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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.)

Azo-incorporating was reported to be an effective strategy for increasing SDH inhibitory activity but for poor in vivo control effects. Herein, the azo-incorporated compounds were structurally optimized to retain a preferential conformation by replacing the azo bond with their bioisosteres. Interestingly, the 1,2,4-oxadiazole compound D2 displayed a broad fungicidal spectrum as well as fluxapyroxad. More excitedly, compound D2 showed excellent antifungal activities against rice sheath blight disease both in vitro (EC 50 = 0.001 μg/mL) and in vivo (EC 50 = 1.08 μg/mL, EC 95 = 4.67 μg/mL). In addition, an extra π-π interaction was found between the 1,2,4-oxadiazole ring of compound D2 and the phenyl ring of residue D&#95;Y586, which might interpret the enhanced potency of compound D2 against Rhizoctonia solani . Further structural optimizations of the 1,2,4-oxadiazole compounds gave several analogues that made a breakthrough in controlling rice blast disease. These 1,2,4-oxadiazole compounds, derived from azobenzene derivatives, could be antifungal leads especially against R. solani and Magnaporthe grisea , exemplifying an interesting mode of pesticide discovery and providing theoretical guidance for innovation of the SDHI fungicide.

In recent years, isoxazole insecticides or parasiticides targeting the γ-aminobutyric acid receptor, such as fluralaner or fluxametamide, featured a novel chemical structure and exhibited potent insecticidal activity with no-cross resistance. Thus, many research institutes have tried to modify the structures of these agents to find a new insecticide. Previously, the majority of researchers stuck to the "phenyl-isoxazole-phenyl" structure, making modifications only to other components. In this study, the "phenyl-isoxazole-phenyl" ternary motif was modified for the first time based on bioisosterism theory. A series of new derivatives carrying pyrazoline and 1,3,4-oxadiazole moieties were designed and synthesized to investigate their insecticidal activities against the diamondback moth ( Plutella xylostella ) and fall armyworm ( Spodoptera frugiperda ). Preliminary bioassay data showed that some of the target compounds exhibited good insecticidal activities against P. xylostella and S. frugiperda . Especially, compound A21 showed insecticidal activity against P. xylostella (LC 50 = 1.2 μg/mL) better than commercial insecticide ethiprole (LC 50 = 2.9 μg/mL) but worse than parasiticide fluralaner (LC 50 = 0.5 μg/mL). Similarly, compound A21 exhibited insecticidal activity to S. frugiperda (LC 50 = 13.2 μg/mL) better than commercial insecticide fipronil (LC 50 = 78.8 μg/mL) but worse than fluralaner (LC 50 = 0.7 μg/mL). Compound A21 could serve as a potential lead compound to control P. xylostella and S. frugiperda . The three-dimensional quantitative structure-activity relationship model revealed that the further introduction of an electron-donating group in the 2- or 3-site may increase the insecticidal activity of A21 . Molecular dynamics simulations showed that the hydrogen bond of A21 and receptor was important for the binding receptor. This study has identified a new substructure called "phenyl-pyrroline-oxadiazole" instead of the previously known "phenyl-isoxazole-phenyl" substructure, offering a useful guide for the design of novel insecticide molecules.

Nitrogen-containing heterocycles are present in most approved drugs, reflecting the significance of their synthetic strategies. By utilizing oxadiazolone as a nitrenoid (nitrene-like) precursor, we have developed a general strategy for the annulation with nucleophilic heterocycles to access various polycyclic aminoheterocycles. We have discovered that 2-pyrryl-substituted substrates undergo a rearrangement, which indicates a spirocyclization-migration pathway. Given their fluorescence and biological activity as kinase hinge binders, these fragment-like aminoheterocycles represent potential starting points for applications in chemical biology and drug discovery.

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.

