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.

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 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.

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.

Novel Hybrid Indole-Based Caffeic Acid Amide Derivatives as Potent Free Radical Scavenging Agents: Rational Design, Synthesis, Spectroscopic Characterization, In Silico and In Vitro Investigations.

Antioxidant small molecules can prevent or delay the oxidative damage caused by free radicals. Herein, a structure-based hybridization of two natural antioxidants (caffeic acid and melatonin) afforded a novel hybrid series of indole-based amide analogues which was synthesized with potential antioxidant properties. A multiple-step scheme of in vitro radical scavenging assays was carried out to evaluate the antioxidant activity of the synthesized compounds. The results of the DPPH assay demonstrated that the indole-based caffeic acid amides are more active free radical scavenging agents than their benzamide analogues. Compared to Trolox, a water-soluble analogue of vitamin E, compounds 3a, 3f, 3h, 3j, and 3m were found to have excellent DPPH radical scavenging activities with IC50 values of 95.81 ± 1.01, 136.8 ± 1.04, 86.77 ± 1.03, 50.98 ± 1.05, and 67.64 ± 1.02 µM. Three compounds out of five (3f, 3j, and 3m) showed a higher capacity to neutralize the radical cation ABTS•+ more than Trolox with IC50 values of 14.48 ± 0.68, 19.49 ± 0.54, and 14.92 ± 0.30 µM, respectively. Compound 3j presented the highest antioxidant activity with a FRAP value of 4774.37 ± 137.20 µM Trolox eq/mM sample. In a similar way to the FRAP assay, the best antioxidant activity against the peroxyl radicals was demonstrated by compound 3j (10,714.21 ± 817.76 µM Trolox eq/mM sample). Taken together, compound 3j was validated as a lead hybrid molecule that could be optimized to maximize its antioxidant potency for the treatment of oxidative stress-related diseases.

Multiple Site Dissimilarities of Herbaceous Species Due to Coal Fly Ash Dumping Based Soil Heavy Metal Toxication.

The present study analyzes the determinants and patterns of the regional, local, and differential plant diversity of two different sites with similar climatic but varied edaphic factors. This research was undertaken to study the plant diversity and population structure as a consequence of variation in the soil quality between two biotopes: Guru Ghasidas Vishwavidyalaya in Koni (site-I) and National Thermal Power Corporation in Sipat (site-II). The soil of site-I was found to be fertile and showed rich vegetation. On the other hand, the soil of site II was found to be contaminated with heavy metals, which impacts the flora of the region. The ecology of both sites was studied, and their quantitative and qualitative aspects were compared and contrasted. The abundance, density, and richness of the plants in site II were fairly lower than in site-I, which was confirmed by utilizing Simpson's and Shannon's diversity indices. Many of the species collected from site II were heavy metal accumulators and could also serve as indicators of heavy metal toxicity.

Pyrazole, imidazole and triazole: In silico, docking and ADMET studies against SARS-CoV-2.

The Coronavirus pandemic, Covid-19 and SARS-Cov-2 put multidisciplinary research by chemists, biologists, pharmacists and theorists necessary and primordial task to find new active biomolecules which will be beneficial for all humanity. The azoles drugs are electronic rich, they should be used with caution, and an understanding of their pharmacokinetic profile, safety, absorption, distribution, excretion, metabolism, toxicity, and drug-drug interaction profiles is important to provide effective and cure therapy. In these objectives and goals, twenty aromatic nitrogen heterocycle compounds were chosen for in silico, docking and AMET studies against SARS-CoV-2. In this paper with respect to the protein S of SARS-CoV-2 properties, the GAUSSIAN 09w program used in the semi-empirical method at the AM1 level with the optimization of the geometry of the structures. Then Toxicity and physicochemical properties were evaluated by AMET. Molecular docking investigations conducted; the binding affinities as well as interactions of the sieve compounds with the SRAS-CoV-2 protein Spike using PyRx software. In general, the preliminary results are fructuous and needs further in vitro testes.

A pair of carbazate derivatives as novel Schiff base ligands: DFT and POM theory supported spectroscopic and biological evaluation.

Schiff bases are mentioned as strongly important molecular scaffolds of industrial and medicinal purposes. Due to wide range applications of carbazate derivatives herein synthesis and characterization of a new Schiff base ligand, (E)-ethyl 2-(4-methoxybenzylidene)hydrazinecarboxylate and 4-(nitrobenzaldehyde)ethylcarbazate are reported. The compound was characterized on the basis of experimental and density functional theory calculations (using the B3LYP and 6-31 G(d,p)formalism combination). Among characterization techniques elemental analysis, FT-IR, UV-Vis and NMR spectroscopic evaluations were mainly employed to carry out the formulation of the compound. In addition to computational validation of characterization other significant molecular parameters were also evaluated including geometry optimization, frontier molecular orbital analysis (FMO) and Columbic interaction of different constituent atoms of the title compound. A good agreement has been found between DFT and experimental outcomes confined to prove the structure of the compound. Moreover, molecular docking and antimicrobial studies have proven the Schiff base as an effective bioactive compound.Communicated by Ramaswamy H. Sarma.

Synthetic star shaped tetra-tailed biocompatible supramolecular amphiphile as an efficient nanocarrier for Amphotericin B.

