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Inhibition of α-glucosidase and -amylase are key tactics for managing blood glucose levels. Currently, stronger, and more accessible inhibitors are needed to treat diabetes. Indeno[1,2- ] quinoxalines-carrying thiazole hybrids were created and described using NMR. All analogues were tested for hypoglycaemic effect against STZ-induced diabetes in mice. Compounds , , , and were the most potent among the synthesised analogues. These hybrids were examined for their effects on plasma insulin, urea, creatinine, GSH, MDA, ALT, AST, and total cholesterol. Moreover, these compounds were tested against -glucosidase and -amylase enzymes . The four hybrids , , , and represented moderate to potent activity with IC values 0.982 ± 0.04, to 10.19 ± 0.21 for -glucosidase inhibition and 17.58 ± 0.74 to 121.6 ± 5.14 μM for -amylase inhibition when compared to the standard medication acarbose with IC =0.316 ± 0.02 μM for -glucosidase inhibition and 31.56 ± 1.33 μM for -amylase inhibition. Docking studies as well as ADMT were done.

The first outbreak in Wuhan, China, in December 2019 was reported about severe acute coronaviral syndrome 2 (SARS-CoV-2). The global coronavirus disease 2019 (COVID-19) pandemic in 2020 resulted in an extremely high potential for dissemination. No drugs are validated in large-scale studies for significant effectiveness in the clinical treatment of COVID-19 patients, despite the worsening trends of COVID-19. This study aims to design a simple and efficient cyclo-condensation reaction of 6-aminouracil derivatives 2a–e and isatin derivatives 1a–c to synthesize spiro-oxindoles 3a–d, 4a–e, and 5a–e. All compounds were tested in vitro against the SARS-CoV-2. Four spiro[indoline-3,5′-pyrido[2,3-d:6,5-d’]dipyrimidine derivatives 3a, 4b, 4d, and 4e showed high activities against the SARS-CoV-2 in plaque reduction assay and were subjected to further RNA-dependent-RNA-polymerase (RdRp) and spike glycoprotein inhibition assay investigations. The four compounds exhibited potent inhibitory activity ranging from 40.23 ± 0.09 to 44.90 ± 0.08 nM and 40.27 ± 0.17 to 44.83 ± 0.16 nM, respectively, when compared with chloroquine as a reference standard, which showed 45 ± 0.02 and 45 ± 0.06 nM against RdRp and spike glycoprotein, respectively. The computational study involving the docking studies of the binding mode inside two proteins ((RdRp) (PDB: 6m71), and (SGp) (PDB: 6VXX)) and geometrical optimization used to generate some molecular parameters were performed for the most active hybrids.

Due to their various pharmacological effects, several substituted sulphur heterocycles containing thiophene have recently attracted a great deal of attention. A novel 2,3-diaryl-2,3,5,6,7,8-hexahydro-4 -benzo[4,5]thieno[3,2- ][1,3]oxazin-4-one was synthesised starting from cyclohexa[ ]thiophene. Compounds and showed the greatest gene expression downregulation of BAX by 75.1% and 79.7%, and upregulation of Bcl-2 gene expression by 8.1 folds for each. It also decreased the level of AChE by 70.2 and 75%; respectively. Compounds and significantly increased Wnt3a levels by 5.8 and 6.6 folds, and β-Catenin levels by 10.1 and 10.5 folds, respectively, compared to donepezil. They significantly downregulated 5-GSK3β gene expression by 77.1%, and 78.7%, respectively. Even though all compounds exhibited potent inhibition of AChE, all synthesised compounds, except for compounds and demonstrated higher selectivity towards BChE (SI < 1). ADMET calculations as well as molecular docking have been performed for synthetic compounds.

