METHODS: Adult female rats were administered AGO (10 mg/kg), QUET (10 mg/kg), CAFF, AGO + CAFF, or QUET + CAFF, once daily for 8 weeks. EEG, estrous cycle progression, and microstructure of the brain and ovaries were examined. Brain and ovarian 17ß-estradiol (E2), antimullerian hormone (AMH), estrogen receptor alpha (E2Rα), adenosine receptor 2A (A2AR), and melatonin receptor 2 (MT2R) were assessed. RESULTS: CAFF, alone or combined with AGO or QUET, reduced the maximum EEG peak, which was positively linked to ovarian E2Rα, negatively correlated to cortical neurodegeneration and ovarian MT2R, and associated with cystic ovaries. A large corpus luteum emerged with AGO + CAFF and QUET + CAFF, antagonizing the CAFF-mediated increased ovarian A2AR and reduced cortical E2Rα. AGO + CAFF provoked TTP delay and increased ovarian AMH, while QUET + CAFF slowed source EEG frequency to δ range and increased brain E2. CONCLUSIONS: CAFF treatment triggered brain and ovarian derangements partially antagonized with concurrent AGO or QUET administration but with no overt affection of estrus cycle progression. Estrogenic, adenosinergic, and melatonergic signaling and brain-ovarian crosstalk may explain these effects.

An intronless tau class glutathione transferase detoxifies several herbicides in flufenacet-resistant ryegrass.

Resistance to preemergence herbicides, e.g. inhibitors of the biosynthesis of very-long-chain fatty acids (VLCFAs), is evolving in response to increased use of these compounds. Grass weeds such as ryegrasses (Lolium spp.) have accumulated resistance to various herbicide modes of action. Here, an RNA-seq analysis was conducted using 3 ryegrass populations resistant to the VLCFA biosynthesis inhibitor flufenacet to investigate this phenomenon. Besides various transcripts, including putative long noncoding RNAs (lncRNAs), a single putatively functional tau class glutathione transferase (GST) was constitutively differentially expressed. It was further induced by herbicide application. This GST was expressed as a recombinant protein in Escherichia coli along with other GSTs and detoxified flufenacet rapidly in vitro. Detoxification rates of other herbicides tested in vitro were in accordance with cross-resistance patterns previously determined in vivo. A genome-wide GST analysis revealed that the candidate GST was located in a cluster of 3 intronless GSTs. Their intronless nature possibly results from the retroposition of cellular mRNAs followed by tandem duplication and may affect gene expression. The large number of GSTs (≥195) in the genome of rigid ryegrass (Lolium rigidum) compared with other plant organisms is likely a key factor in the ability of this weed to evolve resistance to different herbicide chemistries. However, in the case of flufenacet resistance, a single upregulated GST with high affinity for the substrate flufenacet possibly contributes overproportionally to rapid herbicide detoxification in planta. The regulation of this gene and the role of differentially expressed transcripts, including various putative lncRNAs, require further investigation.

In silico Exploration of a Novel ICMT Inhibitor with More Solubility than Cysmethynil against Membrane Localization of KRAS Mutant in Colorectal Cancer.

BACKGROUND: ICMT (isoprenylcysteine carboxyl methyltransferase) is an enzyme that plays a key role in the post-translational modification of the K-Ras protein. The carboxyl methylation of this protein by ICMT is important for its proper localization and function. Cysmethynil (2-[5-(3-methylphenyl)-l-octyl-lH-indolo-3-yl] acetamide) causes K-Ras mislocalization and interrupts pathways that control cancer cell growth and division through inhibition of ICMT, but its poor water solubility makes it difficult and impractical for clinical use. This indicates that relatively high amounts of cysmethynil would be required to achieve an effective dose, which could result in significant adverse effects in patients. OBJECTIVE: The general objective of this work was to find virtually new compounds that present high solubility in water and are similar to the pharmacological activity of cysmethynil. MATERIALS AND METHODS: Pharmacophore modeling, pharmacophore-based virtual screening, prediction of ADMET properties (absorption, distribution, metabolism, excretion, and toxicity), and water solubility were performed to recover a water-soluble molecule that shares the same chemical characteristics as cysmethynil using Discovery Studio v16.1.0 (DS16.1), SwissADME server, and pkCSM server. RESULTS: In this study, ten pharmacophore model hypotheses were generated by exploiting the characteristics of cysmethynil. The pharmacophore model validated by the set test method was used to screen the "Elite Library®" and "Synergy Library" databases of Asinex. Only 1533 compounds corresponding to all the characteristics of the pharmacophore were retained. Then, the aqueous solubility in water at 25°C of these 1533 compounds was predicted by the Cheng and Merz model. Among these 1533 compounds, two had the optimal water solubility. Finally, the ADMET properties and Log S water solubility by three models (ESOL, Ali, and SILICOS-IT) of the two compounds and cysmethynil were compared, resulting in compound 2 as a potential inhibitor of ICMT. CONCLUSION: According to the results obtained, the identified compound presented a high solubility in water and could be similar to the pharmacological activity of cysmethynil.

Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1.

With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite's lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.