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To achieve malaria eradication, new preventative agents that act differently to front-line treatment drugs are needed. To identify potential chemoprevention starting points we screened a sub-set of the CSIRO Australia Compound Collection for compounds with slow-action in vitro activity against Plasmodium falciparum. This work identified N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines as a new antiplasmodial chemotype (e.g., 1 96 h IC 50 550 nM; 3 96 h IC 50 160 nM) with a different action to delayed-death slow-action drugs. A series of analogues were synthesized from thiotetrazoles and carbomoyl derivatives using Huisgen 1,3,4-oxadiazole synthesis followed by oxidation of the resultant thioethers to target sulfones. Structure activity relationship analysis of analogues identified compounds with potent and selective in vitro activity against drug-sensitive and multi-drug resistant Plasmodium parasites (e.g., 31 and 32 96 h IC 50 <40 nM; SI > 2500). Subsequent studies in mice with compound 1, which had the best microsomal stability of the compounds assessed (T 1/2 >255 min), demonstrated rapid clearance and poor oral in vivo efficacy in a P. berghei murine malaria model. These data indicate that while N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines are a novel class of slow-acting antiplasmodial agents, the further development of this chemotype for malaria chemoprophylaxis will require pharmacokinetic profile improvements., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Katherine Andrews, Tina Skinner-Adams, Oliver Hutt, John Ryan, Andrew Riches reports financial support was provided by National Health and Medical Research Council of Australia. Anjana Rai reports financial support was provided by Griffith University GUIPRS and GUPRS PhD scholarships. Katherine Andrews reports equipment, drugs, or supplies was provided by Australian Red Cross Lifeblood. Katherine Andrews reports writing assistance was provided by Monash Institute of Pharmaceutical Sciences Centre for Drug Candidate Optimisation. Katherine Andrews reports equipment, drugs, or supplies was provided by Compounds Australia, Griffith University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ozanimod (Zeposia ® ), an orally administered sphingosine 1-phosphate (S1P) receptor modulator (S1PRM) that is selective for the S1P 1 and S1P 5 receptor subtypes, is approved in the USA for relapsing forms of multiple sclerosis (RMS). In pivotal phase III clinical trials in patients with RMS, ozanimod significantly reduced annualised relapse rates and the number of new or enlarging T2 lesions and gadolinium-enhancing lesions, and was associated with reduced brain volume loss, compared with interferon (IFN)-β1a. However, there were no significant differences in 3- and 6-month disability progression between the groups. Ozanimod was generally well tolerated, with the most common adverse reactions including upper respiratory tract infection and hepatic transaminase elevation. Efficacy and tolerability were sustained over more than 6 years with continued treatment. S1PRM-related adverse events seen with ozanimod are generally manageable with screening and/or monitoring. Notably, ozanimod does not require first-dose cardiac monitoring in the USA. In conclusion, ozanimod is a valuable once-daily oral disease-modifying therapy that extends the available treatment options for patients with RMS., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Several sphingosine-1-phosphate receptor (S1PR) modulators are available in the US for treating relapsing forms of multiple sclerosis (RMS). Given that these S1PR modulators have similar efficacy and safety, patients may consider the clinical management characteristics of the S1PR modulators when deciding among treatments. However, none of the S1PR modulators is clearly superior in every aspect of clinical management, and for some treatments, clinical management varies based on a patient's comorbid health conditions (e.g., heart conditions [HC])., Objectives: This study aimed to determine which S1PR modulator patients with relapsing-remitting multiple sclerosis (RRMS) would prefer based on clinical management considerations, and to estimate how different clinical management considerations might drive these preferences. Preferences were explored separately for patients with and without comorbid HC., Methods: A multicriteria decision analysis was conducted on S1PR modulators approved to treat RMS: fingolimod, ozanimod, siponimod, and ponesimod. Clinical management preferences of patients with RRMS were elicited in a discrete choice experiment (DCE) in which participants repeatedly chose between hypothetical S1PR modulator profiles based on their clinical management attributes. Attributes included first-dose observations, genotyping, liver function tests, eye examinations, drug-drug interactions, interactions with antidepressants, interactions with foods high in tyramine, and immune system recovery time. Preferences were estimated separately for patients with HC and without HC (noHC). Marginal utilities were calculated from the DCE data for each attribute and level using a mixed logit model. In the multicriteria decision analysis, partial value scores were created by applying the marginal utilities for each attribute and level to the real-world profiles of S1PR modulators. Partial value scores were summed to determine an overall clinical management value score for each S1PR modulator., Results: Four hundred patients with RRMS completed the DCE. Ponesimod had the highest overall value score for patients both without (n = 341) and with (n = 59) HC (noHC: 5.1; HC: 4.0), followed by siponimod (noHC: 4.9; HC: 3.3), fingolimod (noHC: 3.4; HC: 2.8), and ozanimod (noHC: 0.9; HC: 0.8). Overall, immune system recovery time contributed the highest partial value scores (noHC: up to 1.9 points; HC: up to 1.2 points), followed by the number of drug-drug interactions (noHC: up to 1.2 points; HC: up to 1.7 points)., Conclusions: When considering the clinical management of S1PR modulators, the average patient with RRMS is expected to choose a treatment with shorter immune system recovery time and fewer interactions with other drugs. Patients both with and without heart conditions are likely to prefer the clinical management profile of ponesimod over those of siponimod, fingolimod, and ozanimod. This information can help inform recommendations for treating RRMS and facilitate shared decision making between patients and their doctors., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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 (EC 50 ) 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., Competing Interests: The authors declare no conflict of interest.

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC) are chronic immune-mediated diseases which primarily target the intestines. In recent years, the development and regulatory approval of various immunotherapies, both biological agents and small molecules, that target specific pathways of the IBD-associated inflammatory cascade have revolutionized the treatment of IBD. Small molecules offer the advantages of oral administration and short wash-out times. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of ceramide, which exerts its functions after binding to five G-protein-coupled receptors (S1PR1-S1PR5). Concerning IBD, S1P participates in the egress of lymphocytes from the secondary lymphoid tissue and their re-circulation to sites of inflammation, mainly through S1PR1 binding. In addition, this system facilitates the differentiation of T-helper cells towards proinflammatory immunophenotypes. Recently, S1P modulators have offered a valuable addition to the IBD treatment armamentarium. They exert their anti-inflammatory function via sequestration of T cell subsets in the lymphoid tissues and prevention of gut homing. In this review, we revisit the role of the S1P/S1PR axis in the pathogenesis of IBD and discuss efficacy and safety data from clinical trials and real-world reports on the two S1PR modulators, ozanimod and etrasimod, that are currently approved for IBD treatment, and comment on their potential positioning in the IBD day-to-day management. We also present recent data on emerging S1P modulators. Finally, based on the successes and failures of S1PR modulators in IBD, we discuss future avenues of IBD treatments targeting the S1P/S1PR axis., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Pesticides play an important role in the development of agriculture, as they can prevent and control crop diseases and pests, improve crop yield and quality. However, the abuse and improper use of pesticides can lead to negative impacts such as environmental pollution and pest resistance issues. There is an urgent need to develop green, safe, and efficient pesticides. In this work, natural product arecoline was selected as parent structure, a series of arecoline derivatives were designed, synthesized, and systematically investigated antiviral activities against tobacco mosaic virus (TMV). These compounds were found to have good to excellent anti-TMV activities for the first time. The antiviral activities of 4a, 4 h, 4 l, 4p, 6a, 6c, and 6f are higher than that of ningnanmycin. Compounds 4 h (EC 50 value 146 µg/mL) and 4p (EC 50 value 161 µg/mL) with simple structures and excellent activities emerged as new antiviral candidates. We chose 4 h to further investigate the antiviral mechanism, which revealed that it can cause virus fragmentation by acting on the viral coat protein (CP). We further validated this result through molecular docking. These compounds also displayed broad-spectrum fungicidal activities against 8 plant pathogenic fungi. This work lays the theoretical foundation for the application of arecoline derivatives in the agricultural field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The wearing-off phenomenon is a key driver of medication change for patients with Parkinson's disease (PD) treated with levodopa. Common first-line options include increasing the levodopa dose or adding a catechol-O-methyltransferase (COMT) inhibitor, but there are no trials comparing the efficacy of these approaches. We evaluated the effectiveness of adjunct opicapone versus an additional 100 mg levodopa dose in PD patients with early wearing-off using pooled data from 2 randomized studies., Methods: The ADOPTION study program included two similarly designed 4-week, open-label studies conducted in South Korea (NCT04821687) and Europe (NCT04990284). Patients with PD, treated with 3-4 daily doses of levodopa therapy and with signs of early wearing-off were randomized (1:1) to adjunct opicapone 50 mg or an additional dose of levodopa 100 mg. Patient-level data from the two studies were pooled., Results: The adjusted mean [SE] change from baseline to week 4 in absolute OFF time (key endpoint) was - 62.8 min [8.8] in the opicapone group and - 33.8 min [9.0] in the levodopa 100 mg group, the difference significantly favoring opicapone (- 29.0 [- 53.8, - 4.2] min, p = 0.02). Significant differences in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III subscore (- 4.1 with opicapone vs - 2.5 with levodopa 100 mg), also favored opicapone (- 1.7 [- 3.3, - 0.04], p < 0.05). Dyskinesia was the most frequently reported adverse event (opicapone 7.2% vs. levodopa 100 mg 4.2%)., Conclusions: In these short-term trials, introducing adjunct opicapone was more effective at reducing OFF time than adding another 100 mg levodopa dose in PD patients with early signs of wearing-off., (© 2024. The Author(s).)

