Discovery of new 1,3-diphenylurea appended aryl pyridine derivatives as apoptosis inducers through c-MET and VEGFR-2 inhibition: design, synthesis, in vivo and in silico studies.

Interest has been generated in VEGFR-2 and c-MET as potential receptors for the treatment of different malignancies. Using aryl pyridine derivatives with 1,3-diphenylurea attached, a number of promising dual VEGFR-2 and c-MET inhibitors were developed and synthesized. Regarding the molecular target, compounds 2d, 2f, 2j, 2k, and 2n had potent IC50 values of 65, 24, 150, 170, and 18 nM against c-MET, respectively. Additionally, they had potent IC50 values of 310, 35, 290, 320, and 24 nM against VEGFR-2, respectively. Regarding cytotoxicity, compounds 2d, 2f, 2j, 2k and 2n exhibited potent cytotoxicity against MCF-7 with IC50 values in the range 0.76-21.5 µM, and they showed promising cytotoxic activity against PC-3 with IC50 values in the range 1.85-3.42 µM compared to cabozantinib (IC50 = 1.06 µM against MCF-7 and 2.01 µM against PC-3). Regarding cell death, compound 2n caused cell death in MCF-7 cells by 87.34-fold; it induced total apoptosis by 33.19% (8.04% for late apoptosis, 25.15% for early apoptosis), stopping their growth in the G2/M phase, affecting the expression of apoptosis-related genes P53, Bax, caspases 3 and 9 and the anti-apoptotic gene, Bcl-2. In vivo study illustrated the anticancer activity of compound 2n by reduction of tumor mass and volume, and the tumor inhibition ratio reached 56.1% with an improvement of hematological parameters. Accordingly, compound 2n can be further developed as a selective target-oriented chemotherapeutic against breast cancer.

Unveiling the potential of isatin-grafted phenyl-1,2,3-triazole derivatives as dual VEGFR-2/STAT-3 inhibitors: Design, synthesis and biological assessments.

The use of VEGFR-2 inhibitors as a stand-alone treatment has proven to be ineffective in clinical trials due to the robustness of cellular response loops that lead to treatment resistance when only targeting VEGFR-2. The over-activation of the signal transducer/activator of transcription 3 (STAT-3) is expected to significantly impact treatment failure and resistance to VEGFR-2 inhibitors. In this study, we propose the concept of combined inhibition of VEGFR-2 and STAT-3 to combat induced STAT-3-mediated resistance to VEGFR-2 inhibition therapy. To explore this, we synthesized new isatin-grafted phenyl-1,2,3-triazole derivatives "6a-n" and "9a-f". Screening on PANC1 and PC3 cancer cell lines revealed that compounds 6b, 6 k, 9c, and 9f exhibited sub-micromolar ranges. The most promising molecules, 6b, 6 k, 9c, and 9f, demonstrated the highest inhibition when tested as dual inhibitors on VEGFR-2 (with IC50 range 53-82 nM, respectively) and STAT-3 (with IC50 range 5.63-10.25 nM). In particular, triazole 9f showed the best results towards both targets. Inspired by these findings, we investigated whether 9f has the ability to trigger apoptosis in prostate cancer PC3 cells via the assessment of the expression levels of the apoptotic markers Caspase-8, Bcl-2, Bax, and Caspase-9. Treatment of the PC3 cells with compound 9f significantly inhibited the protein expression levels of VEGFR-2 and STAT-3 kinases compared to the control.

Biochemical and genetic mechanisms in Pieris rapae (Lepidoptera: Pieridae) resistance under Emamectin benzoate stress.

