Synthesis, in vitro and in silico study of novel 1,3-diphenylurea derived Schiff bases as competitive α-glucosidase inhibitors.

Diabetes mellitus has become a major global health burden because of several related consequences, including heart disease, retinopathy, cataracts, metabolic syndrome, collapsed renal function, and blindness. In the recent study, thirty Schiff base derivatives of 1,3-diphenylurea were synthesized and their anti-diabetic activity was evaluated by targeting α-glucosidase. The compounds exhibited an overwhelming inhibitory potential for α-glucosidase with higher potency ranging from 2.49-37.16 µM. The most effective compound, 5h, showed competitive inhibition of α-glucosidase (K i = 3.96 ± 0.0048 µM) in the kinetic analysis and strong binding interactions with key residues α-glucosidase in docking analysis, indicating its potential for better glycemic control in diabetes patients.

In silico analysis of potential inhibitors for breast cancer targeting 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyses.

Breast cancer (BC) is still one of the major issues in world health, especially for women, which necessitates innovative therapeutic strategies. In this study, we investigated the efficacy of retinoic acid derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), which plays a crucial role in the biosynthesis and metabolism of oestrogen and thereby influences the progression of BC and, the main objective of this investigation is to identify the possible drug candidate against BC through computational drug design approach including PASS prediction, molecular docking, ADMET profiling, molecular dynamics simulations (MD) and density functional theory (DFT) calculations. The result has reported that total eight derivatives with high binding affinity and promising pharmacokinetic properties among 115 derivatives. In particular, ligands 04 and 07 exhibited a higher binding affinity with values of -9.9 kcal/mol and -9.1 kcal/mol, respectively, than the standard drug epirubicin hydrochloride, which had a binding affinity of -8.2 kcal/mol. The stability of the ligand-protein complexes was further confirmed by MD simulations over a 100-ns trajectory, which included assessments of hydrogen bonds, root mean square deviation (RMSD), root mean square Fluctuation (RMSF), dynamic cross-correlation matric (DCCM) and principal component analysis. The study emphasizes the need for experimental validation to confirm the therapeutic utility of these compounds. This study enhances the computational search for new BC drugs and establishes a solid foundation for subsequent experimental and clinical research.

Novel candidates synthesis of indenopyrazole, indenoazine and indenothiophene, with anticancer and in silico studies.

Aim: The indandione nucleus, is one of the most amazing nuclei in medicinal chemistry, is used to design new derivatives.Methods & materials: Novel indandione derivatives are prepared with different electrophilic and nucleophilic reagents to yield 3, 4, 8, 11, 14, 16, 19, 20, 21, 22 and 23. Compounds 8, 11, 16, 20 and 23 are investigated against OVCAR-3 and HeLa, using LLC-MK2 and cis-Pt as references. in silico and spectral studies were analyzed for the selected compounds.Results: Compounds 20 and 23 at 100 ns were the most potent compounds, so molecular dynamics studies were performed.Conclusion: Compound 23 was the most active toward the HeLa cervical cell line, and compound 20 was the most active toward the Ovcar-3 cell line.

[Box: see text].

Synthesis, in vitro, and in silico study of novel pyridine based 1,3-diphenylurea derivatives as tyrosinase inhibitors.

Tyrosinase inhibitors are studied in the cosmetics and pharmaceutical sectors as tyrosinase enzyme is involved in the biosynthesis and regulation of melanin, hence these inhibitors are beneficial for the management of melanogenesis and hyperpigmentation-related disorders. In the current work, a novel series of diphenyl urea derivatives containing a halo-pyridine moiety (5a-t) was synthesized via a multi-step synthesis. In vitro, tyrosinase inhibitory assay results showed that, except for two compounds, the derivatives were excellent inhibitors of human tyrosinase. The average IC50 value of the inhibitors (15.78 µM) is lower than that of kojic acid (17.3 µM) used as the reference compound, indicating that, on average, these molecules are more potent than the reference. Derivative 5a was identified as the most potent human tyrosinase inhibitor of the series, with an IC50 value of 3.5 ± 1.2  µM, approximately 5 times more potent than kojic acid. To get further insights into the nature of binding site interactions, molecular docking and molecular dynamics simulation studies were carried out. Moreover, the evaluation of in silico ADME properties showed a highly favorable profile for the synthesized compounds. These findings suggested that the further development of this class of compounds could be useful to get potent drug-like compounds that can target hyperpigmentation-related disorders.