Anti-virulence agents are non-bacteriostatic and non-bactericidal emerging therapeutic options which hamper the production of virulence factors in pathogenic flora. In Staphylococcus aureus and Enterococcus faecalis, regulation of virulence genes’ expression occurs through the cyclic peptide-mediated accessory gene regulator (agr) and its ortholog fsr quorum sensing systems, respectively. In the present study, we screened a set of 54 actinomycetales secondary metabolites as novel anti-virulence compounds targeting quorum sensing system of the Gram-positive bacteria. The results indicated that four compounds, Phenalinolactones A–D, BU–4664LMe, 4,5-dehydrogeldamycin, and Questinomycin A, potentially inhibit the agr quorum sensing system and hemolytic activity of S. aureus. On the other hand, Decatromicin A and B, Okilactomycin, Rishirilide A, Abyssomicin I, and Rebeccamycin selectively blocked the fsr quorum sensing system and the gelatinase production in E. faecalis at sub-lethal concentrations. Interestingly, Synerazol uniquely showed the capability to inhibit both fsr and agr quorum sensing systems. Further, in silico molecular docking studies were performed which provided closer insights into the mode of action of these compounds and proposed that the inhibitory activity of these compounds could be attributed to their potential ability to bind to the ATP-active site of S. aureus AgrA. Taken together, our study highlights the potential of actinomycetales secondary metabolites with diverse structures as anti-virulence quorum sensing inhibitors.

Quorum sensing inhibitor (QSI) has been attracting attention as anti-virulence agent which disarms pathogens of their virulence rather than killing them. QSI marking cyclic peptide-mediated QS in Gram-positive bacteria is an effective tool to overcome the crisis of antibiotic-dependent chemotherapy due to the emergence of drug resistance strain, e.g., methicillin resistant Staphylococcus aureus (MRSA) and Vancomycin resistant Enterococci (VRE). From a semi-large-scale screening thus far carried out, two Epoxide compounds, Ambuic acid and Synerazol, have been found to efficiently block agr and fsr QS systems, suggesting that the Epoxide group is involved in the mode of action of these QSIs. To address this notion, known natural Epoxide compounds, Cerulenin and Fosfomycin were examined for QSI activity for the agr and fsr systems in addition to in silico and SAR studies. As a result, most of investigated Epoxide containing antibiotics correlatively interfere with QSI activity for the agr and fsr systems under sublethal concentrations.

Although inflammation triggers immune-mediated healing and repair, chronic inflammation can result in several diseases. Cyclooxygenase (COX) enzymes are inhibited by NSAIDs, which are used to relieve the symptoms of inflammation. Meclofenamic and Zileuton are examples of dual COX/LOX inhibitors that provide improved stomach protection and safer cardiovascular characteristics. This study was aimed to develop anti-inflammatory medications with improved safety profiles by presenting novel flufenamate conjugates that combine 5-LOX inhibitor efficacy with COX inhibition. The COX-1 inhibition of compounds 14 and 15 was higher than that of Celecoxib (IC 50  = 77.4 µM), with an IC 50 range of 15–26 µM. Compounds 14 and 16 showed the best selectivity indices (ratio between IC 50 of COX-1 and COX-2), which were 5.01 and 5.86 µM, respectively. Conjugates 14 and 16 displayed excellent COX-2 inhibiting activity, with IC 50 values of 5.0 -17.6 µM. Outstanding 5-LOX inhibition was demonstrated by all conjugates, with IC 50 values varying between 0.6 and 8.5 µM. In RAW 264.7 cells, compounds 14 and 15 significantly decreased PGE2 levels to a range of 61–89 pg/mL in contrast to Celecoxib (119.9 pg/mL). Compounds 14 and 17 showed exceptional NO scavenging action, with IC 50 values of 0.238 × 10 6 and 0.289 × 10 6  µM, respectively. mTOR levels dramatically diminished for all conjugates. Conjugates 14 and 17 markedly raised levels nrf2. Molecular docking studies were used to validate the findings of this investigation.

Background: Alzheimer’s disease (AD) is largely linked with oxidative stress, the accumulation of amyloid-β plaques, and hyperphosphorylated τ-protein aggregation. Alterations in dopaminergic and serotonergic neurotransmission have also been implicated in various AD-related symptoms. Methods: To explore new therapeutic agents, a series of bicyclic and tricyclic thieno-oxazepine derivatives were synthesized as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The resultant compounds were purified via HPLC and characterized using spectral analysis techniques. Histopathological examinations, other antioxidants, and anti-inflammatory biomarkers were evaluated, and in silico ADMET calculations were performed for synthetic hybrids. Molecular docking was utilized to validate the new drugs’ binding mechanisms. Results: The most powerful AChE inhibitors were 14 and 16, with respective values of IC50 equal to 0.39 and 0.76 µM. Derivative 15 demonstrated remarkable BChE-inhibitory efficacy, on par with tacrine, with IC50 values of 0.70 µM. Hybrids 13 and 15 showed greater selectivity towards BChE, despite substantial inhibition of AChE. Compounds 13 and 15 reduced escape latency and raised residence time, with almost equal activity to donepezil. Conclusions: According to these findings, the designed hybrids constitute multipotent lead compounds that could be used in the creation of novel anti-AD medications.