Pieris rapae (Lepidoptera: Pieridae) poses a significant threat to Brassicaceae crops, leading to substantial losses annually. Repeated insecticide applications are widely used to protect crops and increase the resistance of P. rapae. Exploring the biochemical and molecular basis of insecticide tolerance in P. rapae is crucial for achieving effective insect suppuration and implementing resistance control strategies. In our research, emamectin benzoate (EBZ) resistance was developed in P. rapae strain through selective pressure over 15 generations. Moreover, the biochemical mechanisms underlying resistance to EBZ and its potential cross-resistance to other insecticides were studied. Additionally, the expression levels of cytochrome P450 (CYP450) and glutathione-s-transferase (GST) genes in P. rapae were quantitatively assessed upon exposure to EBZ using real-time PCR. Our data exhibited that the LC50 value of susceptible strain (Sus) and EBZ resistance strain (EBZ-R) were 0.009 and 8.09 mg/L, with a resistance ratio (RR) reaching 898.8-fold. The EBZ-R stain displayed notably low cross-resistance to lambda-cyhalothrin, spinetoram, and cypermethrin. However, it demonstrated a moderate level of cross-resistance to deltamethrin. Conversely, no cross-resistance was noted to chlorantraniliprole and indoxacarb. Notably, enzyme inhibitors of detoxification enzymes revealed that piperonyl butoxide (PBO) and diethyl maleate (DEM) enhanced the EBZ toxicity to the resistant strain, indicating the potential involvement of CYP450 and GST in avermectin resistance. A remarkable enhancement in CYP450 and GST activity was observed in the EBZ-R stain. CYP450 and GST genes are upregulated in the EBZ-R stain compared to the Sus strain, which serves as a basis for comprehending the mechanism behind P. rapae resistance to EBZ. The molecular docking analysis demonstrated that EBZ has a high binding affinity with CYP6AE120 and PrGSTS1 with docking energy values of -20.19 and -22.57 kcal/mol, respectively. Our findings offer valuable insights into crafting efficient strategies to monitor and manage resistance in P. rapae populations in Egypt.

New coumarin linked thiazole derivatives as antimycobacterial agents: Design, synthesis, enoyl acyl carrier protein reductase (InhA) inhibition and molecular modeling.

Tuberculosis is a global serious problem that imposes major health, economic and social challenges worldwide. The search for new antitubercular drugs is extremely important which could be achieved via inhibition of different druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein reductase (InhA) enzyme is essential for the survival of M. tuberculosis. In this investigation, a series of coumarin based thiazole derivatives was synthesized relying on a molecular hybridization approach and was assessed against thewild typeMtb H37Rv and its mutant strain (ΔkatG) via inhibiting InhA enzyme. Among the synthesized derivatives, compounds 2b, 3i and 3j were the most potent against wild type M. tuberculosis with MIC values ranging from 6 to 8 µg/ mL and displayed low cytotoxicity towards mouse fibroblasts at concentrations 8-13 times higher than the MIC values. The three hybrids could also inhibit the growth of ΔkatGmutant strain which is resistant to isoniazid (INH). Compounds 2b and 3j were able to inhibit the growth of mycobacteria inside human macrophages, indicating their ability to penetrate human professional phagocytes. The two derivatives significantly suppress mycobacterial biofilm formation by 10-15 %. The promising target compounds were also assessed for their inhibitory effect against InhA and showed potent effectiveness with IC50 values of 0.737 and 1.494 µM, respectively. Molecular docking studies revealed that the tested compounds occupied the active site of InhA in contact with the NAD+ molecule. The 4-phenylcoumarin aromatic system showed binding interactions within the hydrophobic pocket of the active site. Furthermore, H-bond formation and π -π stacking interactions were also recorded for the promising derivatives.

Lethal and Sublethal Effects of Cyantraniliprole on the Biology and Metabolic Enzyme Activities of Two Lepidopteran Pests, Spodoptera littoralis and Agrotis ipsilon, and A Generalist Predator, Chrysoperla carnea (Neuroptera: Chrysopidae).

Cyantraniliprole is a novel anthranilic diamide insecticide registered for controlling chewing and sucking insect pests. Here, the lethal and sublethal effects of this insecticide on two destructive lepidopteran pests, Spodoptera littoralis Boisduval and Agrotis ipsilon Hufnagel, were evaluated. Because the effects of novel insecticides on beneficial and non-target arthropods must be considered, the impact of cyantraniliprole on a generalist biological control agent, Chrysoperla carnea [Stephens 1836], were also examined. Overall, our study revealed that cyantraniliprole was more toxic to A. ipsilon than to S. littoralis. Moreover, the LC15 and LC50 of the insecticide significantly prolonged the duration of the larval and pupal stages and induced enzymatic detoxification activity in both species. Treatment of the second-instar larvae of C. carnea with the recommended concentration of cyantraniliprole (0.75 mg/L) doubled the mortality rates and resulted in a slight negative effect on the biology and detoxification enzymes of C. carnea. Our results indicate that both sublethal and lethal concentrations of cyantraniliprole can successfully suppress S. littoralis and A. ipsilon populations. They also suggest that C. carnea, as a generalist predator, is compatible with cyantraniliprole under the modelled realistic field conditions. In future investigations, insights into the effects of cyantraniliprole on S. littoralis, A. ipsilon, and C. carnea under field conditions will be required to appropriately validate our results.