Discovery of Novel and Selective Schiff Base Inhibitors as a Key for Drug Synthesis, Molecular Docking, and Pharmacological Evaluation.

Diabetes mellitus (DM) is a chronic disorder and still a challenge throughout the world, and therefore the search for safe and effective inhibitors for α-amylase and α-glucosidase is increasing day by day. In this work, we try to carry out the synthesis, modification, and computer-aided results of and biological research on thiadiazole-based Schiff base derivatives and evaluate their in vitro α-amylase and α-glucosidase inhibitory potential (1-15). In the current series, all of the synthesized analogues were shown to have potential inhibitory effects on targeted enzymes. The IC50 values for α-amylase values ranged from 20.10 ± 0.40 to 0.80 ± 0.05 µM, compared with the standard drug acarbose having an IC50 value of 10.30 ± 0.20 µM, while for α-glucosidase, the IC50 values ranged from 20.10 ± 0.50 to 1.20 ± 0.10 µM, compared to acarbose with an IC50 value of 9.80 ± 0.20 µM. For better understanding, a SAR investigation was undertaken. In this series, nine scaffolds (1, 2, 3, 6, 9, 10, 11, 13, and 15) were more active than the reference drug and the docking parameter RMSD values for α-glucosidase and α-amylase were 1.766, 2.7746, 1.6025, 2.2112, 3.5860, 2.3360, 1.6178, 2.0254, and 2.0797 and 2.6020, 1.9509, 3.1642, 1.7547, 2.2130, 1.4221, and 1.1087, respectively. The toxicity of the selected analogues was calculated by using the OSIRIS tool, and the TPSA values were found to be lower than 140 to represent the drug-like properties; those from Molinspiration were studied as well. The following properties were studied and found to have better biological properties. The remaining analogues (4, 5, 7, 8, 12, and 14) were also identified as potential inhibitors of both enzymes, but they were less active than the reference due to the substituents attached to the aromatic parts. The structures of synthesized compounds were confirmed through different spectroscopic analyses.

Identification of therapeutic drug target of Shigella Flexneri serotype X through subtractive genomic approach and in-silico screening based on drug repurposing.

Shigellosis, induced by Shigella flexneri, constitutes a significant health burden in developing nations, particularly impacting socioeconomically disadvantaged communities. Designated as the second most prevalent cause of diarrheal illness by the World Health Organization (WHO), it precipitates an estimated 212,000 fatalities annually. Within the spectrum of S. flexneri strains, serotype X is notably pervasive and resilient, yet its comprehensive characterization remains deficient. The present investigation endeavors to discern potential pharmacological targets and repurpose existing drug compounds against S. flexneri serotype X. Employing the framework of subtractive genomics, the study interrogates the reference genome of S. flexneri Serotype X (strain 2,002,017; UP000001884) to delineate its proteome into categories of non-homologous, non-paralogous, essential, virulent, and resistant constituents, thereby facilitating the identification of therapeutic targets. Subsequently, a screening of approximately 9000 compounds from the FDA library against the identified drug target aims to delineate efficacious agents for combating S. flexneri serotype X infections. The application of subtractive genomics methodology yields prognostic insights, unveiling non-paralogous proteins (n = 4122), non-homologues (n = 1803), essential (n = 1246), drug-like (n = 389), resistant (n = 167), alongside 42 virulent proteins within the reference proteome. This iterative process culminates in the identification of Serine O-acetyltransferase as a viable drug target. Subsequent virtual screening endeavors to unearth FDA-approved medicinal compounds capable of inhibiting Serine O-acetyltransferase. Noteworthy candidates such as DB12983, DB15085, DB16098, DB16185, and DB16262 emerge, exhibiting potential for mitigating S. flexneri Serotype X. Despite the auspicious findings, diligent scrutiny is imperative to ascertain the efficacy and safety profile of the proposed drug candidates vis-à-vis S. flexneri.

Rational design, synthesis, biological evaluation, and molecular modeling of novel naphthamide derivatives possessing potent, reversible, and competitive inhibitory mode of action over human monoamine oxidase.