Uracil derivatives have a great attraction because they play an important role in pharmacological activities. Pyrimidodiazepines, lumazines, triazolopyrimidines and xanthines have significant wide spectrum activities including anticancer, antiviral as well as antimicrobial activities. A newly synthesized compounds pyrimido[4,5-b][1, 4]diazepines 5a–e, 6a–d, lumazines 7a–d, triazolo[4,5-d]pyrimidine 8 and xanthines 9, 10 was prepared in a good yields. The antimicrobial and antioxidant activities of compounds 5a, 5b, 6a, 6d and 8 exhibited a wide range activity against the pathogenic tested microbes (Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Candida albicans, and Saccharomyces cerevisiae). Compound 8 showed activity against the fungus Aspergillus niger. The highest antioxidant activity was noticed for compound 5a. A series of novel pyrimido[4,5-b][1, 4]diazepines 5a–e, 6a–d, lumazines 7a–d, triazolo[4,5-d]pyrimidine 8 and xanthines 9, 10 was prepared from 5,6-diamino-1-(2-chlorobenzyl)uracil 3 in good yields. Compounds 5a–e, 6a–d were prepared by sequential manipulation of 3 with α,β-unsaturated ketones. Lumazines 7a–d were obtained from 3 by treatment with phenacyl bromides in the presence of TEA. Compound 8 was prepared by treatment of 3 with HNO2, while xanthines 9, 10 were obtained from 3 by consecutive acetylation then intramolecular cyclodehydration or heating with malononitrile under solvent-free condition. The antimicrobial and antioxidant activity of this series was evaluated in vitro and they showed either weak or moderate activities.[Figure not available: see fulltext.]

Thrombosis is the leading cause of illness and mortality worldwide, posing a serious risk to human health and life. Because antithrombotic drugs can prevent the beginning and progression of thrombotic disorders, they are essential in the management of thrombotic diseases. The substantial side effects and unsatisfactory efficacy of present antithrombotic drugs stimulate the search for novel, effective, and safer antithrombotic therapies. Natural and synthetic coumarins have been shown to have antithrombotic action, specifically anticoagulation, and antiplatelet aggregation. In particular, coumarin-based medications like warfarin, phenprocoumon, and cloricromen have long been used to treat thrombosis in clinical settings. The favored structure for creating novel antithrombotic medications with diverse modes of action is coumarin, which has low toxicity. The goal of the current review is to consolidate recent findings on the development of coumarins as antithrombotic agents, with a focus on the connection between these compounds’ chemical compositions and therapeutic potency. It aims to offer promising suggestions for the identification of new coumarin compounds with potent antithrombotic properties.

Several coumarin-containing substitute nitrogen heterocycles have recently received considerable importance due to their diverse pharmacological properties. One-pot and rapid synthesis of coumarin derivatives was achieved via reactions of acetyl-coumarin with p -chloro-benzaldehyde and malononitrile to provide compound 2-containing cyano-amine using conventional heating. Compound 2 was condensed with different carbon electrophiles triethyl orthoformate, phenyl isocyanate, carbon disulfide, benzoyl chloride, and acetyl chloride that afforded the corresponding chromene derivatives 3–17 . All the newly synthesized compounds were characterized by elemental and spectroscopic evidences. All of the synthesized compounds were tested for antimicrobial activity against S. Pneumoniae , S. Epidermidis , S. Aureus, and E. coli as Gram + ve Bacteria, K. Pneumoniae , S. Paratyphi as Gram -ve Bacteria, P. Italicum , A. Fumigatus representative for Fungi. The preliminary screening results showed that most of the compounds had moderate to high activity against all tested organisms. The most potent four compounds were subjected to further investigation against E. Coli DNA gyrase and topoisomerase IV inhibitory activity, and the results showed that all of these derivatives inhibit DNA gyrase and thus cell division. Also, in silico studies were done for the most active compounds which showed good results. Graphic abstract