Neurofibromatosis type 1 (NF1) is a human genetic disorder caused by variants in the NF1 gene. Plexiform neurofibromas, one of many NF1 manifestations, are benign peripheral nerve sheath tumors occurring in up to 50% of NF1 patients. A substantial fraction of NF1 pathogenetic variants are nonsense mutations, which result in the synthesis of truncated non-functional NF1 protein (neurofibromin). To date, no therapeutics have restored neurofibromin expression or addressed the consequences of this protein's absence in NF1 nonsense mutation patients, but nonsense suppression is a potential approach to the problem. Ataluren is a small molecule drug that has been shown to stimulate functional nonsense codon readthrough in several models of nonsense mutation diseases, as well as in Duchenne muscular dystrophy patients. To test ataluren's potential applicability in nonsense mutation NF1 patients, we evaluated its therapeutic effects using three treatment regimens in a previously established NF1 patient-derived (c.2041C > T; p.Arg681X) nonsense mutation mouse model. Collectively, our experiments indicate that: i) ataluren appeared to slow the growth of neurofibromas and alleviate some paralysis phenotypes, ii) female Nf1-nonsense mutation mice manifested more severe paralysis and neurofibroma phenotypes than male mice, iii) ataluren doses with apparent effectiveness were lower in female mice than in male mice, and iv) age factors also influenced ataluren's effectiveness., Competing Interests: Declaration of competing interest A.J. is co-founder, director, consultant and shareholder for PTC Therapeutics Inc. M.J.G. is a consultant for Alembic LLC, Astrocyte Pharmaceuticals, BendIt Technologies, Cerenovus, Imperative Care, Jacob's Institute, Medtronic Neurovascular, Mivi Neurosciences, phenox GMbH, Q'Apel, Route 92 Medical, Scientia, Simcerre, Stryker Neurovascular, Stryker Sustainability Solutions, and Wallaby Medical and shareholder of Imperative Care, InNeuroCo, Galaxy Therapeutics, Kapto, Neurogami and Synchron. M.S.S. is a consultant for Sanofi. All other authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

In the search for new anticancer agents, we synthesized a new series of thiazole derivatives carried on thiadiazole-oxadiazole hybrid. Final compounds ( 5a-5i ) were analyzed via 1 H NMR, 13 C NMR, and HRMS. The pharmacokinetic profile of the targeted compounds was predicted via in silico calculations. Their anticancer properties were determined using MTT method against MCF7 and A549 cell lines. Compounds 5a , 5b and 5c were found more active against MCF7 cells than A549 cells while they were not cytotoxic on L929 healthy cells. Generally, it can be summarized that acetamide moiety has a pivotal role in anticancer activity. For further studies, their aromatase inhibitory activity was evaluated. After determination all these features, the binding modes of the active compounds and the stability and relation of the ligand-enzyme complex were investigated using molecular docking and molecular dynamics simulation studies, respectively. In vitro and in silico studies suggest two important structure-activity relationship (SAR) points that at least one azole ring is essential, and if there is approximately 8.0 ± 0.5 Å distance between the H-bond rich zone of ligand and the heteroaryl ring system of ligand has a major impact on aromatase inhibitory activity. Compounds with small group substitution on thiazole are found potentially may be used for the treatment of anti-breast cancer orally.Communicated by Ramaswamy H. Sarma.

Visceral leishmaniasis (VL), caused by protozoa of the genus Leishmania , remains a significant public health concern due to its potentially lethal nature if untreated. Current chemotherapy options are limited by severe toxicity and drug resistance. Derivatives of 1,2,4-oxadiazole have emerged as promising drug candidates due to their broad biological activity. This study investigated the effects of novel 1,2,4-oxadiazole derivatives ( Ox1 - Ox7 ) on Leishmania infantum , the etiological agent of VL. In silico predictions using SwissADME suggest that these compounds have high oral absorption and good bioavailability. Among them, Ox1 showed the most promise, with higher selectivity against promastigotes and lower cytotoxicity towards L929 fibroblasts and J774.G8 macrophages. Ox1 exhibited selectivity indices of 18.7 and 61.7 against L. infantum promastigotes and amastigotes, respectively, compared to peritoneal macrophages. Ultrastructural analyses revealed severe morphological damage in both parasite forms, leading to cell death. Additionally, Ox1 decreased the mitochondrial membrane potential in promastigotes, as shown by flow cytometry. Molecular docking and dynamic simulations indicated a strong affinity of Ox1 for the L. infantum CYP51 enzyme. Overall, Ox1 is a promising and effective compound against L. infantum .

IL-17, a pro-inflammatory cytokine produced mainly by Th17 cells, is involved in the immune response to fungal and bacterial infections, whereas its aberrant production is associated with autoimmune and inflammatory diseases. IL-17 blocking antibodies like secukinumab (Cosentyx) have been developed and are used to treat conditions like psoriasis, psoriatic arthritis, and ankylosing spondylitis. Recently, the low molecular weight IL-17 inhibitor LY3509754 entered the clinic but was discontinued in Phase 1 due to adverse effects. In this study, we explored the replacements of furazan moiety posing a potential toxicology risk in LY3509754. By exploring replacements such as heterocycles as amide-isosteres as well as α-F-acrylamides, two compounds ( 18 and 26 ) were identified. Both compounds effectively reduced knee swelling in a rat arthritis model. However, early rat and dog toxicity studies revealed adverse findings, preventing their further development and indicating that furazan might not be responsible for the adverse effects of LY3509754.

To find novel inhibitors of α-glucosidase and α-amylase, a series of new carbazole-oxadiazole derivatives (6a-6n) were prepared, and screened for their anti-α-glucosidase and anti-α-amylase effects. Most of the tested derivatives showed different degrees of α-glucosidase and α-amylase inhibitory activity (IC 50 : 21.39 ± 0.69-92.05 ± 1.54 μM, 45.53 ± 1.50-126.14 ± 6.33 μM, respectively) compared to the standard acarbose (IC 50 : 427.00 ± 9.56 μM, 24.68 ± 1.10 μM, respectively). Thereinto, 6c (IC 50  = 21.39 ± 0.69 μM) displayed the most effective anti-α-glucosidase activity and 6e presented the best anti-α-amylase activity with an IC 50 value of 45.53 ± 1.50 μM. Lineweaver-Burk plot analysis suggested that 6c and 6e behaved as mixed α-glucosidase inhibitor and mixed α-amylase inhibitor, respectively. The results of circular dichroism, atomic force microscope, and molecular docking simulation exposed interaction mechanisms between two preferred compounds (6c and 6e) and their corresponding enzymes. Combined with the possible properties of reducing the elevation in postprandial blood glucose, oral activity, positive bioavailability, and low cytotoxicity of 6c and 6e, it could be concluded that the target derivatives may be able to act as lead molecules for the development of new hypoglycemic agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Introduction: Ulcerative colitis is a chronic inflammatory bowel disease, affecting the colorectal mucosae, with a relapsing-remitting course, characterized by the trafficking and gathering of lymphocytes in the inflammatory intestinal mucosa. Sphingosine-1-phosphate (S1P) receptor modulators preventing lymphocytes egress from lymphoid tissues to the active inflammation site is an alternative therapeutic option in this condition., Area Covered: We carried out a comprehensive review of the literature available on Medline, Scopus and Embase regarding the pharmacokinetics of S1P receptor modulators. For each compound, we reviewed the mechanism of action, pharmacokinetic data and efficacy and safety data from phase 3 studies and real-life studies when available., Expert Opinion: S1P receptor modulators, including ozanimod and etrasimod (both currently on the market) as well as VTX002 (under development), are a new class of drugs for the treatment of moderate to severe ulcerative colitis, inducing and maintaining the remission. Due to its pharmacokinetic features, this class of drugs has certain advantages such as an oral administration, a short half-life, a high volume of distribution, and no immunogenicity. On the other hand, there are risks of cardiological and ophthalmological side-effects, as well as drug-drug interactions risk, that require special attention from the healthcare providers.