Herein, a novel series of naphthamide derivatives has been rationally developed, synthesized, and evaluated for their inhibitory activity against monoamine oxidase (MAO) and cholinesterase (ChE) enzymes. Compared to the reported naphthalene-based hit IV, the new naphthamide hybrids 2a, 2c, 2g and 2h exhibited promising MAO inhibitory activities; with an IC50 value of 0.294 µM, compound 2c most potently inhibited MAO-A, while compound 2g exhibited most potent MAO-B inhibitory activity with an IC50 value of 0.519 µM. Compounds 2c and 2g showed selectivity index (SI) values of 6.02 for MAO-A and 2.94 for MAO-B, respectively. On the other hand, most compounds showed weak inhibitory activity against ChEs except 2a and 2h over butyrylcholinesterase (BChE). The most potent compounds 2c and 2g were found to be competitive and reversible MAO inhibitors based on kinetic and reversibility studies. Plausible interpretations of the observed biological effects were provided through molecular docking simulations. The drug-likeness predicted by SwissADME and Osiris property explorer showed that the most potent compounds (2a, 2c, 2g, and 2h) obey Lipinski's rule of five. Accordingly, in the context of neurological disorders, hybrids 2c and 2g may contribute to the identification of safe and potent therapeutic approaches in the near future.

Correction: Elsherbeny et al. 2-(3-Bromophenyl)-8-fluoroquinazoline-4-carboxylic Acid as a Novel and Selective Aurora A Kinase Inhibitory Lead with Apoptosis Properties: Design, Synthesis, In Vitro and In Silico Biological Evaluation. Life 2022, 12, 876.

In the original publication [...].

New 1,3,4-Thiadiazole Derivatives as α-Glucosidase Inhibitors: Design, Synthesis, DFT, ADME, and In Vitro Enzymatic Studies.

Diabetes is an emerging disorder in the world and is caused due to the imbalance of insulin production as well as serious effects on the body. In search of a better treatment for diabetes, we designed a novel class of 1,3,4-thiadiazole-bearing Schiff base analogues and assessed them for the α-glucosidase enzyme. In the series (1-12), compounds are synthesized and 3 analogues showed excellent inhibitory activity against α-glucosidase enzymes in the range of IC50 values of 18.10 ± 0.20 to 1.10 ± 0.10 µM. In this series, analogues 4, 8, and 9 show remarkable inhibition profile IC50 2.20 ± 0.10, 1.10 ± 0.10, and 1.30 ± 0.10 µM by using acarbose as a standard, whose IC50 is 11.50 ± 0.30 µM. The structure of the synthesized compounds was confirmed through various spectroscopic techniques, such as NMR and HREI-MS. Additionally, molecular docking, pharmacokinetics, cytotoxic evaluation, and density functional theory study were performed to investigate their behavior.

Synthesis of new class of non-sulfonamide bis-benzimidazoles as antitumor agents by inhibiting carbonic anhydrase-IX enzyme.

In several types of cancers, the expression of carbonic anhydrase-IX (CA-IX) enzyme is elevated than its normal level which ultimately plays a key role in the tumor growth of epithelial cells in breast and lung cancer by acidifying tumor microenvironment, therefore, inhibition of this target is important in antitumor therapy. We have synthesized bis-benzimidazole derivatives (1-25) by using 3,3'-diaminobenzidine and various aromatic aldehydes and characterized by various spectroscopic methods (UV/Visible, 1HNMR, 13CNMR, and mass spectrometry). Their inhibitory potential for human CA-IX (hCA-IX) was evaluated in-vitro, where several synthesized derivatives showed potent inhibition of hCA-IX (IC50 values in range of 5.23 ± 1.05 to 40.10 ± 1.78 µM) and compounds 3-5, 7-8, 13-16, 21 and 23 showed superior activity than the standard drug "acetazolamide" (IC50 = 18.24 ± 1.43 µM). Furthermore, all these compounds showed no toxicity on human fibroblast cell lines (BJ cell lines). Moreover, molecular docking was carried out to predict their binding modes in the active site of CA-IX and revealed a significant role of imidazole ring of synthesized entities in their effective binding with the specific residues of CA-IX. The obtained results paved the way for further in vivo and other pharmacological studies for the optimization of these molecules as possible anti-cancer agents.

In vitro and in vivo evaluation of the antimicrobial, antioxidant, cytotoxic, hemolytic activities and in silico POM/DFT/DNA-binding and pharmacokinetic analyses of new sulfonamide bearing thiazolidin-4-ones.