A new framework for novel analogues of pazopanib as potent and selective human carbonic anhydrase inhibitors: Design, repurposing rational, synthesis, crystallographic, in vivo and in vitro biological assessments.

Herein, we describe the design and synthesis of novel aryl pyrimidine benzenesulfonamides APBSs 5a-n, 6a-c, 7a-b, and 8 as pazopanib analogues to explore new potent and selective inhibitors for the CA IX. All APBSs were examined in vitro for their promising inhibition activity against a small panel of hCAs (isoforms I, II, IX, and XII). The X-ray crystal structure of CA I in adduct with a representative APBS analogue was solved. APBS-5m, endowed with the best hCA IX inhibitory efficacy and selectivity, was evaluated for antiproliferative activity against a small panel of different cancer cell lines, SK-MEL-173, MDA-MB-231, A549, HCT-116, and HeLa, and it demonstrated one-digit IC50 values range from 2.93 µM (MDA-MB-231) to 5.86 µM (A549). Furthermore, compound APBS-5m was evaluated for its influence on hypoxia-inducible factor (HIF-1α) production, apoptosis induction, and colony formation in MDA-MB-231 cancer cells. The in vivo efficacy of APBS-5m as an antitumor agent was additionally investigated in an animal model of Solid Ehrlich Carcinoma (SEC). In order to offer perceptions into the conveyed hCA IX inhibitory efficacy and selectivity in silico, a molecular docking investigation was also carried out.

The Synergistic Effect of Lemongrass Essential Oil and Flometoquin, Flonicamid, and Sulfoxaflor on Bemisia tabaci (Genn.) (Hemiptera: Aleyrodidae): Insights into Toxicity, Biochemical Impact, and Molecular Docking.

The whitefly, Bemisia tabaci (Genn.), is one of the most dangerous polyphagous pests in the world. Eco-friendly compounds and new chemical insecticides have gained recognition for whitefly control. In this study, the toxicity and biochemical impact of flometoquin, flonicamid, and sulfoxaflor, alone or combined with lemongrass essential oil (EO), against B. tabaci was studied. In addition, a molecular docking study was conducted to assess the binding affinity of the tested compounds to AchE. Based on the LC values, the descending order of the toxicity of the tested compounds to B. tabaci adults was as follows: sulfoxaflor > flonicamid > flometoquin > lemongrass EO. The binary mixtures of each of the tested compounds with lemongrass EO exhibited synergism in all combinations, with observed mortalities ranging from 15.09 to 22.94% higher than expected for an additive effect. Sulfoxaflor and flonicamid, alone or in combination with lemongrass EO, significantly inhibited AchE activity while only flonicamid demonstrated a significant impact on α-esterase, and none of the tested compounds affected cytochrome P450 or GST. However, the specific activity of P450 was significantly inhibited by the lemongrass/sulfoxaflor mixture while α-esterase activity was significantly inhibited by the lemongrass/flometoquin mixture. Moreover, the lemongrass EO and all the tested insecticides exhibited significant binding affinity to AchE with energy scores ranging from -4.69 to -7.06 kcal/mol. The current findings provide a foundation for utilizing combinations of essential oils and insecticides in the integrated pest management (IPM) of B. tabaci.

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles.

A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles (5a-h, 6, and 7a-e) were designed and constructed as potential carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a, 5d, and 5e can effectively inhibit both targets. 5a, 5d, and 5e cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of 5e to interrupt the PANC1 cell progression in the S stage by triggering the apoptotic cascade, as seen by increased levels of caspases 3, 9, and BAX, alongside the Bcl-2 decline. Moreover, the in vivo efficacy of compound 5e as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between 5e and CA IX and VEGFR-2 binding pockets.

Enhancing physical characteristics and antibacterial efficacy of chitosan through investigation of microwave-assisted chemically formulated chitosan-coated ZnO and chitosan/ZnO physical composite.

