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This study highlights the significance of the Ullmann coupling reaction in modern organic synthesis and advances catalytic methodologies through the introduction of a kanamycin−copper complex as a highly efficient catalyst for the synthesis of diverse N−aryl compounds. We demonstrate the catalyst's versatility by synthesizing 20 diaryl−amine instances, 21 Ar(het)−N compounds, and 10 miscellaneous examples. NMR, IR, and UV spectroscopy offer insights into the catalyst's behaviour. Additionally, DFT studies support the catalyst's proficiency in generating SO4−⋅ radicals by stabilizing with amino sugar moieties. Ex‐situ NMR experiments confirm a ternary complex‐based mechanism at concentrations below 0.1 μM. Furthermore, we showcase the degradation of methylene blue to its precursor amine under optimized conditions. Overall, this research underscores the potential of Ullmann condensation reactions in contemporary organic synthesis and contributes significantly to the advancement of catalytic methodologies. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is associated with secondary complications such as diabetic retinopathy (DR), nephropathy (DN), and cardiomyopathy (DCM), all of which significantly impact patient health. Intercellular adhesion molecule‐1 (ICAM‐1) has been implicated in inflammatory responses and endothelial dysfunction, both crucial in the pathogenesis of these complications. The goal of this review is to investigate at potential therapy methods that target ICAM‐1 pathways and to better understand the multifaceted role of ICAM‐1 in secondary diabetic problems. A meticulous analysis of scholarly literature published globally was conducted to examine ICAM‐1involvement in inflammatory processes, endothelial dysfunction, and oxidative stress related to diabetes and its complications. Elevated ICAM‐1 levels are strongly associated with augmented leukocyte adhesion, compromised microvascular function, and heightened oxidative stress in diabetes. These pathways contribute significantly to DR, DN, and DCM pathogenesis, highlighting ICAM‐1 as a key player in their progression. Understanding ICAM‐1 role in secondary diabetic complications offers insights into novel therapeutic strategies. Targeting ICAM‐1 pathways may mitigate inflammation, improve endothelial function, and ultimately attenuate diabetic complications, thereby enhancing patient health outcomes. Continued research in this area is crucial for developing effective targeted therapies. Significance statement: This review centers its attention on the function of intercellular adhesion molecule‐1 (ICAM‐1) in the development and progression of diabetic retinopathy, nephropathy, and cardiomyopathy.The role of ICAM‐1 in the pathophysiology of various disorders is investigated.The article emphasizes the significance of ICAM‐1 as a critical target for therapeutic interventions and the molecular mechanisms behind the contribution of ICAM‐1 are explored. [ABSTRACT FROM AUTHOR]

Cervical cancer is a global health risk primarily caused by the human papillomavirus (HPV). India has a high incidence of cervical cancer, with 23% of cases occurring in the country. The lack of widespread population-based screening and low awareness contribute to late-stage diagnoses and high death rates. The Indian government has pledged to focus on cervical cancer vaccination for girls aged 9 to 14, but specific plans are unknown. Efforts to increase HPV vaccination coverage and screening rates are crucial in the fight against cervical cancer in India. [Extracted from the article]

A series of 20 newly designed (E)-1-(4-sulphamoylphenylethyl)-3-arylidene-5-aryl-1H-pyrrol-2(3H)-ones was synthesised and assessed as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors towards four human isoforms of pharmaceutical interest, that is, hCA I, II, IX and XII. The compounds displayed low to high nanomolar potency against all the isoforms. Introducing strong electron withdrawing groups at the para position of the arylidene ring increased the binding affinity to the enzyme. All compounds showed acceptable pharmacokinetic range and physicochemical characteristics as determined by computational ADMET analysis. Density Functional Theory (DFT) calculations of 3n were carried to gain understanding on the stability of the E and Z isomers. The energy values clearly indicate the stability of E isomer over Z isomer by −8.2 kJ mol−1. Our findings indicate that these molecules are useful as leads for discovering new CA inhibitors. [ABSTRACT FROM AUTHOR]