In this work, Schiff bases and Thiazolidin-4-ones, were synthesized using Sonication and Microwave techniques, respectively. The Schiff base derivatives (3a-b) were synthesized via the reaction of Sulfathiazole (1) with benzaldehyde derivatives (2a-b), followed by the synthesis of 4-thiazoledinone (4a-b) derivatives by cyclizing the synthesized Schiff bases through thioglycholic acid. All the synthesized compounds were characterized by spectroscopic techniques such as FT IR, NMR and HRMS. The synthesized compounds were tested for their in vitro antimicrobial and antioxidant and in vivo cytotoxicity and hemolysis ability. The synthesized compounds displayed better antimicrobial and antioxidant activity and low toxicity in comparison to reference drugs and negative controls, respectively. The hemolysis test revealed the compounds exhibit lower hemolytic effects and hemolytic values are comparatively low and the safety of compounds is in comparison with standard drugs. Theoretical calculations were carried out by using the molecular operating environment (MOE) and Gaussian computing software and observations were in good agreement with the in vitro and in vivo biological activities. Petra/Osiris/Molinspiration (POM) results indicate the presence of three combined antibacterial, antiviral and antitumor pharmacophore sites. The molecular docking revealed the significant binding affinities and non-bonding interactions between the compounds and Erwinia Chrysanthemi (PDB ID: 1SHK). The molecular dynamics simulation under in silico physiological conditions revealed a stable conformation and binding pattern in a stimulating environment. HighlightsNew series of Thaiazolidin-4-one derivatives have been synthesized.Sonication and microwave techniques are used.Antimicrobial, Antioxidant, cytotoxicity, and hemolysis activities were observed for all synthesized compounds.Molecular Docking and DFT/POM analyses have been predicted.Communicated by Ramaswamy H. Sarma.

Synthesis of novel pyrazolone candidates with studying some biological activities and in-silico studies.

Pyranopyrazole derivatives have a vital role in the class of organic compounds because of their broad spectrum of biological and pharmacological importance. Our current goal is the [3 + 3] cycloaddition of benzoyl isothiocyanate and pyrazolone 1 to undergo oxidation cyclization, producing pyrazoloxadiazine 3. The diol 5 was obtained as a condensation of two equivalents of 1 with thiophene-2-carboxaldehyde in acetic acid above the sodium acetate mixture. When the condensation was carried out in piperidine under fusion, unsaturated ketone 4 was obtained. The pyrazolo pyran derivative 11 resulted from the [3 + 3] cycloaddition of 1 and cinnamic acid, while the Pyrone derivative was prepared by acylation of 12 with two equivalents of acetic anhydride. Phthalic anhydride undergoes arylation using zinc chloride as a catalyst. The cyclic keto acid 23 was synthesized by the action of succinic anhydride on 12 in the acetic medium, while the latter reacted with cinnamic acid, leading to pyrazole derivative 24. All of these reactions were through the Michael reaction mechanism. All the tested compounds showed good antimicrobial activity against pathogenic microorganisms; newly synthesized compounds were also screened for their antioxidant activity. Rational studies were carried out by the ABTs method to allow a broader choice of activities. In addition, similar off-compounds were conducted. Molecular docking studies with the CB-Dock server and MD simulations were created with the default settings of the Solution Builder on the CHARMM-GUI server at 150 nm. A good correlation was obtained between the experimental results and the theoretical bioavailability predictions using POM theory.

Anti-Inflammatory Study and Phytochemical Characterization of Zingiber officinale Roscoe and Citrus limon L. Juices and Their Formulation.

Zingiber officinale and Citrus limon, well known as ginger and lemon, are two vegetals widely used in traditional medicine and the culinary field. The juices of the two vegetals were evaluated based on their inflammation, both in vivo and in vitro. High-performance liquid chromatography (HPLC) was used to characterize different juices from Zingiber officinale Roscoe and Citrus limon. After the application of the HPLC method, different compounds were identified, such as 6-gingerol and 6-gingediol from the ginger juice and isorhamnetin and hesperidin from the lemon juice. In addition, the two juices and their formulation were assessed for their anti-inflammatory activity, in vitro by utilizing the BSA denaturation test, in vivo using the carrageenan-induced inflammation test, and the vascular permeability test. Important and statistically significant anti-inflammatory activities were observed for all juices, especially the formulation. The results of our work showed clearly that the Zingiber officinale and Citrus limon juices protect in vivo the development of the rat paw edema, especially the formulation F composed of the Zingiber officinale and Citrus limon juices, which shows an anti-inflammatory activity equal to -35.95% and -44.05% using 10 and 20 mg/kg of the dose, respectively. Our work also showed that the formulation was the most effective tested extract since it inhibits the vascular permeability by -37% and -44% at the doses of 200 and 400 mg/kg, respectively, and in vitro via the inhibition of the denaturation of BSA by giving a synergetic effect with the highest IC50 equal to 684.61 ± 7.62 µg/mL corresponding to the formulation F. This work aims to develop nutraceutical preparations in the future and furnishes the support for a new investigation into the activities of the various compounds found in Zingiber officinale Roscoe and Citrus limon.