Photoaffinity labeling is a widely used technique for studying ligand-protein and protein-protein interactions. Traditional photoaffinity labels utilize nonspecific C-H bond insertion reactions mediated by a highly reactive intermediate. Despite being the most widely used photoaffinity labels, diazirines exhibit limited compatibility with downstream organic reactions and suffer from storage stability concerns. This study introduces oxadiazolines as innovative and complementary photoactivatable labels for addition to the toolbox and demonstrates their application in vitro and through in cellulo labeling experiments. Oxadiazolines can be easily synthesized from ketone moieties and cleaved with 302-330 nm light to cleanly liberate a diazo reactive moiety that can covalently modify nucleophilic amino acid residues. Notably, oxadiazolines are compatible with various organic reaction conditions and functional groups, allowing for the exploration of a large chemical space. Several known inhibitors featuring the oxadiazoline functionality were prepared without affecting their binding affinity. Furthermore, we confirmed the ability of oxadiazolines to form covalent bonds with proteins upon UV-irradiation, both in vitro and in cellulo , yielding comparable results to those of the matched diazirine compounds.

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.)

In this study, six different donor-π-acceptor 1 -π-donor-acceptor 2 type random co-polymers containing benzodithiophene as a donor, benzooxadiazole (BO), and thieno[3,4-c]pyrrole-4,6-dione (TPD) as acceptor, have been synthesized and characterized. In addition to the acceptor core ratio at different values, the effect of aromatic bridge structures on the optical, electronic, and photovoltaic properties of six different random co-polymers is investigated by using thiophene and selenophene structures as aromatic bridge units. To investigate how the acceptor unit ratio and replacement of aromatic bridge units impact the structural, electronic, and optical properties of the polymers, density functional theory (DFT) calculations are carried out for the tetramer models. The open-circuit voltage (V OC ), which is strongly correlated with the HOMO levels of the donor material, is enhanced with the increasing ratio of the TPD moiety. On the other hand, the short-circuit current (J SC ), which is associated with the absorption ability of the donor material, is improved by the increasing ratio of BO moiety with the π-bridges. BO moiety dominant selenophene π-bridged co-polymer (P 4 ) showed the best performance with a power conversion efficiency (PCE) of 6.26%, a J SC of 11.44 mA cm 2 , a V OC of 0.80 V, and a fill factor (FF) of 68.81%., (© 2024 The Author(s). Macromolecular Rapid Communications published by Wiley‐VCH GmbH.)

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.

Tioxazafen (TXF) is the first 1,2,4-oxadiazole nematicide. In the present study, the aqueous degradation of TXF was investigated in terms of hydrolysis and photolysis. Under the irradiation of simulated sunlight, TXF degraded very fast in ultrapure water and buffers with half-lives (t 1/2 s) <8.3 min. A sole photoproduct (PP) PP228a was isolated, and identified by spectroscopic means (UV, IR, HRMS, and 1 H NMR) to be the thiophen-3-yl isomer converted from its thiophen-2-yl parent. Comparing with TXF, PP228a had quite extended t 1/2 s ranging from 6.9 to 7.9 d. The photolysis kinetics of TXF and PP228a showed no pH-dependence, and varied for each individual compound as affected by nitrate, fulvic acid, and humic acid. Besides, both compounds were hydrolytically stable. 6 PPs of PP228a were identified, with two of them being its isomers. The mechanisms involved in the process included the biradical photosensitization, photoinduced electron transfer, and ring contraction-ring expansion reactions. The 48 h-EC 50 to Daphnia magna was 0.808 mg/L for PP228a comparing to >1.12 mg/L for TXF, while the results of Vibrio fischeri assays indicated that one or more PPs of PP228a might have higher toxicity., 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 B.V. All rights reserved.)

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.)

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.)

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.

Dinophysistoxin 1 (DTX1, 1) and okadaic acid (OA, 2), produced by the dinoflagellates Dinophysis spp. and Prorocentrum spp., are primary diarrhetic shellfish toxins (DSTs), which may cause gastric illness in people consuming such as bivalves. Both compounds convert to dinophysistoxin 3 (DTX3, 3; generic name for 1 and 2 with fatty acids conjugated at 7-OH) in bivalves. The enzyme okadaic acid O-acyl transferase (OOAT) is a membrane protein found in the microsomes of the digestive glands of bivalves. In this study, we established an in vitro enzymatic conversion reaction using 4-nitro-2,1,3-benzoxadiazole (NBD)-OA (4), an OA derivative conjugated with (R)-(-)-4-nitro-7-(3-aminopyrrolidin-1-yl)-2,1,3-benzoxadiazole (NBD-APy) on 1-CO2H, as a substrate. We detected the enzymatically produced 3, NBD-7-O-palmitoyl-OA (NBD-Pal-OA), using high-performance liquid chromatography-fluorescence detection. We believe that an OOAT assay using 4 will facilitate the fractionation and isolation of OOAT in the future., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

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.