A series of 5‐arylidene‐2,4‐thiazolidinediones were synthesized using Knoevenagel condensation and evaluated for their anti‐leishmanial activity against L. donovani promastigotes and axenic amastigotes. Among the compounds tested, three were the most active, with IC50 values of 0.82–1.42 μM against L. donovani promastigotes and 0.69–1.19 μM against L. donovani amastigote. (Z)‐5‐(4‐(trifluoromethyl)benzylidene)thiazolidine‐2,4‐dione was the most prominent among all the tested compounds and demonstrated better anti‐leishmanial properties when compared to the standard drug miltefosine (1.26 μM against L. donovani promastigotes and 1.17 μM against L. donovani amastigotes). It was insignificantly toxic compared to the standard miltefosine in THP‐1 human monocytic cells. It was further evaluated for its in vitro cysteine protease (papain) inhibitory activity using Z‐RR‐AMC fluorogenic peptide substrate. It demonstrated promising inhibitory activity with the IC50 value of 3.42 μM. In silico docking studies also supported that the (Z)‐5‐(4‐(trifluoromethyl)benzylidene)thiazolidine‐2,4‐dione is bound to cysteine protease proteins′ catalytic active binding site. Anti‐leishmanial properties of this class of compounds have been evaluated for the first time, and (Z)‐5‐(4‐(trifluoromethyl)benzylidene)thiazolidine‐2,4‐dione emerged as a lead molecule from the library of compounds tested. This may serve as a template for further drug discovery in Leishmania. [ABSTRACT FROM AUTHOR]

Objective(s): Cardiovascular diseases are widespread across the globe, and heart failure (HF) accounts for the majority of heart-associated deaths. Target-based drug therapy is much needed for the management of heart failure. We have designed this study to evaluate icariin for its cardioprotective activity in the isoproterenol (ISO) induced postinfarction model. We have randomly distributed Wistar rats into seven groups, i.e., vehicle control; isoproterenol-treated; icariin per se; sildenafil per se; ISO + icariin 5; ISO + icariin 10; and ISO + sildenafil groups. ISO (85 mg/kg, subcutaneous) was administered at 24 hr for two consecutive days to produce cardiac injury, followed by icariin administration at 5 mg/kg and 10 mg/kg orally for 56 days. Materials and Methods: Rats were subjected to hemodynamic measurements biweekly. After 24 hr of the completion of dosing, animals were sacrificed, and markers for oxidative stress, fibrosis, inflammation, and cell death were measured. Transmission electron microscopy (TEM), histopathology, and MT staining of cardiac tissue were also done to assess the pathological and fibrotic architectural damage. Results: A significant decline in hemodynamics and an anti-oxidant collapse were found in ISOintoxicated rats. Alterations in the levels of cyclic guanosine monophosphate (cGMP), interleukin-10 (IL-10), Tumor necrosis factor (TNF-α), and brain natriuretic peptide (BNP) were also observed in serum. Up-regulation of caspase-3, nuclear factor (NF-ĸB), and decline in expression of nuclear factor (NrF-2) contribute to cardiac damage. The treatment with icariin and sildenafil considerably reversed the toxic changes toward normal. Conclusion: Increased cGMP and Nrf2 expression and suppressed NF-ĸB-caspase-3 signaling play a pivotal role in icariin-mediated cardioprotection. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor receptor‐2 (VEGFR‐2) is crucial in promoting tumor angiogenesis and cancer metastasis. Thus, inhibition of VEGFR‐2 has appeared as a good tactic for cancer treatment. To find out novel VEGFR‐2 inhibitors, first, the PDB structure of VEGFR‐2, 6GQO, was selected based on atomic nonlocal environment assessment (ANOLEA) and PROCHECK assessment. 6GQO was then further used for structure‐based virtual screening (SBVS) of different molecular databases, including US‐FDA approved drugs, US‐FDA withdrawn drugs, may bridge, MDPI, and Specs databases using Glide. Based on SBVS, receptor fit, drug‐like filters, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis of 427877 compounds, the best 22 hits were selected. From the 22 hits, hit 5 complex with 6GQO was put through molecular mechanics/generalized born surface area (MM/GBSA) study and hERG binding. The MM/GBSA study revealed that hit 5 possesses lesser binding free energy with more inferior stability in the receptor pocket than the reference compound. The VEGFR‐2 inhibition assay of hit 5 disclosed an IC50 of 165.23 nM against VEGFR‐2, which can be possibly enhanced through structural modifications. [ABSTRACT FROM AUTHOR]