Synthesis and In Vitro α-Amylase and α-Glucosidase Dual Inhibitory Activities of 1,2,4-Triazole-Bearing bis-Hydrazone Derivatives and Their Molecular Docking Study.

There is an increasing prevalence of diabetes mellitus throughout the world, and new compounds are necessary to combat this. The currently available antidiabetic therapies are long-term complicated and side effect-prone, and this has led to a demand for more affordable and more effective methods of tackling diabetes. Research is focused on finding alternative medicinal remedies with significant antidiabetic efficacy as well as low adverse effects. In this research work, we have focused our efforts to synthesize a series of 1,2,4-triazole-based bis-hydrazones and evaluated their antidiabetic properties. In addition, the precise structures of the synthesized derivatives were confirmed with the help of various spectroscopic techniques including 1H-NMR, 13C-NMR, and HREI-MS. To find the antidiabetic potentials of the synthesized compounds, in vitro α-glucosidase and α-amylase inhibitory activities were characterized using acarbose as the reference standard. From structure-activity (SAR) analysis, it was confirmed that any variation found in inhibitory activities of both α-amylase and α-glucosidase enzymes was due to the different substitution patterns of the substituent(s) at variable positions of both aryl rings A and B. The results of the antidiabetic assay were very encouraging and showed moderate to good inhibitory potentials with IC50 values ranging from 0.70 ± 0.05 to 35.70 ± 0.80 µM (α-amylase) and 1.10 ± 0.05 to 30.40 ± 0.70 µM (α-glucosidase). The obtained results were compared to those of the standard acarbose drug (IC50 = 10.30 ± 0.20 µM for α-amylase and IC50 = 9.80 ± 0.20 µM for α-glucosidase). Specifically, compounds 17, 15, and 16 were found to be significantly active with IC50 values of 0.70 ± 0.05, 1.80 ± 0.10, and 2.10 ± 0.10 µM against α-amylase and 1.10 ± 0.05, 1.50 ± 0.05, and 1.70 ± 0.10 µM against α-glucosidase, respectively. These findings reveal that triazole-containing bis-hydrazones act as α-amylase and α-glucosidase inhibitors, which help develop novel therapeutics for treating type-II diabetes mellitus and can act as lead molecules in drug discovery as potential antidiabetic agents.

Eco-Friendly Synthesis of 1H-benzo[d]imidazole Derivatives by ZnO NPs Characterization, DFT Studies, Antioxidant and Insilico Studies.

Benzimidazoles are classified as a category of heterocyclic compounds. Molecules having benzimidazole motifs show promising utility in organic and scientific studies. A series of mono-substituted benzimidazoles were synthesized by ZnO-NPs via cyclocondensation between substituted aromatic aldehydes and o-phenylene diamine. The synthesized compounds were characterized and compared with the traditional methods. The nano-catalyzed method displayed a higher yield, shorter time and recyclable catalyst. The DFT study and antioxidant activity were investigated for benzo[d]imidazole derivatives. Compound 2a exhibited the highest antioxidant activity among the tested compounds. We focused on the catalytic activity of ZnO in the synthesis of heterocyclic structures with the goal of stimulating further progress in this field. The superiorities of this procedure are high yield of product, low amounts of catalyst and short reaction time.

In Silico Development of Novel Benzofuran-1,3,4-Oxadiazoles as Lead Inhibitors of M. tuberculosis Polyketide Synthase 13.