This study investigates the creation and analysis of chitosan-zinc oxide (CS-ZnO) nanocomposites, exploring their effectiveness in inhibiting bacteria. Two synthesis approaches, physical and chemical, were utilized. The CS-ZnO nanocomposites demonstrated strong antibacterial properties, especially against Staphylococcus aureus, a Gram-positive bacterium. Chemically synthesized nanocomposites (CZ10 and CZ100) exhibited larger inhibition zones (16.4 mm and 18.7 mm) compared to physically prepared CS-Z5 and CS-Z20 (12.2 mm and 13.8 mm) against Staphylococcus aureus. Moreover, CZ nanocomposites displayed enhanced thermal stability, with decomposition temperatures of 281°C and 290°C, surpassing CS-Z5 and CS-Z20 (260°C and 258°C). The residual mass percentages at 800°C were significantly higher for CZ10 and CZ100 (58% and 61%) than for CS-Z5 and CS-Z20 (36% and 34%). UV-Visible spectroscopy revealed reduced band gaps in the CS-ZnO nanocomposites, indicating improved light absorption. Transmission electron microscopy (TEM) confirmed uniform dispersion of ZnO nanoparticles within the chitosan matrix. In conclusion, this research underscores the impressive antimicrobial potential of CS-ZnO nanocomposites, especially against Gram-positive bacteria, and highlights their enhanced thermal stability. These findings hold promise for diverse applications in industries such as medicine, pharmaceuticals, and materials science, contributing to the development of sustainable materials with robust antimicrobial properties.

DFT and molecular simulation validation of the binding activity of PDEδ inhibitors for repression of oncogenic k-Ras.

The development of effective drugs targeting the K-Ras oncogene product is a significant focus in anticancer drug development. Despite the lack of successful Ras signaling inhibitors, recent research has identified PDEδ, a KRAS transporter, as a potential target for inhibiting the oncogenic KRAS signaling pathway. This study aims to investigate the interactions between eight K-Ras inhibitors (deltarazine, deltaflexin 1 and 2, and its analogues) and PDEδ to understand their binding modes. The research will utilize computational techniques such as density functional theory (DFT) and molecular electrostatic surface potential (MESP), molecular docking, binding site analyses, molecular dynamic (MD) simulations, electronic structure computations, and predictions of the binding free energy. Molecular dynamic simulations (MD) will be used to predict the binding conformations and pharmacophoric features in the active site of PDEδ for the examined structures. The binding free energies determined using the MMPB(GB)SA method will be compared with the observed potency values of the tested compounds. This computational approach aims to enhance understanding of the PDEδ selective mechanism, which could contribute to the development of novel selective inhibitors for K-Ras signaling.

Towards Sustainable Pest Management: Toxicity, Biochemical Effects, and Molecular Docking Analysis of Ocimum basilicum (Lamiaceae) Essential Oil on Agrotis ipsilon and Spodoptera littoralis (Lepidoptera: Noctuidae).

Over the last decade, essential oils (EOs) have become potential ingredients for insecticide formulations due to their widespread availability and perceived safety. Therefore, this study aimed to evaluate the toxicity and biochemical efficacy of basil (Ocimum basilicum) (Lamiaceae) against two destructive pests Noctuidae, Agrotis ipsilon (Hufnagel) and Spodoptera littoralis (Boisduval) (Lepidoptera: Noctuidae). In addition, a molecular docking study was performed to gain insight into the binding pattern between glutathione S-transferase (GST) and linalool, the main component of EO. GC-MS analysis of O. basilicum EO revealed that linalool is the most abundant compound (29.34%). However, the toxicity tests showed no significant difference between the values of LC50 of O. basilicum EO to A. ipsilon and S. littoralis. On the other hand, the sublethal experiments indicated that treating the second instar larvae with LC15 or LC50 values of O. basilicum EO significantly prolonged the larval duration in both insects, compared to the control. Regarding the biochemical effect of O. basilicum EO, the treatments significantly impacted the activity of detoxification enzymes. A notable elevation in glutathione S-transferase (GST) activity was recorded in A. ipsilon larvae compared with a reduction in S. littoralis larvae. The molecular docking analysis revealed that linalool bonded with the amino acid serine (SER 9) of GST, indicating its binding affinity with the enzyme. The obtained results could offer valuable insights into the mode of action of O. basilicum and can encourage the adoption of sustainable pest control practices that incorporate essential oils.

Characterization of Spodoptera littoralis (Lepidoptera: Noctuidae) resistance to indoxacarb: inheritance mode, realized heritability, and fitness costs.