It is well‐documented that pro‐inflammatory cytokines and inflammation play a significant role in the expansion of cancer disease. Gallic acid (GA), a natural compound, and metformin (Met), a synthetic drug exhibit potent anticancer potential via the distinct molecular mechanism. However, whether both these compounds can act synergistically to preclude and treat cancer is still unknown. This prompted us to scrutinize, the synergism between GA and Met, and that of a new co‐drug synthesizing of GA and Met (GA‐Met) and investigated the chemo‐protective effect against breast cancer with possible intervention of cytokines. In vivo studies were based on chemical carcinogenesis, challenging breast tissue by dimethylbenz[α]anthracene (DMBA). Tumour incidence, tumour burden, pro‐inflammatory cytokines in serum, breast, hepatic tissue, macroscopically and histological analysis of mammary tumours were carried out and estimated. GA, Met and GA‐Met co‐drug exhibited the inhibition of cell proliferation; higher reduction of cell proliferation was observed by GA‐Met. The inhibitory effect of GA‐Met was linked to cell cycle arrest at G0/G1 phase, along with induction of apoptosis and accumulation in the sub‐G1 phase. GA‐Met significantly inhibited the cytokines production along with protection against DMBA‐induced hyperplasia. Taken altogether, the current result suggests that GA‐Met co‐drug endows a safe and protective effect against cancer metastasis and can possibly use for the treatment of human breast cancer. [ABSTRACT FROM AUTHOR]

The latest SARS-CoV-2 variant of concern (VOC), Omicron (B.1.1.529), has diversified into more than 300 sublineages. With an expanding number of newly emerging sublineages, the mutation profile is also becoming complicated. There exist mutually exclusive and revertant mutations in different sublineages. Omicron sublineages share some common mutations with previous VOCs (Alpha, Beta, Gamma, and Delta), indicating an evolutionary relationship between these VOCs. A diverse mutation profile at the spike–antibody interface, flexibility of the regions harboring mutations, mutation types, and coexisting mutations suggest that SARS-CoV-2's evolution is far from over. [ABSTRACT FROM AUTHOR]

The quinoline scaffolds are privileged for their numerous biological activities in the pharmaceutical field. This moiety constitutes a well‐known space in several marketed preparations. The quinoline scaffolds gained attention in modern days being an important chemical moiety in the identification, designing, and synthesis of novel potent derivatives. The current review is developed to shine the light on critical and significant insights on the quinoline derivatives possessing diverse biological activities such as analgesic, anti‐inflammatory, antialzheimer, anti‐convulsant, anti‐oxidant, antimicrobial, anti‐cancer activities and so on. A detailed summary of quinoline ring from its origin to the recent advancements regarding its synthesis, green chemistry approaches, patented methods, and its marketed drugs is presented in the review. We attempted to review the literature compiling the critical information that has potential to encourage fellow researchers and scientists for the design and development of quinoline scaffold based active molecules that have improved therapeutic performance along with profound pharmacological properties. [ABSTRACT FROM AUTHOR]

The present study aims to design, develop and characterize kNGR (Asn-Gly-Arg) peptide-conjugated lipid–polymer-based nanoparticles for the target-specific delivery of anticancer bioactive(s), i.e., Paclitaxel (PTX). The kNGR-PEG-DSPE conjugate was synthesized and characterized by using spectral analysis. The dual-targeted PLGA–lecithin–PEG core-shell nanoparticles (PLNs-kNGR-NPs) were synthesized using a modified nanoprecipitation process, and their physiological properties were determined. The results support that, compared to other NPs, PLNs-kNGR-NPs are highly cytotoxic, owing to higher apoptosis and intracellular uptake. The significance of rational nanoparticle design for synergistic treatment is shown by the higher tumor volume inhibition percentage rate (59.7%), compared to other designed formulations in Balb/c mice in the HT-1080 tumor-induced model. The overall results indicate that the PLNs-kNGR-NPs-based hybrid lipid–polymer nanoparticles present the highest therapeutic efficacy against solid tumor overexpressing the CD13 receptors. [ABSTRACT FROM AUTHOR]

BA.2, a sublineage of Omicron BA.1, is now prominent in many parts of the world. Early reports have indicated that BA.2 is more infectious than BA.1. To gain insight into BA.2 mutation profile and the resulting impact of mutations on interactions with receptor and/or monoclonal antibodies, we analyzed available sequences, structures of Spike/receptor and Spike/antibody complexes, and conducted molecular dynamics simulations. The results showed that BA.2 had 50 high-prevalent mutations, compared to 48 in BA.1. Additionally, 17 BA.1 mutations were not present in BA.2. Instead, BA.2 had 19 unique mutations and a signature Delta variant mutation (G142D). The BA.2 had 28 signature mutations in Spike, compared to 30 in BA.1. This was due to two revertant mutations, S446G and S496G, in the receptor-binding domain (RBD), making BA.2 somewhat similar to Wuhan-Hu-1 (WT), which had G446 and G496. The molecular dynamics simulations showed that the RBD consisting of G446/G496 was more stable than S446/S496 containing RBD. Thus, our analyses suggested that BA.2 evolved with novel mutations (i) to maintain receptor binding similar to WT, (ii) evade the antibody binding greater than BA.1, and (iii) acquire mutation of the Delta variant that may be associated with the high infectivity. [ABSTRACT FROM AUTHOR]