This review article offers an environmentally benign synthesis of 1,3,4-oxadiazole derivatives, with a focus on sustainable methodologies that have minimal impact on the environment. These derivatives, known for their diverse applications, have conventionally been associated with synthesis methods that utilize hazardous reagents and produce significant waste, thereby raising environmental concerns. The green synthesis of 1,3,4-oxadiazole derivatives employs renewable substrates, nontoxic catalysts, and mild reaction conditions, aiming to minimize the environmental impact. Innovative techniques such as catalyst-based, catalyst-free, electrochemical synthesis, green-solvent-mediated synthesis, grinding, microwave-mediated synthesis, and photosynthesis are implemented, providing benefits in terms of scalability, cost-effectiveness, and ease of purification. This review emphasizes the significance of sustainable methodologies in the synthesis of 1,3,4-oxadiazole and boots for continued exploration in this research domain., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

The gut microbiota is a complex ecosystem, home to hundreds of bacterial species and a vast repository of enzymes capable of metabolising a wide range of pharmaceuticals. Several drugs have been shown to affect negatively the composition and function of the gut microbial ecosystem. Janus Kinase (JAK) inhibitors and Sphingosine-1-phosphate (S1P) receptor modulators are drugs recently approved for inflammatory bowel disease through an immediate release formulation and would potentially benefit from colonic targeted delivery to enhance the local drug concentration at the diseased site. However, their impact on the human gut microbiota and susceptibility to bacterial metabolism remain unexplored. With the use of calorimetric, optical density measurements, and metagenomics next-generation sequencing, we show that JAK inhibitors (tofacitinib citrate, baricitinib, filgotinib) have a minor impact on the composition of the human gut microbiota, while ozanimod exerts a significant antimicrobial effect, leading to a prevalence of the Enterococcus genus and a markedly different metabolic landscape when compared to the untreated microbiota. Moreover, ozanimod, unlike the JAK inhibitors, is the only drug subject to enzymatic degradation by the human gut microbiota sourced from six healthy donors. Overall, given the crucial role of the gut microbiome in health, screening assays to investigate the interaction of drugs with the microbiota should be encouraged for the pharmaceutical industry as a standard in the drug discovery and development process., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Two series of vanillin derivatives containing 1,3,4-oxadiazole and 1,3-thiazolidin-4-one scaffolds were prepared and evaluated for their antifungal activity. The results revealed that compounds 6j (29.73 μg/ml) and 7a (38.15 μg/ml) displayed excellent inhibitory activity against the spore of Fusarium solani . The inhibitory activity of compound 7d (10.53 μg/ml) against the spore of Alternaria solani was more than 42-fold that of vanillin. Compound 7a (37.54 μg/ml) showed better antifungal activity against the spore of B. cinerea than positive controls. The cytotoxicity assay confirmed that compounds 6k , 7a , and 7d showed good selectivity and less toxicity to normal mammalian cells.

Sphingosine-1-phosphate (S1P) receptor (S1PR) agonists, such as fingolimod (FTY720), alleviate nociception in preclinical pain models by either activation (agonism) or inhibition (functional antagonism) of S1PR type-1 (S1PR1). However, the dose-dependence and temporal relationship between reversal of nociception and modulation of S1PR1 signaling has not been systematically investigated. This study examined the relationship between FTY720-induced antinociception and S1PR1 adaptation using a sciatic nerve chronic constriction injury (CCI) model of neuropathic pain in male and female C57Bl/6J mice. Daily injections of FTY720 for 14 days dose-dependently reversed CCI-induced mechanical allodynia without tolerance development, and concomitantly resulted in a dose-dependent reduction of G-protein activation by the S1PR1-selective agonist SEW2871 in the lumbar spinal cord and brain. These findings indicate FTY720-induced desensitization of S1PR1 signaling coincides with its anti-allodynic effects. Consistent with this finding, a single injection of FTY720 reversed mechanical allodynia while concomitantly producing partial desensitization of S1PR1-stimulated G-protein activation in the CNS. However, mechanical allodynia returned 24-hr post injection, despite S1PR1 desensitization at that time, demonstrating a dissociation between these measures. Furthermore, CCI surgery led to elevations of sphingolipid metabolites, including S1P, which were unaffected by daily FTY720 administration, suggesting FTY720 reversed mechanical allodynia by targeting S1PR1 rather than sphingolipid metabolism. Supporting this hypothesis, acute administration of the S1PR1-selective agonist CYM-5442 mimicked the anti-allodynic effect of FTY720. In contrast, the S1PR1-selective antagonist NIBR-0213 prevented the anti-allodynic effect of FTY720, but NIBR-0213 given alone did not affect nociception. These results indicate that FTY720 alleviates CCI-induced allodynia through a mechanism distinct from functional antagonism., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure-activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) has a high status in the development of new inhibitors. To develop novel and highly effective PPO inhibitors, active substructure linking and bioisosterism replacement strategies were used to design and synthesize novel tetrahydrophthalimide derivatives containing oxadiazole/thiadiazole moieties, and their inhibitory effects on Nicotiana tobacco PPO ( Nt PPO) and herbicidal activity were evaluated. Among them, compounds B11 ( K i = 9.05 nM) and B20 ( K i = 10.23 nM) showed significantly better inhibitory activity against Nt PPO than that against flumiclorac-pentyl ( K i = 46.02 nM). Meanwhile, compounds A20 and B20 were 100% effective against three weeds ( Abutilon theophrasti , Amaranthus retroflexus , and Portulaca oleracea ) at 37.5 g a.i./ha. It was worth observing that compound B11 was more than 90% effective against three weeds ( Abutilon theophrasti , Amaranthus retroflexus , and Portulaca oleracea ) at 18.75 and 9.375 g a.i./ha. It was also safer to rice, maize, and wheat than flumiclorac-pentyl at 150 g a.i./ha. In addition, the molecular docking results showed that compound B11 could stably bind to Nt PPO and it had a stronger hydrogen bond with Arg98 (2.9 Å) than that of flumiclorac-pentyl (3.2 Å). This research suggests that compound B11 could be used as a new PPO inhibitor, and it could help control weeds in agricultural production.

The close association between inflammation and cancer inspired the synthesis of a series of 1,3,4-oxadiazole derivatives (compounds H4-A-F) of 6-methoxynaphtalene. The chemical structures of the new compounds were validated utilizing Fourier-transform infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques and CHN analysis. Computer-aided drug design methods were used to predict the compounds biological target, ADMET properties, toxicity, and to evaluate the molecular similarities between the design compounds and erlotinib, a standard epidermal growth factor receptor (EGFR) inhibitor. The antiproliferative effects of the new compounds were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell cycle analysis, apoptosis detection by microscopy, quantitative reverse transcription-polymerase chain reaction, and immunoblotting, and EGFR enzyme inhibition assay. In silico analysis of the new oxadiazole derivatives indicated that these compounds target EGFR, and that compounds H4-A, H4-B, H4-C, and H4-E show similar molecular properties to erlotinib. Additionally, the results indicated that none of the synthesized compounds are carcinogenic, and that compounds H4-A, H4-C, and H4-F are nontoxic. Compound H4-A showed the best-fit score against EGFR pharmacophore model, however, the in vitro studies indicated that compound H4-C was the most cytotoxic. Compound H4-C caused cytotoxicity in HCT-116 colorectal cancer cells by inducing both apoptosis and necrosis. Furthermore, compounds H4-D, H4-C, and H4-B had potent inhibitory effect on EGFR tyrosine kinase that was comparable to erlotinib. The findings of this inquiry offer a basis for further investigation into the differences between the synthesized compounds and erlotinib. However, additional testing will be needed to assess all of these differences and to identify the most promising compound for further research., (© 2024 Wiley Periodicals LLC.)