Macrocycle-based amphiphiles are capable of self-assembling into multidimensional nano-architecture with defined dimensions for various applications. Herein we report the synthesis, physio-chemical characterizations and oral drug delivery profiling of resorcinarene-based amphiphilic supramolecular macrocycle. The macrocycle was synthesized in two-step reaction and characterized using 1H NMR, Mass spectrometry and IR spectroscopic techniques. The synthesized macrocycle was assessed for vesicles formation, checked for biocompatibility and then Amphotericin B (Amp-B) was entrapped in macrocycle-based vesicles. The drug loaded vesicles were characterized for shape, size, homogeneity, drug entrapment, surface charge, in-vitro release profile and stability. Amp-B loaded macrocycle based vesicles were examined in rabbits for in-vivo bioavailability and compared with plan drug suspension. The synthesized macrocycle was non-toxic in normal mouse fibroblast cells, compatible with blood and safe in mice. The drug loaded macrocycle based vesicles appeared spherical with 279.4 nm size and - 12.2 mV zeta potential loading 85.45 % drug. The drug loaded vesicles storage stability for 30 days and gastric fluid stability for 1 h were it retained nearly 90 % drug at 30th day and 83.79 % drug at 1 h in gastric fluid. Oral bioavailability of Amp-B in rabbits was markedly enhanced when delivered in synthesized macrocycle based vesicles in comparison with plan drug suspension. Results of this study indicate that the synthesized star shaped tetra-tailed supramolecular amphiphile could be used as an efficient nanocarrier for enhancing oral bioavailability of drugs with solubility and bioavailability issues like Amp-B.

Evaluation of the Chemical Composition, Antioxidant and Antidiabetic Activity of Rhaponticoides iconiensis Flowers: Effects on Key Enzymes Linked to Type 2 Diabetes In Vitro, In Silico and on Alloxan-Induced Diabetic Rats In Vivo.

Diabetes mellitus (DM) is one of the globally worst killer diseases. In this study, the in vitro and in vivo antidiabetic activity and antioxidant capacity were determined and the phytochemical analyses were carried out on flower extract and sub-extracts of Rhaponticoides iconiensis. The in vitro antidiabetic activity was tested with α-amylase and α-glucosidase enzyme inhibition methods and an in vivo OGTT test in healthy and alloxan-induced rats. Although, the antioxidant activity was investigated with DPPH●, ABTS●+ and FRAP tests, the phytochemical composition analysis was carried out by LC-MS/MS. The highest α-glucosidase and α-amylase activity even from positive control acarbose were found in the ethyl acetate sub-extract of R. iconiensis (IC50 = 11.737 ± 0.823 µg/mL and 84.247 ± 0.721 µg/mL, respectively). This sub-extract also was active according to the results of in vivo tests. Moreover, the highest antioxidant activity on DPPH● (IC50 = 0.126 ± 0.002 mg/mL), FRAP (at a concentration of 1 mg/mL equivalent to 3112.052 ± 2.023 mmol Fe2+) and ABTS+● (at a concentration of 0.5 mg/mL equivalent to 0.608 ± 0.005 µM Trolox) tests. In addition, LC-MS/MS analyses of the active sub-extract revealed mainly the presence of patuletin, patuletin 3,7-diglucoside, naringin and 3,4-dicaffeoylquinic acid detected in the active sub-extract. In silico molecular docking and dynamics simulations studies were performed on these compounds with α-amylase and α-glucosidase enzymes for protein-ligand interactions and stability.

Novel saccharin analogs as promising antibacterial and anticancer agents: synthesis, DFT, POM analysis, molecular docking, molecular dynamic simulations, and cell-based assay.

Saccharine is a pharmacologically significant active scaffold for various biological activities, including antibacterial and anticancer activities. Herein, saccharinyl hydrazide (1) was synthesized and converted into 2-[(2Z)-2-(1,1-dioxo-1,2-dihydro-3H-1λ6,2- benzothiazole-3-ylidene) hydrazinyl] acetohydrazide (5), which was employed as a key precursor for synthesizing a novel series of small molecules bearing different moieties of monosaccharides, aldehydes, and anhydrides. Potent biological activities were found against Staphylococcus and Escherichia coli , and the results indicated that compounds 6c and 10a were the most active analogs with an inhibition zone diameter of 30-35 mm . In cell-based anticancer assay over Ovcar-3 and M-14 cell lines, compound 10a was the most potent analog with IC50 values of 7.64 ± 0.01 and 8.66 ± 0.01 µM, respectively. The Petra Orisis Molinspiration (POM) theoretical method was used to calculate the drug score of tested compounds and compare them with their experimental screening data. Theoretical DFT calculations were carried out in a gas phase in a set of B3LYP 6-311G (d,p). Molecular docking studies utilizing the MOE indicated the best binding mode with the highest energy interaction within the binding sites. The molecular docking for Ovcar-3 was carried out on the ovarian cancer protein (3W2S), while the molecular docking for M-14 melanoma was carried out on the melanoma cancer protein (2OPZ). The MD performed about 2ns simulations to validate selected compounds' theoretical studies.

Synthesis and In Silico Study of Some New bis-[1,3,4]thiadiazolimines and bis-Thiazolimines as Potential Inhibitors for SARS-CoV-2 Main Protease.

A novel series of bis-[1,3,4]thiadiazolimines, and bis-thiazolimines, with alkyl linker, were synthesized through general routes from cyclization of 1,1'-(hexane-1,6-diyl)bis(3-phenylthiourea) and hydrazonoyl halides or α-haloketones, respectively. Docking studies were applied to test the binding affinity of the synthesized products against the Mpro of SARS-CoV-2. The best compound, 5h, has average binding energy (-7.50 ± 0.58 kcal/mol) better than that of the positive controls O6K and N3 (-7.36 ± 0.34 and -6.36 ± 0.31 kcal/mol). Additionally, the docking poses (H-bonds and hydrophobic contacts) of the tested compounds against the Mpro using the PLIP web server were analyzed.