Objective(s): Excess intake of a high-fatty diet (HFD) together with zymosan administration mediates vasculitis response which leads to impaired serum lipid levels and causes arterial stiffness. In the development of new cholesterol-lowering medications, PCSK9 inhibitor (proprotein convertase subtilisin/kexin type 9) is an emerging therapeutic. The goal of the present study was to see whether anti-PCSK9 mAb1 might prevent vasculitis in C57BL/6 mice by blocking TLR2/NF-B activation in HFD and Zymosan-induced vasculitis. Materials and Methods: Protein-protein molecular docking was performed to validate the binding affinity of anti-PCSK9 mAb1 against TLR2. Under the experimental study, mice were randomly allocated to the following groups: Group I: standard mice diet (30 days) + Zymosan vehicle (sterile PBS solution of 5mg/ml on 8th day); Group II: HFD (30 days) + Zymosan (single IP dose 80 mg/kg on day 8th); Group III: HFD+Zymosan + anti-PCSK9 mAb1 (6 mg/kg, s.c. on 10th and 20th days); Group IV: HFD+Zymosan+anti-PCSK9 mAb1 (10 mg/kg, s.c. on 10th and 20th days). Results: In comparison with the low dose of anti-PCSK9 mAb1 (6 mg/kg), the high dose of anti-PCSK9 mAb1 (10 mg/kg) together with HFD and Zymosan inhibited vasculitis more effectively by decreasing aortic TLR2 and NF-B levels, reducing serum TNF- and IL-6, and up-regulating liver LDLR levels, which down-regulated serum LDL-C and improved serum lipids levels. Histopathological studies showed that anti-PCSK9 mAb1 treatment reduced plaque accumulation in the aorta of mice. Conclusion: These findings indicate that anti-PCSK9 mAb1 has therapeutic potential in reducing HFD and Zymosan-induced vascular inflammation. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme 2 (ACE2), the host cell-binding site for SAR-CoV-2, poses two-fold drug development problems. First, the role of ACE2 itself is still a matter of investigation, and no specific drugs are available targeting ACE2. Second, as a consequence of SARS-CoV-2 interaction with ACE2, there is an impairment of the renin-angiotensin system (RAS) involved in the functioning of vital organs like the heart, kidney, brain, and lungs. In developing antiviral drugs for COVID-19, ACE2, RNA-dependent RNA polymerase (RdRp), and the specific enzymes involved in the viral and cellular gene expression have been the primary targets. SARS-CoV-2 being a new virus with unusually high mortality, there has been a need to get medicines in an emergency, and the drug repurposing has been a primary strategy. Considering extensive mortality and morbidity throughout the world, we have made a maiden attempt to discover the drugs interacting with RAS and identify the lead compounds from herbal plants using molecular docking. Both host ACE2 and viral RNA-dependent RNA polymerase (RdRp) and ORF8 appear to be the primary targets for the treatment of COVID-19. While the drug repurposing of currently approved drugs seems to be one strategy for the treatment of COVID-19, purposing phytochemicals may be another essential strategy for discovering lead compounds. Using in silico molecular docking, we have identified a few phytochemicals that may provide insights into designing herbal and synthetic therapeutics to treat COVID-19. [ABSTRACT FROM AUTHOR]

This work evaluates nano-lipid carrier of ganoderic acid (GA) and molecular docking on various cancer signaling pathways, an attempt to improve the hepatic condition associated with hepatic carcinoma (HCC) induced by diethyl-nitrosamine (DEN) in Wistar rats. Molecular docking mechanism of GA was performed through binding simulation analysis for various cancer signaling pathway, viz., Bcl-2, Pl3K, NF-κB, Akt/PKB, and Stat-3. Double emulsion solvent displacement method was implied for preparation of GA-loaded nano-lipid carrier. GA-NLCs were evaluated for drug loading capacity, entrapment efficiency, particle size, gastric stability, in vitro drug release, cytotoxicity, cellular uptake, and in vivo studies including macroscopical, hepatic injury markers, non-hepatic, biochemical, antioxidant parameters, and histopathological evaluation. HCC was induced by intraperitoneal injection of DEN (200 mg/kg). Both in vivo and molecular docking results were compatible in establishing the alteration in hepatic nodules, hepatic, non-hepatic, and antioxidant parameters, in a significant manner (p <.001) by GA and GA-NLC along with signal alteration of Bcl-2, Pl3K, NF-κB Akt/PKB, and Stat-3 pathway. Histopathological observation confirmed and supported the above result by GA and GA-NLC. On the basis of our results, we can advocate that, GA interferes with various cancer signaling proteins involved in pathogenesis of cancer and was able to cease the progression of disease. Additionally, GA-NLCs proved its chemoprotective effect against the DEN-induced HCC by modulation of hepatic and non-hepatic parameters through various mechanisms. [ABSTRACT FROM AUTHOR]