This study examines the synthesis and evaluation of 11 newly developed compounds as potential anti-Alzheimer's agents that occur via cholinesterase and β-secretase inhibition. The compounds were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using the modified Ellman method. The results showed that several compounds exhibited significant inhibition of AChE, particularly compounds 6d, 7a, and 7e, which demonstrated high inhibitory activity at lower concentrations, with IC 50 values of 0.120, 0.039, and 0.063 µM, respectively. However, the compounds showed limited effectiveness against BChE, with only a few compounds exhibiting moderate inhibition. Compound 7e showed an inhibitory effect against BACE-1 close to that of the standard drug. Structural analysis revealed that the compounds with substituted benzothiazole and thiazole moieties exhibited the most promising inhibitory activity. This study provides valuable insights into the potential of these synthesized derivatives as a treatment against Alzheimer's disease. Moreover, the structure, stability, and properties of the active compounds were further investigated using density functional theory calculations. As a final note, the utilization of molecular docking and molecular dynamics simulation studies allowed us to elucidate the action mechanism of the active compounds and gain insights into the structure-activity relationship against AChE and β-secretase proteins. These computational techniques provide valuable information on the binding modes, interactions with target enzymes, dynamic behavior, and conformational changes of the compounds, enabling a comprehensive understanding of their biological activity., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

To increase the success rate of drug discovery, one practical strategy is to begin molecular hybridisation. The presence of two or more pharmacophores in a single unit leads to a pharmacological potency greater than the sum of each individual moiety's potency. Heterocyclic compounds are very widely distributed in nature and are essential for life activities. Benzimidazole and oxadiazole are privileged structures in medicinal chemistry and are widely used in drug discovery and development due to their vast biological properties. The drug-like properties (like pharmacokinetics and pharmacodynamics) of the individual scaffolds can be improved by benzimidazole-oxadiazole chimeric molecules via a molecular hybridisation approach. Benzimidazole and oxadiazole cores can either be fused or incorporated using either functional groups/bonds. Over the last few decades, drug discovery scientists have predicted that these moieties could be interconnected to yield a novel or modified hybrid compound. Benzimidazole and oxadiazole hybrids were identified as the most potent anticancer, antimicrobial, anti-inflammatory, antioxidant, anticonvulsant, antidepressant, antihypertensive and antitubercular agents. In this context, the present review describes the biological properties of benzimidazole-oxadiazole (1,3,4 and 1,2,4) hybrids, their possible structure-activity relationship and the mechanism of action studies presented. This review article is intended to stimulate fresh ideas in the search for rational designs of more active and less toxic benzimidazole-oxadiazole hybrid prospective therapeutic candidates, as well as more effective diagnostic agents and pathologic probes., (© 2024 John Wiley & Sons Ltd.)

RIPK1 plays a key role in necroptosis and is associated with various inflammatory diseases. Using structure-based virtual screening, a novel hit with 5-(1-benzyl-1H-imidazol-4-yl)-1,2,4-oxadiazole scaffold was identified as an RIPK1 inhibitor with an IC 50 value of 1.3 μM. Further structure-activity relationship study was performed based on similarity research and biological evaluation. The molecular dynamics simulation of compound 2 with RIPK1 indicated that it may act as a type II kinase inhibitor. This study provides a highly efficient way to discover novel scaffold RIPK1 inhibitors for further development., (© 2024 Wiley Periodicals LLC.)

A series of 13 new 3-substituted 5-(5-nitro-2-furyl)-1,2,4-oxadiazoles was synthesized from different aminonitriles. All compounds were screened in the disc diffusion test at a 100 μg/mL concentration to determine the bacterial growth inhibition zone presence and diameter, and then the minimum inhibitory concentrations (MICs) were determined for the most active compounds by serial dilution. The compounds showed antibacterial activity against ESKAPE bacteria, predominantly suppressing the growth of 5 species out of the panel. Some compounds had similar or lower MICs against ESKAPE pathogens compared to ciprofloxacin, nitrofurantoin, and furazidin. In particular, 3-azetidin-3-yl-5-(5-nitro-2-furyl)-1,2,4-oxadiazole ( 2h ) inhibited S. aureus at a concentration lower than all comparators. Compound 2e (5-(5-nitro-2-furyl)-3-[4-(pyrrolidin-3-yloxy)phenyl]-1,2,4-oxadiazole) was active against Gram-positive ESKAPE pathogens as well as M. tuberculosis . Differences in the molecular periphery led to high selectivity for the compounds. The induced-fit docking (IFD) modeling technique was applied to in silico research. Molecular docking results indicated the targeting of compounds against various nitrofuran-associated biological targets.

KKL-35 is a new oxadiazole compound with potent broad-spectrum antibacterial activity against a number of gram-positive and gram-negative bacteria. However, its influences on bacterial growth are unclear. This study is to investigate phenotypic changes of Staphylococcus aureus (SA) caused by KKL-35 and evaluate antibacterial activity of combinations of KKL-35 with 7 class of antibiotics available in medical facilities. KKL-35-treated SA showed significantly lower survival under stresses of NaCl and H 2 O 2 than DMSO (21.03 ± 2.60% vs. 68.21 ± 5.31% for NaCl, 4.91 ± 3.14% vs. 74.78 ± 2.88% for H 2 O 2 ). UV exposure significantly decreased survival of SA treated with KKL-35 than DMSO-treated ones (23.91 ± 0.71% vs. 55.45 ± 4.70% for 4.2 J/m 2 , 12.80 ± 1.03% vs. 31.99 ± 5.99% for 7.0 J/m 2 , 1.52 ± 0.63% vs. 6.49 ± 0.51% for 14.0 J/m 2 ). KKL-35 significantly decreased biofilm formation (0.47 ± 0.12 vs. 1.45 ± 0.21) and bacterial survival in the serum resistance assay (42.27 ± 2.77% vs. 78.31 ± 5.64%) than DMSO. KKL-35 significantly decreased ethidium bromide uptake and efflux, as well as the cell membrane integrity. KKL-35 had low cytotoxicity and low propensity for resistance. KKL-35 inhibited SA growth in concentration-independent and time-dependent manners, and showed additivity when combined with the majority class of available antibiotics. Antibiotic combinations of KKL-35 with ciprofloxacin, rifampicin, or linezolid significantly decreased bacterial loads than the most active antibiotic in the corresponding combination. Thus, KKL-35 inhibits growth of SA by decreasing bacterial environmental adaptations, biofilm formation, membrane uptake and efflux, as well as increasing antibiotic sensitivity. Its potent antibacterial activity, low cytotoxicity, low propensity for resistance, and wide choices in antibiotic combinations make KKL-35 a promising leading compound to design new antibiotics in monotherapies and combination therapies to treat bacterial infections., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chemical agonism of human caseinolytic protease P (HsClpP) is increasingly being recognized as a potential anticancer strategy due to its critical role in maintaining mitochondrial homeostasis. We unveil the discovery of 5-(piperidin-4-yl)-1,2,4-oxadiazole derivatives as a novel class of HsClpP agonists and demonstrate for the first time the application of HsClpP agonists in the treatment of hepatocellular carcinoma (HCC) (Pace, A.; Pierro, P. The new era of 1,2,4-oxadiazoles. Org. Biomol. Chem . 2009, 7 (21), 4337-4348). Compound SL44 exhibited potent HsClpP agonistic activity in the α-casein hydrolysis assay (EC 50 = 1.30 μM) and inhibited the proliferation of HCCLM3 cells (IC 50 = 3.1 μM, 21.4-fold higher than hit ADX-47273). Mechanistically, SL44 induces degradation of respiratory chain complex subunits and leads to apoptosis in HCC cells. In vivo results demonstrated that SL44 has potent tumor growth inhibitory activity and has a superior safety profile compared to the kinase inhibitor sorafenib. Overall, we developed a novel class of HsClpP agonists that can potentially be used for the treatment of HCC.