Benzofuran and 1,3,4-oxadiazole are privileged and versatile heterocyclic pharmacophores which display a broad spectrum of biological and pharmacological therapeutic potential against a wide variety of diseases. This article reports in silico CADD (computer-aided drug design) and molecular hybridization approaches for the evaluation of the chemotherapeutic efficacy of 16 S-linked N-phenyl acetamide moiety containing benzofuran-1,3,4-oxadiazole scaffolds BF1-BF16. This virtual screening was carried out to discover and assess the chemotherapeutic efficacy of BF1-BF16 structural motifs as Mycobacterium tuberculosis polyketide synthase 13 (Mtb Pks13) enzyme inhibitors. The CADD study results revealed that the benzofuran clubbed oxadiazole derivatives BF3, BF4, and BF8 showed excellent and remarkably significant binding energies against the Mtb Pks13 enzyme comparable with the standard benzofuran-based TAM-16 inhibitor. The best binding affinity scores were displayed by 1,3,4-oxadiazoles-based benzofuran scaffolds BF3 (-14.23 kcal/mol), BF4 (-14.82 kcal/mol), and BF8 (-14.11 kcal/mol), in comparison to the binding affinity score of the standard reference TAM-16 drug (-14.61 kcal/mol). 2,5-Dimethoxy moiety-based bromobenzofuran-oxadiazole derivative BF4 demonstrated the highest binding affinity score amongst the screened compounds, and was higher than the reference Pks13 inhibitor TAM-16 drug. The bindings of these three leads BF3, BF4, and BF8 were further confirmed by the MM-PBSA investigations in which they also exhibited strong bindings with the Pks13 of Mtb. Moreover, the stability analysis of these benzofuran-1,3,4-oxadiazoles in the active sites of the Pks13 enzyme was achieved through molecular dynamic (MD) simulations at 250 ns virtual simulation time, which indicated that these three in silico predicted bio-potent benzofuran tethered oxadiazole molecules BF3, BF4, and BF8 demonstrated stability with the active site of the Pks13 enzyme.

Transcriptional Analysis of TP53 Gene in Chronic Hepatitis C Patients Treated with Sofosbuvir, Daclatasvir, Pegylated Interferon, and Ribavirin.

Hepatitis C virus (HCV) is a major public health problem that affects more than 170 million people globally. HCV is a principal cause of hepatocellular carcinoma (HCC) around the globe due to the high frequency of hepatitis C infection, and the high rate of HCC is seen in patients with HCV cirrhosis. TP53 is considered as a frequently altered gene in all cancer types, and it carries an interferon response element in its promoter region. In addition to that, the TP53 gene also interacts with different HCV proteins. HCV proteins especially NS3 protein and core protein induce the mutations in the TP53 gene that lower the expression of this gene in HCV patients and leads to HCC development. In this study, we examined the transcriptional analysis of the TP53 gene in HCV-infected patients administered with different combinations of antiviral therapies including sofosbuvir + daclatasvir, sofosbuvir + ribavirin, and pegylated interferon + ribavirin. This study included 107 subjects; 15 treated with sofosbuvir + daclatasvir, 58 treated with sofosbuvir + ribavirin, 11 treated with interferon + ribavirin, 8 untreated, 10 HCC patients, and 5 were healthy controls. Total RNA was extracted from the PMBCs of HCV infected patients and reverse transcribed into cDNA using a gene specific reverse primer. The expression level of TP53 mRNA was analyzed using quantitative PCR. The expression of TP53 mRNA was notably upregulated in rapid virological response (RVR), early virological response (EVR), and sustained virological response (SVR) groups as compared to non-responders and naïve groups. The expression of TP53 mRNA was seen high in HCC as compared to control groups. Additionally, it has been demonstrated that sofosbuvir + daclatasvir treatment stimulates significant elevation in TP53 gene expression as compared to (sofosbuvir + ribavirin) and (IFN + ribavirin) treatment. This study indicates that the TP53 gene expression is highly upregulated in RVR, EVR, and SVR groups as compared to control groups. Moreover, sofosbuvir + daclatasvir therapy induces significant rise in TP53 mRNA expression levels as compared to (sofosbuvir + ribavirin) and (IFN + ribavirin) treatment. According to these results, it can be concluded that sofosbuvir + daclatasvir plays a significant role in preventing HCV patients from developing severe liver complications as compared to other administered therapies. This study is novel as no such type of study has been conducted previously on the expression of TP53 in local HCV-infected population treated with different combinations of therapies. This study is helpful for the development of new therapeutic strategies and for improving existing therapies.

Molecular Modeling and Synthesis of Indoline-2,3-dione-Based Benzene Sulfonamide Derivatives and Their Inhibitory Activity against α-Glucosidase and α-Amylase Enzymes.