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.

The design and radiosynthesis of [ 18 F]NT376, a high potency inhibitor of class-IIa histone deacetylases (HDAC) is reported. We utilized a three-step radiochemical approach that led to the radiosynthesis of [ 18 F]NT376 in a good radiochemical yield, (17.0 ± 3%, decay corrected), high radiochemical purity (> 97%) and relatively high molar activity of 185.0 GBq/µmol (> 5.0 Ci/µmol). The repositioning of the 18 F-radiolabel into a phenyl ring ( 18 F-Fluoro-aryl) of the class-IIa HDAC inhibitor avoided the shortcomings of the direct radiolabeling of the 5-trifluoromethyl-1,2,4-oxadiazole moiety that was reported by us previously and was associated with low molar activity (0.74-1.51 GBq/µmol, 20-41 mCi/µmol). This radiochemical approach could find a wider application for radiolabeling similar molecules with good radiochemical yield and high molar activity., (© 2024. The Author(s).)

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.)

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.

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.)

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.)

An unparalleled copper(I)-catalyzed synthesis of 1,3,4-oxadiazoles from tertiary amines in one step has been described. The one-pot reactions involving (N-isocyanimine)triphenylphosphorane, tertiary amines, and carboxylic acids resulted in the formation of 1,3,4-oxadiazoles in moderate to good yields through a consecutive oxidative Ugi/aza-Wittig reaction, enabling the direct functionalization of sp 3 C-H bonds adjacent to the nitrogen atom. This method offered several notable advantages, including ligands-free, exceptional productivity and a high functional group tolerance. The preliminary biological evaluation demonstrated that compound 4f inhibited hepatoma cells efficiently, suggesting potentially broad applications of the approach for synthesis and medicinal chemistry.

A new class of chiral pyranone fused indole derivatives were prepared by means of N-heterocyclic carbene (NHC) organocatalysis and demonstrated notable antibacterial activity against Xanthomonas oryzae pv oryzae (Xoo) . Bioassays showed that compounds (3 S, 4 R )- 5b , (3 S, 4 R )- 5d , and (3 S, 4 R )- 5l exhibited promising in vitro efficacy against Xoo , with EC 50 values of 9.05, 9.71, and 5.84 mg/L, respectively, which were superior to that of the positive controls with commercial antibacterial agents, bismerthiazol (BT, EC 50 = 27.8 mg/L) and thiodiazole copper (TC, EC 50 = 70.1 mg/L). Furthermore, single enantiomer (3 S, 4 R )- 5l was identified as an optimal structure displaying 55.3% and 52.0% curative and protective activities against Xoo in vivo tests at a concentration of 200 mg/L, which slightly surpassed the positive control with TC (curative and protective activities of 47.2% and 48.8%, respectively). Mechanistic studies through molecular docking analysis revealed preliminary insights into the distinct anti- Xoo activity of the two single enantiomers (3 S, 4 R )- 5l and (3 R, 4 S )- 5l , wherein the (3 S, 4 R )-configured stereoisomer could form a more stable interaction with Xoo DHPS (dihydropteroate synthase). These findings underscore the significant anti- Xoo potential of these chiral pyranone fused indole derivatives, and shall inspire further exploration as promising lead structures for a novel class of bactericides to combat bacterial infections and other plant diseases.