Herein, we report the synthesis, and characterization of a new series of 1,3,4-oxadiazole and 1,2,4-triazole derivatives based on azaindole acetamides and assigned as potential antibacterial and antitubercular substances. The structures of these compounds were established by 1 H NMR, 13 C NMR, and HRMS spectral analysis. In preliminary antibacterial studies, analogues 6b , 6d , and 6e were found to be most effective against S. aureus with MIC of 12.5, 6.25, and 12.5 μg/mL, whereas 8d displayed excellent activity against S. aureus, B. subtilis, E. coli bacterial strains with zones of inhibition 12.5, 25, and 12.5 μg/mL respectively. Particularly, the prepared scaffolds 8c , 8d , and 8e showed remarkable antifungal activity with MIC value 12.5, 12.5, and 6.25 μg/mL against A. flavus and 6d , 6c producing an increase in the activity against C. Albicans with zones of inhibition 12.5 and 12.5 μg/mL respectively. Also, through the antitubercular studies, we found that compounds 6e and 8b have a strong activity with M. tuberculosis H 37 Rv with MICs 3.26, and 6.48 μg/mL, respectively. The protein stability, fluctuations of APO-Protein, and protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3, and potential lead molecules were identified. Our findings were further confirmed using molecular docking, revealing that azaindole based ligand 6e, 6f, and 8a has strong hydrophobic Tyr179, Trp183, Ile177, Ile445, and H-bondings interactions Arg151 and Arg454 through molecular dynamics simulation studies, making it potential biological compound. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME.Communicated by Ramaswamy H. Sarma.

In our study, a series of novel 4-aminophenol benzamide-1,2,4-oxadiazole hybrid analogues have been designed and synthesized by condensing 4-hydroxyphenyl arylamides (3a-c) and 5-chloromethyl-3-aryl-1,2,4-oxadiazoles (6a-d). The structure of the synthesised compounds was verified by various spectroscopic techniques ( 1 H NMR, 13 C NMR, IR and LC-MS). All the prepared compounds were subjected to in silico and in vitro antiproliferative study against TNBC cell lines MDA-MB-468 and MDA-MB-231. The investigations revealed that compound 7k significantly promoted apoptosis against MDA-MB-468 and MDA-MB-231 cells with IC 50 values of 22.31 µM and 26.27 µM, respectively. Compound 7k interacted with crucial active sites of MAPK and exhibited the highest docking score of -7.06 kcal/mol. Docking was validated with molecular dynamic studies with simulation for 100 ns, depicting various stable interactions with MAPK. Consequently, 7k forms stable H-Bonds and π-π stacking with amino acid residues along with π-cation. Our investigations reveal that the in vitro antiproliferative study of 7k was in good correlation with the in silico studies. Hence, 7k serves as a potential novel lead for the inhibition of TNBCs by downregulating MAPK P38.Communicated by Ramaswamy H. Sarma.

The NAD + -dependent lysine deacylase sirtuin 2 (Sirt2) is involved in multiple pathological conditions such as cancer. Targeting Sirt2 has thus received an increased interest for therapeutic purposes. Furthermore, the orthologue from Schistosoma mansoni ( Sm Sirt2) has been considered for the potential treatment of the neglected tropical disease schistosomiasis. We previously identified a 1,2,4-oxadiazole-based scaffold from the screening of the "Kinetobox" library as a dual inhibitor of human Sirt2 (hSirt2) and Sm Sirt2. Herein, we describe the structure-activity studies on 1,2,4-oxadiazole-based analogues, which are potent inhibitors of human Sirt2 deacetylation. As proposed by docking studies, a substrate-competitive and cofactor-noncompetitive binding mode of inhibition could be determined in vitro via binding assays and kinetic analysis and further confirmed by a crystal structure of an oxadiazole inhibitor in complex with hSirt2. Optimized analogues reduced cell viability and inhibited prostate cancer cell migration, in correlation with Sirt2 deacetylase inhibition both in vitro and in cells.

Papain-like protease (PLpro) is a promising therapeutic target for its pivotal role in the life cycle of SARS-CoV-2. A series of 1,2,4-oxadiazole derivatives was designed and synthesized via a ring formation strategy based on SARS-CoV-2 PLpro-GRL0617 complex structure. Systematic structure-activity relationship studies revealed that introducing oxadiazole and aryl carboxylic acid moieties to GRL0617 enhanced the enzymatic inhibition activity, affinity, and deubiquitination capacity toward PLpro. 1,2,4-Oxadiazole compounds 13f and 26r , which had PLpro inhibition activity (IC 50 = 1.8 and 1.0 μM) and antiviral activity against SARS-CoV-2 (EC 50 = 5.4 and 4.3 μM), exhibited good metabolic stability ( t 1/2 > 93.2 min) and higher plasma exposure (AUC 0-t = 17,380.08 and 24,289.76 ng·h/mL) in mice. Especially, compound 26r with moderate oral bioavailability of 39.1% and potent antiviral activity is worthy of further studies in vivo . Our findings provide a new insight for the discovery of antiviral agents targeting PLpro.

Vector-borne parasitic diseases (VBPDs) pose a significant threat to public health on a global scale. Collectively, Human African Trypanosomiasis (HAT), Leishmaniasis, and Malaria threaten millions of people, particularly in developing countries. Climate change might alter the transmission and spread of VBPDs, leading to a global burden of these diseases. Thus, novel agents are urgently needed to expand therapeutic options and limit the spread of drug-resistant parasites. Herein, we report the development of broad-spectrum antiparasitic agents by screening a known library of antileishmanial and antimalarial compounds toward Trypanosoma brucei ( T. brucei ) and identifying a 1,3,4-oxadiazole derivative ( 19 ) as anti- T. brucei hit with predicted blood-brain barrier permeability. Subsequently, extensive structure-activity-relationship studies around the lipophilic tail of 19 led to a potent antitrypanosomal and antimalarial compound ( 27 ), with moderate potency also toward Leishmania infantum ( L. infantum ) and Leishmania tropica . In addition, we discovered a pan-active antiparasitic molecule ( 24 ), showing low-micromolar IC 50 s toward T. brucei and Leishmania spp. promastigotes and amastigotes, and nanomolar IC 50 against Plasmodium falciparum , together with high selectivity for the parasites over mammalian cells (THP-1). Early ADME-toxicity assays were used to assess the safety profile of the compounds. Overall, we characterized 24 and 27 , bearing the 1,3,4-oxadiazole privileged scaffold, as broad-spectrum low-toxicity agents for the treatment of VBPDs. An alkyne-substituted chemical probe ( 30 ) was synthesized and will be utilized in proteomics experiments aimed at deconvoluting the mechanism of action in the T. brucei parasite.

The eukaryotic initiation factor 2B (eIF2B) is a key regulator in protein-regulated signaling pathways and is closely related to the function of the central nervous system. Modulating eIF2B could retard the process of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and vanishing white matter disease (VWM) et al. Here, we designed and synthesized a series of novel eIF2B activators containing oxadiazole fragments. The activating effects of compounds on eIF2B were investigated through testing the inhibition of ATF4 expression. Of all the targeted compounds, compounds 21 and 29 exhibited potent inhibition on ATF4 expression with IC 50 values of 32.43 nM and 47.71 nM, respectively, which were stronger than that of ISRIB (IC 50 =67.90 nM). ATF4 mRNA assay showed that these two compounds could restore ATF4 mRNA to normal levels in thapsigargin-stimulated HeLa cells. Protein Translation assay showed that both compounds were effective in restoring protein synthesis. Compound potency assay showed that both compounds had similar potency to ISRIB with EC 50 values of 5.844 and 37.70 nM. Cytotoxicity assay revealed that compounds 21 and 29 had low toxicity and were worth further investigation., (© 2024 Wiley-VCH GmbH.)