Diabetes is also known as a critical and noisy disease. Hyperglycemia, that is, increased blood glucose level is a common effect of uncontrolled diabetes, and over a period of time can cause serious effects on health such as blood vessel damage and nervous system damage. However, many attempts have been made to find suitable and beneficial solutions to overcome diabetes. Considering this fact, we synthesized a novel series of indoline-2,3-dione-based benzene sulfonamide derivatives and evaluated them against α-glucosidase and α-amylase enzymes. Out of the synthesized sixteen compounds (1-16), only three compounds showed better results; the IC50 value was in the range of 12.70 ± 0.20 to 0.90 ± 0.10 µM for α-glucosidase against acarbose 11.50 ± 0.30 µM and 14.90 ± 0.20 to 1.10 ± 0.10 µM for α-amylase against acarbose 12.20 ± 0.30 µM. Among the series, only three compounds showed better inhibitory potential such as analogues 11 (0.90 ± 0.10 µM for α-glucosidase and 1.10 ± 0.10 µM for α-amylase), 1 (1.10 ± 0.10 µM for α-glucosidase and 1.30 ± 0.10 µM for α-amylase), and 6 (1.20 ± 0.10 µM for α-glucosidase and 1.60 ± 0.10 µM for α-amylase). Molecular modeling was performed to determine the binding affinity of active interacting residues against these enzymes, and it was found that benzenesulfonohydrazide derivatives can be indexed as suitable inhibitors for diabetes mellitus.

Structure-based identification of potential substrate antagonists for isethionate sulfite-lyase enzyme of Bilophila Wadsworthia: Towards novel therapeutic intervention to curb gut-associated illness.

Bilophila wadsworthia is one of the prominent sources of hydrogen sulfide (H2S) production in appendices, excessive levels of which can result in a weaker colonic mucus barrier, inflammatory bowel disease, and colorectal cancer. Isethionate sulfite-lyase (IslA) enzyme catalyzes H2S production by cleaving CS bond in isethionate, producing acetaldehyde and sulfite. In this study, we aimed to identify potential substrate antagonists for IsIA using a structure-based drug design. Initially, pharmacophore-based computational screening of the ZINC20 database yielded 66 hits that were subjected to molecular docking targeting the isethionate binding site of IsIA. Based on striking docking scores, nine compounds showed strong interaction with critical IsIA residues (Arg189, Gln193, Glu470, Cys468, and Arg678), drug-like features, appropriate adsorption, metabolism, excretion, and excretion profile with non-toxicity. Molecular dynamics simulations uncovered the significant impact of binding the compounds on protein conformational dynamics. Finally, binding free energies revealed substantial binding affinity (ranging from -35.23 to -53.88 kcal/mol) of compounds (ZINC913876497, ZINC913856647, ZINC914263733, ZINC914137795, ZINC915757996, ZINC914357083, ZINC913934833, ZINC9143362047, and ZINC913854740) for IsIA. The compounds proposed herein through a multi-faceted computational strategy can be experimentally validated as potential substrate antagonists of B. wadsworthia's IsIA for developing new medications to curb gut-associated illness in the future.

An inclusive outlook on the fate and persistence of pesticides in the environment and integrated eco-technologies for their degradation.

Intensive and inefficient exploitation of pesticides through modernized agricultural practices has caused severe pesticide contamination problems to the environment and become a crucial problem over a few decades. Due to their highly toxic and persistent properties, they affect and get accumulated in non-target organisms, including microbes, algae, invertebrates, plants as well as humans, and cause severe issues. Considering pesticide problems as a significant issue, researchers have investigated several approaches to rectify the pesticide contamination problems. Several analyses have provided an extensive discussion on pesticide degradation but using specific technology for specific pesticides. However, in the middle of this time, cleaner techniques are essential for reducing pesticide contamination problems safely and environmentally friendly. As per the research findings, no single research finding provides concrete discussion on cleaner tactics for the remediation of contaminated sites. Therefore, in this review paper, we have critically discussed cleaner options for dealing with pesticide contamination problems as well as their advantages and disadvantages have also been reviewed. As evident from the literature, microbial remediation, phytoremediation, composting, and photocatalytic degradation methods are efficient and sustainable and can be used for treatment at a large scale in engineered systems and in situ. However, more study on the bio-integrated system is required which may be more effective than existing technologies.