Spodoptera littoralis (Boisd.) (Lepidoptera: Noctuidae) is a major economic pest attacking a variety of crops in Egypt and other Mediterranean countries. S. littoralis has developed resistance to both traditional and novel insecticides. The current study investigated S. littoralis resistance to indoxacarb regarding inheritance mode, realized heritability (h2), and fitness costs. An indoxacarb-resistant strain (Indoxa-SEL) was obtained by selecting a field strain with indoxacarb. Indoxa-SEL strain outperformed the susceptible one (Indoxa-S) by 29.77-fold after 16 consecutive generations of selection. Based on the LC50 values of the progenies of reciprocal crosses F1 (R♂ × S♀) and F1' (R♀ × S♂), S. littoralis resistance to indoxacarb was found to be autosomal and partially recessive. Chi-square tests for goodness-of-fit between observed and expected mortalities of self-bred F1 and resistant strain reciprocal crosses revealed that the resistance was controlled by multiple genes. The resistant strain had a relative fitness of 0.80, with significantly increased total preovipositional period of females, egg, larvae, pupae, preadult, adult, and total longevity period. The estimated realized heritability value in the Indoxa-SEL strain was 0.21. The current study will contribute to sustaining indoxacarb efficacy and designing effective resistance management programs against S. littoralis.

Validity of the Triglyceride-Glucose Indices for Predicting the Severity of Coronary Artery Disease in Patients With Nondiabetic Chronic Coronary Syndrome.

BACKGROUND: The triglyceride-glucose (TyG) index was shown to be an independent predictor of coronary artery disease (CAD) progression and prognosis. However, whether the TyG index can predict the severity of CAD in nondiabetic patients with chronic coronary syndrome remains unclear. METHODS: A total of 118 individuals who underwent elective coronary angiography were classified into group A (59 with coronary lesions) and group B (59 with normal coronary arteries; as a control group) after coronary angiography and laboratory tests for fasting and the postprandial (PP) TyG index. The complexity of CAD was determined by the Synergy Between Percutaneous Coronary Intervention (SYNTAX) score (SYNTAX score >22 indicated moderate-high risk), and patients diagnosed with diabetes or prediabetes were excluded. RESULTS: The TyG index was not related to the SYNTAX score in groups A and B; however, in the CAD group with an low-density lipoprotein (LDL) concentration <70 mg/dL (group A1), a fasting TyG index ≥8.25 and a PP TyG index ≥11 could predict moderate-high SYNTAX risk score; in addition, the odds ratio (OR) was 4.3× higher and the relative risk (RR) was 1.8× greater (OR = 4.3, RR = 1.8, 95% confidence interval = 1.4-13.5, P < 0.05) for individuals with a higher fasting TyG index ≥8.25 to have a moderate-high SYNTAX risk score. Individuals with a higher PP TyG index ≥11 had OR of 2.6× higher and a RR of 1.4× greater to have moderate-high SYNTAX risk score. CONCLUSIONS: Both fasting and PP TyG levels were associated with greater coronary anatomical complexity (SYNTAX score >22) in nondiabetic chronic coronary patients with LDL <70 mg/dL. Fasting and the PP TyG indices can serve as noninvasive predictors of CAD complexity in nondiabetic patients with LDL <70 mg/dL and could change the management and therapeutic approaches.

Paratesticular solitary fibrous tumor: A case report.

Paratesticular solitary fibrous tumors are a very rare benign tumor that are usually low-grade neoplasms of pericytes and myofibroblast-like cells. They're slow growing and painless. We report a case of a male patient of 32 years old who came to our medical structure complaining about the appearance of scrotal mass, painful sometimes. Investigations revealed a scrotal mass which was surgically removed. Immunohisochemical study concluded to the presence of a solitary fibrous tumor.

Chemical composition of four essential oils and their adulticidal, repellence, and field oviposition deterrence activities against Culex pipiens L. (Diptera: Culicidae).

Effective mosquito repellents can limit the transmission of vector-borne diseases to humans. Consequently, there is an urgent need to develop mosquito control strategies that prioritize eco-friendly and cost-effective repellents. Essential oils (EOs) have enormous potential for mosquito repellency. Here, cinnamon, basil, eucalyptus, and peppermint EOs were investigated for adulticide and repellency properties against Culex pipiens as well on the oviposition behavior of gravid females from laboratory (lab test) and field (field test) populations. Cinnamon oil was an effective oviposition deterrent regardless of the population and had high adulticidal activity with toxicity index of 75.00% at 24 h of exposure, relative to deltamethrin. In addition, it exhibited effective repellency at 98.01% and 71.22% at 6.67 and 1.71 µl/cm2, respectively. Peppermint oil had the least adulticidal activity with toxicity index of 6.2% at 24 h, and it resulted in low repellency at 70.90% and 50.64% at 6.67 and 1.71 µl/cm2, respectively. On average, basil and eucalyptus oils showed some adulticidal efficiency, repellency, and oviposition deterrent activity. For all treatments, the oviposition deterrent index values of gravid females from natural populations (field test) were lower than those from lab-reared (lab test) females. Different ratios of monoterpenoids, phenylpropanoids, and fatty acids in the EOs tested likely account for the activity variations observed. Our results suggest cinnamon, basil, eucalyptus, and peppermint EOs, which are widely available, economical, and eco-friendly, with good potential for mosquito control strategies.