We report herein, the design and synthesis of benzimidazole-oxadiazole derivatives as new inhibitors for vascular endothelial growth factor receptor-2 (VEGFR-2). The designed members were assessed for their in vitro anticancer activity against three cancer cell lines and two normal cell lines; A549, MCF-7, PANC-1, hTERT-HPNE and CCD-19Lu. Compounds 4c and 4d were found to be the most effective compounds against three cancer cell lines. Compounds 4c and 4d were then tested for their in vitro VEGFR-2 inhibitory activity, safety profiles, and selectivity indices using the normal hTERT-HPNE and CCD-19Lu cell lines. It was determined that compound 4c was the most effective and safe member of the produced chemical family. Vascular endothelial growth factor A (VEGFA) immunolocalizations of compounds 4c and 4d were evaluated relative to control by VEGFA immunofluorescence staining. Compounds 4c and 4d inhibited VEGFR-2 enzyme with half-maximal inhibitory concentration values of 0.475 ± 0.021 and 0.618 ± 0.028 µM, respectively. Molecular docking of the target compounds was carried out in the active site of VEGFR-2 (Protein Data Bank: 4ASD)., (© 2024 The Author(s). Drug Development Research published by Wiley Periodicals LLC.)

The five-membered 1,3,4-oxadiazole heterocyclic ring has received considerable attention because of its unique bio-isosteric properties and an unusually wide spectrum of biological activities. After a century since 1,3,4-oxadiazole was discovered, its uncommon potential attracted medicinal chemist's attention, leading to the discovery of a few presently accessible drugs containing 1,3,4-oxadiazole units, and a large number of patents have been granted on research related to 1,3,4-oxadiazole. It is worth noting that interest in 1,3,4-oxadiazoles' biological applications has doubled in the last few years. Herein, this review presents a comprehensive overview of the recent achievements in the synthesis of 1,3,4-oxadiazole-based compounds and highlights the major advances in their biological applications in the last 10 years, as well as brief remarks on prospects for further development. We hope that researchers across the scientific streams will benefit from the presented review articles for designing their work related to 1,3,4-oxadiazoles., (© 2024 John Wiley & Sons Ltd.)

Introduction: In BIPARK-1 and BIPARK-2, addition of once-daily opicapone to levodopa/carbidopa significantly reduced daily "OFF"-time relative to placebo in adults with Parkinson's disease (PD) and motor fluctuations. Diary data from these studies were pooled and analyzed post hoc to characterize "OFF"-times around nighttime sleep and to explore the effects of opicapone 50 mg., Methods: "OFF" before sleep (OBS), "OFF during the nighttime sleep period" (ODNSP), early morning "OFF" (EMO), and duration of nighttime sleep and awake periods were analyzed descriptively at baseline. Mean changes from baseline to Week 14/15 (end of double-blind treatment) were analyzed using two-sided t-tests in participants with data for both visits., Results: At baseline, 88.3 % (454/514) of participants reported having OBS (34.0 %), ODNSP (17.1 %), or EMO (79.6 %). Those with ODNSP had substantially shorter mean duration of uninterrupted sleep (4.4 h) than the overall pooled population (7.1 h). At Week 14/15, mean decrease from baseline in ODNSP duration was significantly greater with opicapone than with placebo (-0.9 vs. -0.4 h, P < 0.05). In participants with ODNSP at baseline, the decrease in total time spent awake during the night-time sleep period was significantly greater with opicapone than with placebo (-1.0 vs. -0.4 h, P < 0.05), as was the reduction in percent time spent awake during the night-time sleep period (-12.8 % vs. -4.5 %, P < 0.05)., Conclusion: "OFF"-times around nighttime sleep were common in BIPARK-1 and BIPARK-2. Opicapone may improve sleep by decreasing the amount of time spent awake during the night in patients with PD who have night-time sleep period "OFF" episodes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R. A. Hauser has received speaking fees from Acorda, Amneal Pharmaceuticals, Cerevel, Inhibikase, Kyowa Kirin, Neurocrine Biosciences Ltd., Sunovion and Supernus; has received consulting fees from AbbVie Ltd., Acsel Health, Amneal Pharmaceuticals, Avanex Ltd., Biogen Ltd., BlueRock Therapeutics, EPI-Q, Forsee Pharmaceuticals, Global Kinetics, Inhibikase, Jazz Pharmaceuticals Ltd., KeifeRX, Krog and Partners, Kyowa Kirin, Magnolia Innovation, MDCE Suzhou, MedRhythms, Medsphere Ltd., Merz Ltd., Neurocrine Ltd., Neuroderm, Ovid Therapeutics, PD Neurotechnology Ltd., Pharma Two B, Regenxbio, Revance Ltd., Sage Therapeutics Ltd., Scion NeuroStim, Stoparkinson, Sunovion, Supernus Pharmaceuticals, Tolmar, Tremor Research Group, Tris Pharma Ltd., UCB, and Vivifi Biotech Ltd. R. A. Hauser serves on a scientific advisory board for Stoparkinson and Inhibikase. R. A. Hauser holds stock in Revance Therapeutics Ltd. and has stock options in Enterin, Inhibikase, and Axial Therapeutics. R. A. Hauser has received intellectual property interests from a PD Diary through his University. R. A. Hauser acknowledges a Center of Excellence grant from the Parkinson Foundation. R. A. Hauser's University has received research support from Annovis Bio Inc., Artizan Biosciences, Parkinson's & Movement Disorder Alliance, Inhibikase Therapeutics, AbbVie Inc., Aeon Biopharma, Biogen MA, Bukwang Pharmaceutical Co. Ltd., Cavion Inc., Cerevance Inc., Cerevel Therapeutics, Cynapsus Therapeutics, Enterin Inc., Genentech, Global Kinetics Corporation, Hoffman-La Roche Inc., Impax Laboratories, Integrative Research Laboratories Sweden, Lundbeck Inc., Michael J. Fox Foundation for Parkinson's Research, National Parkinson's Foundation, Neuraly Inc., Neurocrine Biosciences, Neuroderm, Pharma Two B Ltd., Revance Therapeutics, Sage Therapeutics, Sanofi Pharmaceuticals, Scion NeuroStim, SunPharma, and UCB BioPharma. A. Videnovic has served as a consultant to Alexion Pharmaceuticals. P. Soares-da-Silva and J. F. Francisco Rocha are employees of BIAL–Portela & C(a) SA. G. Liang, K. Olson, E. Jen, and O. Klepitskaya are employees of Neurocrine Biosciences., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A series of new indole-oxadiazole derivatives was designed and synthesized to develop potential anti-breast cancer agents. The compounds exhibited significant inhibitory activity with IC 50 values ranging from 1.78 to 19.74 μM against ER-positive human breast cancer (BC) cell lines T-47D and MCF-7. Among them, compounds (5a, 5c, 5e-5h, 5j-5o) displayed superior activity against ER-α dominant (ratio of ER-α/ER-β is 9/1) T-47D cells compared to the standard drug bazedoxifene (IC 50  = 12.78 ± 0.92 μM). Compounds 5c and 5o exhibited remarkable anti-proliferative activity with IC 50 values of 3.24 ± 0.46 and 1.72 ± 1.67 μM against T-47D cells, respectively. Further, compound 5o manifested 1589-fold higher ER-α binding affinity (213.4 pM) relative to bazedoxifene (339.2 nM) in a competitive ER-α binding assay, while compound 5c showed a binding affinity of 446.6 nM. The Western blot analysis proved that both compounds influenced the ER-α protein's expression, impeding its subsequent transactivation and signalling pathway within T-47D cells. Additionally, a molecular docking study suggests that compounds 5c and 5o bind in such a fashion that induces conformational changes in the protein, culminating in their antagonistic effect. Also, pharmacokinetic profiles showed that all compounds have drug-like properties. Further, molecular dynamic (MD) simulations and density functional theory (DFT) analysis confirmed the stability, conformational behaviour, reactivity, and biological feasibility of compounds 5c and 5o. In conclusion, based on our findings, compounds 5c and 5o, which exhibit significant ER-α antagonistic activity, can act as potential lead compounds for developing anti-breast cancer agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Selective inhibition of microsomal prostaglandin E 2 synthase-1 (mPGES-1) is implicated as a new therapeutic modality for the development of new-generation anti-inflammatory drugs. Here, we present the discovery of new and potent inhibitors of human mPGES-1, i.e., compounds 13, 15-25, 29-30 with IC 50 values in the range of 5.6-82.3 nM in a cell-free assay of prostaglandin (PG)E 2 formation. We also demonstrate that 20 (TG554, IC 50  = 5.6 nM) suppresses leukotriene (LT) biosynthesis at low µM concentrations, providing a benchmark compound that dually intervenes with inflammatory PGE 2 and LT biosynthesis. Comprehensive lipid mediator (LM) metabololipidomics with activated human monocyte-derived macrophages showed that TG554 selectively inhibits inflammatory PGE 2 formation over all cyclooxygenase (COX)-derived prostanoids, does not cause substrate shunting towards 5-lipoxygenase (5-LOX) pathway, and does not interfere with the biosynthesis of the specialized pro-resolving mediators as observed with COX inhibitors, providing a new chemotype for effective and safer anti-inflammatory drug development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Erden Banoglu reports financial support was provided by Scientific and Technological Research Council of Turkey. Oliver Werz reports financial support was provided by German Research Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Heterocycles are fundamental moieties for the construction of new compounds with perspective applications ranging from drugs to materials [...].