Thirty new aryl-pyridazinone-substituted benzenesulphonylurea derivatives (I–XXX) were synthesized and evaluated for their anti-hyperglycaemic activity in glucose-fed hyperglycaemic normal rats. Twenty-three compounds (III–XI,XIV–XVII,XIX–XXIV,XXVIandXXVIII–XXX) showed more or comparable area under the curve (AUC) reduction percentage (ranging from 21.9% to 35.5%) as compared to the standard drug gliclazide (22.0%). On the basis of docking results, 18 compounds were screened for theirin vitroability to inhibit rat lens aldose reductase. Ten compounds (III–VI,XII,XVI–XVIII,XXIandXXVII) showed ARI activity with IC50 ranging from 34 to 242 μM. Out of these, two compounds IV and V showed best ARI activity which is comparable with that of quercetin. As a result, two compounds (IV and V) possessing significant dual action (anti-hyperglycaemic and aldose reductase inhibition) were identified and may be used as lead compounds for developing new drugs. [ABSTRACT FROM PUBLISHER]

Development of new therapeutic approach to treat leishmaniasis has become a priority. In the present study, the antileishmanial effect of b-nitrostyrenes was investigated against in vitro promastigotes and amastigotes. A series of β-nitrostyrenes have been synthesized by using Henry reaction and were evaluated for their antimicrobial activities by broth microdilution assay and in vitro antileishmanial activities against Leishmania donovani promastigotes by following standard guidelines. The most active compounds were futher evaluated for their in vitro antileishmanial activities against intracellular amastigotes. Among the tested β-nitrostyrenes, compounds 7, 8, 9, 12, and 17 exhibited potential activities (MICs range, 0.25-8µg/mL) against clinically significant human pathogenic fungi. However, the microbactericidal concentrations (MBCs) and the microfungicidal concentrations (MFCs) were found to be either similar or only two-fold greater than the MICs. Anti-leishmanial results demonstrated that compounds 9, 12, 14, and 18 were found to be most active among the tested samples and exhibited 50% inhibitory concentration (IC50) by 23.40 ± 0.71, 37.83 ± 3.74, 40.50 ± 1.47, 55.66 ± 2.84nM against L. donovani promastigotes and 30.5 ± 3.42, 21.46 ± 0.96, 26.43 ± 2.71, and 61.63 ± 8.02nM respectively against intracellular L. donovani promastigotes amastigotes respectively which are comparable with standard AmB (19.60 ± 1.71nM against promastigotes and 27.83 ± 3.26nM against amastigotes). Compounds 9, 12, 14, and 18 were found to have potent in vitro leishmanicidal activity against L. donovani and found to be non-toxic against mammalian macrophages even at a concentration of 25µM. Nitric oxide (NO) estimation studies reveals that these compounds are moderately inducing NO levels. [ABSTRACT FROM AUTHOR]

A novel series of oxazolo[4,5-b]pyridine-2-one based 1,2,3-triazoles has been synthesized by click chemistry approach and evaluated for in vitro GSK-3 β inhibitory activity. Compound 4g showed maximum inhibition with IC50 value of 0.19 μ m. Keeping in view the effect of GSK-3 β inhibition on inflammation, compounds 4g, 4d, 4f, 4i, 4n and 4q exhibiting significant GSK-3 β inhibition were examined for in vivo anti-inflammatory activity in rat paw edema model. The compounds 4g, 4d, 4f and 4i showed pronounced in vivo anti-inflammatory activity (76.36, 74.54, 72.72 and 70.90%, respectively, after 5h post-carrageenan administration) and were further found to inhibit the pro-inflammatory mediators, viz. NO, TNF- α, IL-1 β, and IL-6 substantially in comparison with indomethacin, an anti-inflammatory drug as well as SB216763, a GSK-3 β inhibitor, reported to exert a similar effect. Histopathology studies confirmed the tolerance of gastric mucosa to these compounds. [ABSTRACT FROM AUTHOR]