Development of new thieno[2,3-d]pyrimidines as dual EGFR and STAT3 inhibitors endowed with anticancer and pro-apoptotic activities.

In part due to the resilience of cellular feedback pathways that develop therapeutic resistance to targeting the EGFR alone, using EGFR inhibitors alone was demonstrated to be unsuccessful in clinical trials. The over-activation of the signal transducer/activator of transcription 3 (STAT3) during the administration of an EGFR inhibitor is expected to play a substantial part in the failure and resistance of EGFR inhibitor treatment. Therein, we proposed a hypothesis that induced STAT3-mediated resistance to EGFR inhibition therapy could be addressed by a dual inhibition of EGFR and STAT3 method. To this end, we tried to discover new thieno[2,3-d]pyrimidine derivatives "5a-o". Results from the screening on A549 and MCF7 cancer cell lines revealed that compounds 5j and 5k showed two-digit nanomolar with appropriate safety towards the WI-38 cell line. The best molecules, 5j and 5k, were subjected to γ-radiation, and their cytotoxic efficacy didn't change after irradiation, demonstrating that not having to use it avoided its side effects. Compounds 5j and 5k demonstrated the highest inhibition when their potency was tested as dual inhibitors on EGFR 67 and 41 nM, respectively, and STAT3 5.52 and 3.34 nM, respectively, proved with in silico molecular docking and dynamic simulation. In light of the results presented above, the capacity of both powerful compounds to alter the cell cycle and initiate the apoptotic process in breast cancer MCF7 cells was investigated. Caspase-8, Bcl-2, Bax and Caspase-9 apoptotic indicators were studied.

Discovery of Novel Pyridazine-Tethered Sulfonamides as Carbonic Anhydrase II Inhibitors for the Management of Glaucoma.

As a progressive neuropathic condition, glaucoma can cause lifelong blindness if left untreated. Novel phenylpyridazine-tethered sulfonamides were designed as selective inhibitors for carbonic anhydrase (CA) isoform II to find effective therapeutic agents for glaucoma. Subsequently, the target inhibitors were synthesized and assessed for their inhibitory action against cytosolic CA I and II. Interestingly, the synthesized molecules poorly inhibited CA I while exhibiting low subnanomolar potency against CA II. Compound 7c disclosed the most potent activity (IC50 = 0.63 nM) with high selectivity against CA II (605-fold than acetazolamide selectivity). Moreover, compound 7c also showed significant in vivo IOP-reducing properties in the in vivo model of glaucoma. Furthermore, the binding of compound 7c to CA II was assessed at the molecular level, exploiting the molecular docking approach.

Rosuvastatin and diosmetin inhibited the HSP70/TLR4 /NF-κB p65/NLRP3 signaling pathways and switched macrophage to M2 phenotype in a rat model of acute kidney injury induced by cisplatin.