Histone deacetylase 6 (HDAC6) is increasingly recognized for its potential in targeted disease therapy. This study delves into the mechanistic and structural nuances of HDAC6 inhibition by difluoromethyl-1,3,4-oxadiazole (DFMO) derivatives, a class of non-hydroxamic inhibitors with remarkable selectivity and potency. Employing a combination of nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) kinetic experiments, comprehensive enzymatic characterizations, and X-ray crystallography, we dissect the intricate details of the DFMO-HDAC6 interaction dynamics. More specifically, we find that the chemical structure of a DMFO and the binding mode of its difluoroacetylhydrazide derivative are crucial in determining the predominant hydrolysis mechanism. Our findings provide additional insights into two different mechanisms of DFMO hydrolysis, thus contributing to a better understanding of the HDAC6 inhibition by oxadiazoles in disease modulation and therapeutic intervention.

Tobacco mosaic virus (TMV), as one of the most traditional and extensive biological stresses, poses a serious threat to plant growth and development. In this work, a series of 1-phenyl/tertbutyl-5-amino-4-pyrazole oxadiazole and arylhydrazone derivatives was synthesized. Bioassay evaluation demonstrated that the title compounds ( P 1 - P 18 ) without a "thioether bond" lost their anti-TMV activity, while some of the ring-opening arylhydrazone compounds exhibited superior in vivo activity against TMV in tobacco. The EC 50 value of title compound T 8 for curative activity was 139 μg/mL, similar to that of ningnanmycin (NNM) (EC 50 = 152 μg/mL). Safety analysis revealed that compound T 8 had no adverse effects on plant growth or seed germination at a concentration of 250 μg/mL. Morphological observation revealed that compound T 8 could restore the leaf tissue of a TMV-stressed host and the leaf stomatal aperture to normal. A mechanism study further revealed that compound T 8 not only restored the photosynthetic and growth ability of the damaged host to normal levels but also enhanced catalase (CAT) activity and reduced the content of malondialdehyde (MDA) and hydrogen peroxide (H 2 O 2 ) in the damaged host, thereby reducing the oxidation damage to the host. TMV-green fluorescent protein (GFP) experiments further demonstrated that compound T 8 not only slowed the transmission speed of TMV in the host but also inhibited its reproduction. All of the experimental results demonstrated that compound T 8 could reduce the oxidative damage caused by TMV stress and regulate the photosynthetic ability of the host, achieving the ability to repair damage, to make the plant grow normally.

Sarcopenia is a musculoskeletal disease that reduces muscle mass and strength in older individuals. The study investigates the effects of azilsartan (AZL) on skeletal muscle loss in natural sarcopenic rats. Male Sprague-Dawley rats aged 4-6 months and 18-21 months were selected as young-matched control and natural-aged (sarcopenic) rats, respectively. Rats were allocated into young and old control (YC and OC) and young and old AZL treatment (YT and OT) groups, which received vehicles and AZL (8 mg/kg, orally) for 6 weeks. Rats were then sacrificed after muscle function analysis. Serum and gastrocnemius (GN) muscles were isolated for further endpoints. AZL significantly improved muscle grip strength and antioxidant levels in sarcopenic rats. AZL also restored the levels of insulin, testosterone, and muscle biomarkers such as myostatin and creatinine kinase in sarcopenic rats. Furthermore, AZL treatment improved the cellular and ultrastructure of GN muscle and prevented the shift of type II (glycolytic) myofibers to type I (oxidative) myofibers. The results showed that AZL intervention restored protein synthesis in natural sarcopenic rats by increasing p-Akt-1 and decreasing muscle RING-finger protein-1 and tumor necrosis factor alpha immunoexpressions. In conclusion, the present findings showed that AZL could be an effective intervention in treating age-related muscle impairments., Competing Interests: There is no competing interest, as stated by the authors.

This paper describes the in vitro inhibition potential of bisoxadiazole-substituted sulfonamide derivatives (6a-t) against bovine carbonic anhydrase (bCA) after they were designed through computational analyses and evaluated the predicted interaction via molecular docking. First, in silico ADMET predictions and physicochemical property analysis of the compounds provided insights into solubility and permeability, then density functional theory (DFT) calculations were performed to analyse their ionization energies, nucleophilicity, in vitro electron affinity, dipole moments and molecular interactions under vacuum and dimethyl sulfoxide (DMSO) conditions. After calculating the theoretical inhibition constants, IC 50 values determined from enzymatic inhibition were found between 12.93 and 45.77 μM. Molecular docking evaluation revealed favorable hydrogen bonding and π-interactions of the compounds within the bCA active site. The experimentally most active compound, 6p, exhibited the strongest inhibitory activity with a theoretical inhibition constant value of 9.41 nM and H-bonds with Gln91, Thr198, and Trp4 residues and His63 Pi-cation interactions with His63 residues. Overall, the study reveals promising bCA blocking potential for the synthesized derivatives, similar to acetazolamide., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial/commercial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Cyclin-dependent kinase 12 (CDK12)-deficient prostate cancer defines a subtype of castration-resistant prostate cancer (CRPC) with a poor prognosis. Current therapy, including PARP inhibitors, shows minimal treatment efficacy for this subtype of CRPC, and the underlying mechanism remains elusive., Methods: Based on bioinformatics analysis, we evaluated the relationship between CDK12 deficiency and prostate cancer patient's prognosis and treatment resistance. Furthermore, we used CRISPR-Cas9 technology and mass spectrometry-based metabolomic profiling to reveal the metabolic characteristics of CDK12-deficient CRPC. To elucidate the specific mechanisms of CDK12 deficiency-mediated CRPC metabolic reprogramming, we utilized cell RNA-seq profiling and other molecular biology techniques, including cellular reactive oxygen species probes, mitochondrial function assays, ChIP-qPCR and RNA stability analyses, to clarify the role of CDK12 in regulating mitochondrial function and its contribution to ferroptosis. Finally, through in vitro drug sensitivity testing and in vivo experiments in mice, we identified the therapeutic effects of the electron transport chain (ETC) inhibitor IACS-010759 on CDK12-deficient CRPC., Results: CDK12-deficient prostate cancers reprogramme cellular energy metabolism to support their aggressive progression. In particular, CDK12 deficiency enhanced the mitochondrial respiratory chain for electronic transfer and ATP synthesis to create a ferroptosis potential in CRPC cells. However, CDK12 deficiency downregulated ACSL4 expression, which counteracts the lipid oxidation stress, leading to the escape of CRPC cells from ferroptosis. Furthermore, targeting the ETC substantially inhibited the proliferation of CDK12-deficient CRPC cells in vitro and in vivo, suggesting a potential new target for the therapy of CDK12-deficient prostate cancer., Conclusions: Our findings show that energy and lipid metabolism in CDK12-deficient CRPC work together to drive CRPC progression and provide a metabolic insight into the worse prognosis of CDK12-deficient prostate cancer patients., Key Points: CDK12 deficiency promotes castration-resistant prostate cancer (CRPC) progression by reprogramming cellular metabolism. CDK12 deficiency in CRPC leads to a more active mitochondrial electron transport chain (ETC), ensuring efficient cell energy supply. CDK12 phosphorylates RNA Pol II to ensure the transcription of ACSL4 to regulate ferroptosis. Mitochondrial ETC inhibitors exhibit better selectivity for CDK12-deficient CRPC cells, offering a promising new therapeutic approach for this subtype of CRPC patients., (© 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