Background: Phytopathogens cause various diseases by parasitizing crops, reducing crop yield and resulting in substantial economic losses in agricultural production. A novel type isolated from the perennial herbaceous Peganum harmala L. seeds, β-carboline alkaloids pegaharine A (PA), has become a hot topic in developing plant-originated green pesticides owing to their significant physiological activities., Results: A scalable bioinspired total synthesis of PA is accomplished in the present work. The systematical biological assay study showed that PA exhibited moderate inhibitory activity against nine tested plant pathogenic fungi and showed significant inhibitory activity in vitro against the three tested plant pathogenic bacteria. Most noteworthy is the inhibitory rates of PA on Xanthomonas oryzae pv. oryzae (Xoo), X. oryzae pv. oryzicola (Xoc) and X. axonopodis pv. citri (Xac) of 93.6%, 92.1% and 86.1%, respectively, which are better than the control drug, bismerthiazol (63.4%, 61.2% and 53.7% at 100 μg mL -1 concentration). Furthermore, the EC 50 value of PA against Xoo, Xoc and Xac was 52.2, 60.0 and 65.1 μg mL -1 , respectively, superior to 72.9, 64.2 and 70.1 μg mL -1 of the control drug. Moreover, the anti-Xoo mechanistic studies revealed that PA exerted its antibacterial effects by increasing the permeability of the bacterial membrane, reducing the extracellular polysaccharide content and inducing morphological changes in bacterial cells., Conclusion: A novel β-carboline alkaloid, PA, was prepared by biomimetic total synthesis. Its significant antibacterial activity was closely related to the permeation of bacterial cell membranes, which was confirmed by anti-Xoo mechanistic studies. More importantly, the structure could be regarded as a model for developing novel bactericides. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

3,5-Dinitrobenzylsulfanyl tetrazoles and 1,3,4-oxadiazoles, previously identified as having high in vitro activities against both replicating and nonreplicating mycobacteria and favorable cytotoxicity and genotoxicity profiles were investigated. First we demonstrated that these compounds act in a deazaflavin-dependent nitroreduction pathway and thus require a nitro group for their activity. Second, we confirmed the necessity of both nitro groups for antimycobacterial activity through extensive structure-activity relationship studies using 32 structural types of analogues, each in a five-membered series. Only the analogues with shifted nitro groups, namely, 2,5-dinitrobenzylsulfanyl oxadiazoles and tetrazoles, maintained high antimycobacterial activity but in this case mainly as a result of DprE1 inhibition. However, these analogues also showed increased toxicity to the mammalian cell line. Thus, both nitro groups in 3,5-dinitrobenzylsulfanyl-containing antimycobacterial agents remain essential for their high efficacy, and further efforts should be directed at finding ways to address the possible toxicity and solubility issues, for example, by targeted delivery.

Diabetes mellitus is one of the biggest challenges for the scientific community in the 21st century. With the increasing number of cases of diabetes and drug-resistant diabetes, there is an urgent need to develop new potent molecules capable of combating this cruel disease. Medicinal chemistry concerns the discovery, development, identification, and interpretation of the mode of action of biologically active compounds at the molecular level. Oxadiazole-based derivatives have come up as a potential option for antidiabetic drug research. Oxadiazole is a five-membered heterocyclic organic compound containing two nitrogen atoms and one oxygen atom in its ring. Oxadiazole hybrids have shown the ability to improve glucose tolerance, enhance insulin sensitivity, and reduce fasting blood glucose levels. The mechanisms underlying the antidiabetic effects of oxadiazole involve the modulation of molecular targets such as peroxisome proliferator-activated receptor gamma (PPARγ), α-glucosidase, α-amylase and GSK-3β which regulate glucose metabolism and insulin secretion. The present review article describes the chemical structure and properties of oxadiazoles and highlights the antidiabetic activity through action on different targets. The SAR for the oxadiazole hybrids has been discussed in this article, which will pave the way for the design and development of new 1,3,4-oxadiazole derivatives as promising antidiabetic agents in the future. We expect that this article will provide comprehensive knowledge and current innovation on oxadiazole derivatives with antidiabetic potential and will fulfil the needs of the scientific community in designing and developing efficacious antidiabetic agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Oxadiazoles, especially 1,3,4-oxadiazole scaffolds, stand among the foremost heterocyclic fragments with a broad spectrum of applications in diverse fields, including pharmacology, polymers, material science, and organic electronics, among others. In this comprehensive review, we summarize the pivotal synthetic strategies for 1,3,4-oxadiazole derivatives including dehydrogenative cyclization of 1,2-diacylhydrazines, oxidative cyclization of acylhydrazones, condensation cyclization, C-H activation of oxadiazole ring, decarboxylative cyclization and oxidative annulation along with plausible mechanisms. The set of 1,3,4-oxadiazoles selected from the literature and discussed herein epitomize the ease of synthesis as well as the possibility of linking π-conjugated groups; thereby encouraging the use of these molecules as important starting building blocks for a wide variety of fluorescent frameworks, particularly in the development of potential chemosensors. High photoluminescent quantum yield, excellent thermal and chemical stability, and the presence of potential coordination (N and O donor atoms) sites make these molecules a prominent choice for metal-ions sensors. An overview of selective metal-ion sensing, the detection limit along with the sensing mechanisms (photo-induced electron transfer, excited-state intramolecular proton transfer, and complex formation) is also included.