Numerous efforts to manage acute kidney injury (AKI) were unsuccessful because its pathophysiology is still poorly understood. Thus, our research hotspot was to explore the possible renoprotective effects of rosuvastatin (Ros) and diosmetin (D) on macrophage polarization and the role of HSP70/TLR4/MyD88/NF-κB p65/NLRP3/STAT3 signaling in cis-induced AKI and study the activity of D against uropathogenic bacteria. Fifty-four albino male rats were randomized into 9 groups equally: Control, Ros, D20, D40, untreated Cis, and Cis groups cotreated with Ros, D20, D40 and Ros+D40 for 10 days. Our results indicated that Ros and D, in a dose-dependent manner, markedly restored body weight, systolic blood pressure, and renal histological architecture besides significantly upregulated SOD levels, expression of anti-inflammatory CD163 macrophages, arginase1levels, IL-10 levels,STAT3 and PCNA immunoreactivity. Also, they significantly downregulated renal index, serum urea, serum creatinine, serum cystatin c, inflammatory biomarkers (C reactive protein, IL1ß & TNF-α), MDA levels, HSP70/TLR4/MyD88/NF-κB p65/NLRP3 expressions, proinflammatory CD68 macrophages and caspase-3 immunoreactivity, resulting in a reversal of cis-induced renal damage. These findings were further confirmed by molecular docking that showed the binding affinity of Ros and D towards TLR4 and NLRP3. Furthermore, D had antibacterial action with a minimum inhibitory concentration ranging from 128 to 256 µg/mL and caused a delay in the growth of the tested isolates, and negatively affected the membrane integrity. In conclusion, Ros and D had antioxidant, anti-inflammatory and antiapoptotic properties and switched macrophage from proinflammatory CD68 to anti-inflammatory CD163. Additionally, the targeting of HSP70/TLR4/MyD88/NF-κB p65/NLRP3/STAT3 signals are effective therapeutic strategy in AKI.

Study of the binding interaction of salmon sperm DNA with nintedanib, a tyrosine kinase inhibitor using multi-spectroscopic, thermodynamic, and in silico approaches.

The study of the intermolecular binding interaction of small molecules with DNA can guide the rational drug design with greater efficacy and improved or more selective activity. In the current study, nintedanib's binding interaction with salmon sperm DNA (ssDNA) was thoroughly investigated using UV-vis spectrophotometry, spectrofluorimetry, ionic strength measurements, viscosity measurements, thermodynamics, molecular docking, and molecular dynamic simulation techniques under physiologically simulated conditions (pH 7.4). The obtained experimental results showed that nintedanib and ssDNA had an apparent binding interaction. Nintedanib's binding constant (Kb) with ssDNA, as determined using the Benesi-Hildebrand plot, was 7.9 × 104 M-1 at 298 K, indicating a moderate binding affinity. The primary binding contact forces were hydrophobic and hydrogen bonding interactions, as verified by the enthalpy and entropy changes (ΔH0 and ΔS0), which were - 16.25 kJ.mol-1 and 39.30 J mol-1 K-1, respectively. According to the results of UV-vis spectrophotometry, viscosity assays, and competitive binding interactions with ethidium bromide or rhodamine B, the binding mode of nintedanib to ssDNA was minor groove. Molecular docking and molecular dynamic simulation studies showed that nintedanib fitted into the B-DNA minor groove's AT-rich region with high stability. This study can contribute to further understanding of nintedanib's molecular mechanisms and pharmacological effects.

Tailored horseshoe-shaped nicotinonitrile scaffold as dual promising c-Met and Pim-1 inhibitors: Design, synthesis, SAR and in silico study.

For the horseshoe tactic to succeed in inhibiting c-Met and Pim-1, the nicotinonitrile derivatives (2a-n) were produced in high quantities by coupling acetyl phenylpyrazole (1) with the proper aldehydes and ethyl cyanoacetate under basic conditions. Consistent basic and spectroscopic data (NMR, IR, Mass, and HPLC) supported the new products' structural findings. With IC50 potency in nanomolar ranges, these compounds had effectively repressed them, particularly compounds 2d and 2 h, with IC50 values below 200 nM. The most potent compounds (2d and 2 h) were tested for their antitumor effects against prostate (PC-3), colon (HCT-116), and breast (MDA-MB-231) and were evaluated in comparison to the anticancer drug tivantinib using the MTT assay. Similar to tivantinib, these compounds showed good antiproliferative properties against the HCT-116 tumor cells while having low cytotoxicity towards healthy fetal colon (FHC) cells. In the HCT-116 cell line, their ability to trigger the apoptotic cascade was also investigated by looking at the level of Bax and Bcl-2 as well as the activation of the proteolytic caspase cascade. When HCT-116 cells were exposed to compounds 2d and 2 h in comparison to the control, active caspase-3 levels increased. The HCT-116 cell line also upregulated Bcl-2 protein levels and downregulated Bax levels. Additionally, when treated with compound 2d, the HCT-116 cell cycle was primarily stopped at the S phase. Compared to the control, compound 2d treatment significantly inhibited the protein expression levels of c-Met and Pim-1 kinases in the treated HCT-116 cells. Thorough molecular modeling analyses, such as molecular docking and dynamic simulation, were performed to ascertain the binding mechanism and stability of the target compounds.