The article discusses current issues of the treatment of arterial hypertension. According to presented data, so-called therapeutic nihilism is becoming one of the main barriers to achieving target blood pressure (BP). This nihilism is that despite evidence of the effectiveness of achieving lower BP values, practitioners do not intensify antihypertensive therapy sufficiently to achieve such values. The article specially addresses new criteria for the effectiveness of antihypertensive therapy, which reflect the therapy sustainability. The most commonly used indicator is the duration of the period, during which systolic BP remains in the therapeutic range. The prognostic significance of such indicators is discussed. In these conditions, it is very important to use the most effective antihypertensive drugs for initial antihypertensive therapy, including as a part of combination therapy. This tactic provides more frequent achievement of BP goals without the need for dose adjustment. In this regard, a systematic review was performed, which included sufficiently large randomized studies of the antihypertensive effectiveness of azilsartan medoxomil. This systematic review will provide comprehensive information on a possible role of using the angiotensin II receptor blocker azilsartan as a basic drug for the treatment of a wide range of patients with high BP. Most of the studies included in the systematic review assessed the effectiveness of combination therapy including azilsartan.

Antituberculosis drugs, mostly developed over 60 years ago, combined with a poorly effective vaccine, have failed to eradicate tuberculosis. More worryingly, multiresistant strains of Mycobacterium tuberculosis (MTB) are constantly emerging. Innovative strategies are thus urgently needed to improve tuberculosis treatment. Recently, host-directed therapy has emerged as a promising strategy to be used in adjunct with existing or future antibiotics, by improving innate immunity or limiting immunopathology. Here, using high-content imaging, we identified novel 1,2,4-oxadiazole-based compounds, which allow human macrophages to control MTB replication. Genome-wide gene expression analysis revealed that these molecules induced zinc remobilization inside cells, resulting in bacterial zinc intoxication. More importantly, we also demonstrated that, upon treatment with these novel compounds, MTB became even more sensitive to antituberculosis drugs, in vitro and in vivo, in a mouse model of tuberculosis. Manipulation of heavy metal homeostasis holds thus great promise to be exploited to develop host-directed therapeutic interventions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Maure et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Drug-resistant Mycobacterium tuberculosis (Mtb) remains a major public health concern requiring complementary approaches to standard anti-tuberculous regimens. Anti-virulence molecules or compounds that enhance the activity of antimicrobial prodrugs are promising alternatives to conventional antibiotics. Exploiting host cell-based drug discovery, we identified an oxadiazole compound (S3) that blocks the ESX-1 secretion system, a major virulence factor of Mtb. S3-treated mycobacteria showed impaired intracellular growth and a reduced ability to lyse macrophages. RNA sequencing experiments of drug-exposed bacteria revealed strong upregulation of a distinct set of genes including ethA, encoding a monooxygenase activating the anti-tuberculous prodrug ethionamide. Accordingly, we found a strong ethionamide boosting effect in S3-treated Mtb. Extensive structure-activity relationship experiments revealed that anti-virulence and ethionamide-boosting activity can be uncoupled by chemical modification of the primary hit molecule. To conclude, this series of dual-active oxadiazole compounds targets Mtb via two distinct mechanisms of action., Competing Interests: Declaration of interests R.G., J.C., and J.R. have a patent pending related to this work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Inspired by our earlier findings regarding neuraminidase (NA) inhibitors interacting with 150-cavity or 430-cavity of NA, sixteen novel polyheterocyclic NA inhibitors with 1,3,4-oxadiazole thioetheramide as core backbone were designed and synthesized based on the lead compound ZINC13401480. Of the synthesized compounds, compound N5 targeting 150-cavity exerts the best inhibitory activity against the wild-type H5N1 NA, with IC 50 value of 0.14 μM, which is superior to oseltamivir carboxylate (OSC) (IC 50  = 0.31 μM). Compound N10 targeting 430-cavity exhibits the best activity against the H5N1-H274Y mutant NA. Although the activity of N10 is comparable to that of OSC for wild-type H5N1 inhibition, it is approximately 60-fold more potent than OSC against the H274Y mutant, suggesting that it is not easy for the virus to develop drug resistance and is attractive for drug development. N10 (EC 50  = 0.11 μM) also exhibits excellent antiviral activity against H5N1, which is superior to the positive control OSC (EC 50  = 1.47 μM). Molecular docking study shows that the occupation of aromatic fused rings and oxadiazole moiety at the active site and the extension of the substituted phenyl to the 150-cavity or 430-cavity make great contributions to the good potency of this series of polyheterocyclic NA inhibitors. Some advancements in the discovery of effective target-specific NA inhibitors in this study may offer some assistance in the development of more potent anti-influenza drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

NS9283, 3-(3-pyridyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole, is a selective positive allosteric modulator of (α4) 3 (β2) 2 nicotinic acetylcholine receptors (nAChRs). It has good subtype selective therapeutic potential afforded by its specific binding to the unique α4-α4 subunit interface present in the (α4) 3 (β2) 2 nAChR. However, there is currently a lack of structure activity relationship (SAR) studies aimed at developing a class of congeners endowed with the same profile of activity that can help consolidate the druggability of the α4-α4 subunit interface. In this study, new NS9283 analogues were designed, synthesized, and characterized for their ability to selectively potentiate the ACh activity at heterologous (α4) 3 (β2) 2 nAChRs vs nAChR subtypes (α4) 2 (β2) 3 , α5α4β2, and α7. With few exceptions, all the NS9283 analogues exerted positive modulation of the (α4) 3 (β2) 2 nAChR ACh-evoked responses. Above all, those modified at the 3-cyanophenyl moiety by replacement with 3-nitrophenyl ( 4 ), 4-cyanophenyl ( 10 ), and N -formyl-4-piperidinyl ( 20 ) showed the same efficacy as NS9283, although with lower potency. Molecular dynamics simulations of NS9283 and some selected analogues highlighted consistency between potentiation activity and pose of the ligand inside the α4-α4 site with the main interaction being with the complementary (-) side and induction of a significant conformational change of the Trp156 residue in the principal (+) side.

Hepatocellular carcinoma (HCC) is a major challenge for human healthy. Daphnane-type diterpenes have attracted increasingly attention due to remarkable pharmaceutical potential including anti-HCC activity. To further develop this class of compounds as inhibitors of HCC, the daphnane diterpenoids 12-O-debenzoyl-Yuanhuacine (YHC) and 12-hydroxydaphnetoxin (YHE) were prepared by a standard chemical transformation from dried flower buds of the Daphne genkwa plant. Subsequently, 22 daphnane diterpenoidal 1,3,4-oxdiazole derivatives were rationally designed and synthesized based on YHC and YHE. The assessment of the target compound's anti-hepatocellular carcinoma activity revealed that YHC1 exhibited comparable activity to sorafenib in the Hep3B cell line, while demonstrating higher selectivity. The mechanistic investigation demonstrates that compound YHC1 induces cell cycle arrest at the G0/G1 phase, cellular senescence, apoptosis, and elevates cellular reactive oxygen species levels. Moreover, molecular docking and CETSA results confirm the interaction between YHC1 and YAP1 as well as TEAD1. Co-IP experiments further validated that YHC1 can effectively inhibit the binding of YAP1 and TEAD1. In conclusion, YHC1 selectively targets YAP1 and TEAD1, exhibiting its anti-hepatocellular carcinoma effects through the inhibition of their interaction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Biothiol-activatable prodrug RK-296 was designed for the delivery of potent anti-cancer agent NBDHEX with concomitant turn-on near infrared (NIR) fluorescence. NBDHEX exhibits anti-cancer activity by selectively inhibiting glutathione- S -transferase pi (GSTP1), which is overexpressed in cancer cells and responsible for the inactivation of chemotherapeutic drugs. The sustained release of NBDHEX from the prodrug would be useful for ameliorating the off-target side-effects of NBDHEX.