Oxadiazoles and thiadiazoles are malleable heterocycles that have recently generated major interest in the field of medicinal chemistry. Compounds based on these moieties have versatile biological applications such as anticonvulsant, anticancer, antidiabetic, and antioxidant agents. Due to the versatile nature and stability of the oxadiazole and thiadiazole nucleus, medicinal chemists have changed the structural elements of the ring in numerous ways. These compounds have shown significant anticonvulsant effects, demonstrating their potential in the management of epileptic disorders. In this review, we have covered numerous biological pathways and in silico targeted proteins of oxadiazole and thiadiazole derivatives for treating various biological disorders. The data compiled in this article will be helpful for researchers, research scientists, and research chemists who work in the field of drug discovery and drug development., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

1, 3, 4-oxadiazole and its derivatives have significant anti-inflammatory and antimicrobial property. Their precise mechanism of action is not known but it is postulated that they act by inhibiting the biosynthesis of certain prostaglandins. 1, 3, 4-oxadiazoles are a class of heterocyclic compounds with wide variety of biological and pharmacological activities. They have been reported to possess analgesic, antimicrobial, antipyretic and anti-inflammatory properties. These compounds are also active against a number of other inflammatory conditions such as arthritis, gout etc. A wide variety of these compounds have been synthesized and some of them are under clinical trials. In this review article, anti-inflammatory and antimicrobial activity of the 1, 3, 4- oxadiazole shall be discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Non-Hodgkin lymphoma of B cell origin is the common type of lymphoma- related malignancy with poor response rate with conventional front-line therapies., Aim: The aim of the present study was to investigate the potential of new anti-inflammatory oxadiazole derivatives of Diclofenac as an anti-lymphoma agent through in vitro and in silico approaches., Methods: Anti-lymphoma potential was evaluated by alamar blue technique. MTT assay employed for cytotoxicity. Gene and protein expression studies was performed by qRT-PCR and ELISA respectively. Docking studies was performed by using MOE program., Results: Among five diclofenac derivatives, (II) showed promising anti-lymphoma effects, where it inhibited the expression of BCL-2, p-38 MAPK and TGF-β in both follicular and Burkitt's lymphoma cells and was non-toxic against normal human fibroblast cells. The in silico studies against BCL-2 revealed that the unsubstituted Sulphur group in (II) is involved in the crucial interactions with the binding site residue., Conclusion: The compound (II) can be a potential therapeutic candidate for B-cell non-Hodgkin lymphoma and deserves further development as a novel anti-lymphoma agent., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: BCRP plays a major role in the efflux of cytotoxic molecules, limiting their antiproliferative activity. We aimed to design and synthesize new BCRP inhibitors to render cancerous tumors more sensitive toward anticancer agents. Materials & methods: Based on our previous work, we conceived potential BCRP inhibitors derived from 1,3,4-oxadiazoles bearing two substituted phenyl rings. Results: Evaluating 19 derivatives, we found that 2,5-diaryl-1,3,4-oxadiazoles possessing methoxy groups were the most active. The highest activity was recorded with derivatives bearing three methoxy groups. The most active compound ( 3j ) was selective in inhibiting BCRP and nontoxic as evidenced by cellular tests. Conclusion: 3j is a promising BCRP inhibitor thanks to its synthetic accessibility and biological profile.