Finding structural requirements of structurally diverse α-glucosidase and α-amylase inhibitors through validated and predictive 2D-QSAR and 3D-QSAR analyses.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemic state. The α-glucosidase and α-amylase are considered two major targets for the management of Type 2 DM due to their ability of metabolizing carbohydrates into simpler sugars. In the current study, cheminformatics analyses were performed to develop validated and predictive models with a dataset of 187 α-glucosidase and α-amylase dual inhibitors. Separate linear, interpretable and statistically robust 2D-QSAR models were constructed with datasets containing the activities of α-glucosidase and α-amylase inhibitors with an aim to explain the crucial structural and physicochemical attributes responsible for higher activity towards these targets. Consequently, some descriptors of the models pointed out the importance of specific structural moieties responsible for the higher activities for these targets and on the other hand, properties such as ionization potential and mass of the compounds as well as number of hydrogen bond donors in molecules were found to be crucial in determining the binding potentials of the dataset compounds. Statistically significant 3D-QSAR models were developed with both α-glucosidase and α-amylase inhibition datapoints to estimate the importance of 3D electrostatic and steric fields for improved potentials towards these two targets. Molecular docking performed with selected compounds with homology model of α-glucosidase and X-ray crystal structure of α-amylase largely supported the interpretations obtained from the cheminformatic analyses. The current investigation should serve as important guidelines for the design of future α-glucosidase and α-amylase inhibitors. Besides, the current investigation is entirely performed by using non-commercial open-access tools to ensure easy accessibility and reproducibility of the investigation which may help researchers throughout the world to work more on drug design and discovery.

In Silico Modeling and Structural Analysis of Soluble Epoxide Hydrolase Inhibitors for Enhanced Therapeutic Design.

Human soluble epoxide hydrolase (sEH), a dual-functioning homodimeric enzyme with hydrolase and phosphatase activities, is known for its pivotal role in the hydrolysis of epoxyeicosatrienoic acids. Inhibitors targeting sEH have shown promising potential in the treatment of various life-threatening diseases. In this study, we employed a range of in silico modeling approaches to investigate a diverse dataset of structurally distinct sEH inhibitors. Our primary aim was to develop predictive and validated models while gaining insights into the structural requirements necessary for achieving higher inhibitory potential. To accomplish this, we initially calculated molecular descriptors using nine different descriptor-calculating tools, coupled with stochastic and non-stochastic feature selection strategies, to identify the most statistically significant linear 2D-QSAR model. The resulting model highlighted the critical roles played by topological characteristics, 2D pharmacophore features, and specific physicochemical properties in enhancing inhibitory potential. In addition to conventional 2D-QSAR modeling, we implemented the Transformer-CNN methodology to develop QSAR models, enabling us to obtain structural interpretations based on the Layer-wise Relevance Propagation (LRP) algorithm. Moreover, a comprehensive 3D-QSAR analysis provided additional insights into the structural requirements of these compounds as potent sEH inhibitors. To validate the findings from the QSAR modeling studies, we performed molecular dynamics (MD) simulations using selected compounds from the dataset. The simulation results offered crucial insights into receptor-ligand interactions, supporting the predictions obtained from the QSAR models. Collectively, our work serves as an essential guideline for the rational design of novel sEH inhibitors with enhanced therapeutic potential. Importantly, all the in silico studies were performed using open-access tools to ensure reproducibility and accessibility.

In silico characterization of aryl benzoyl hydrazide derivatives as potential inhibitors of RdRp enzyme of H5N1 influenza virus.

RNA-dependent RNA polymerase (RdRp) is a potential therapeutic target for the discovery of novel antiviral agents for the treatment of life-threatening infections caused by newly emerged strains of the influenza virus. Being one of the most conserved enzymes among RNA viruses, RdRp and its inhibitors require further investigations to design novel antiviral agents. In this work, we systematically investigated the structural requirements for antiviral properties of some recently reported aryl benzoyl hydrazide derivatives through a range of in silico tools such as 2D-quantitative structure-activity relationship (2D-QSAR), 3D-QSAR, structure-based pharmacophore modeling, molecular docking and molecular dynamics simulations. The 2D-QSAR models developed in the current work achieved high statistical reliability and simultaneously afforded in-depth mechanistic interpretability towards structural requirements. The structure-based pharmacophore model developed with the docked conformation of one of the most potent compounds with the RdRp protein of H5N1 influenza strain was utilized for developing a 3D-QSAR model with satisfactory statistical quality validating both the docking and the pharmacophore modeling methodologies performed in this work. However, it is the atom-based alignment of the compounds that afforded the most statistically reliable 3D-QSAR model, the results of which provided mechanistic interpretations consistent with the 2D-QSAR results. Additionally, molecular dynamics simulations performed with the apoprotein as well as the docked complex of RdRp revealed the dynamic stability of the ligand at the proposed binding site of the receptor. At the same time, it also supported the mechanistic interpretations drawn from 2D-, 3D-QSAR and pharmacophore modeling. The present study, performed mostly with open-source tools and webservers, returns important guidelines for research aimed at the future design and development of novel anti-viral agents against various RNA viruses like influenza virus, human immunodeficiency virus-1, hepatitis C virus, corona virus, and so forth.

Feruloyl Sucrose Esters: Potent and Selective Inhibitors of α-glucosidase and α-amylase.

INTRODUCTION: Feruloyl Sucrose Esters (FSEs) are a class of Phenylpropanoid Sucrose Esters (PSEs) widely distributed in plants. They were investigated as potential selective Alpha Glucosidase Inhibitors (AGIs) to eliminate the side effects associated with the current commercial AGIs. The latter effectively lowers blood glucose levels in diabetic patients but causes severe gastrointestinal side effects. METHODS: Systematic structure-activity relationship (SAR) studies using in silico, in vitro and in vivo experiments were used to accomplish this aim. FSEs were evaluated for their in vitro inhibition of starch and oligosaccharide digesting enzymes α-glucosidase and α- amylase followed by in silico docking studies to identify the binding modes. A lead candidate, FSE 12 was investigated in an STZ mouse model. RESULTS: All active FSEs showed desired higher % inhibition of α-glucosidase and desired lower inhibition of α -amylase in comparison to AGI gold standard acarbose. This suggests a greater selectivity of the FSEs towards α -glucosidase than α -amylase, which is proposed to eliminate the gastrointestinal side effects. From the in vitro studies, the position and number of the feruloyl substituents on the sucrose core, the aromatic 'OH' group, and the diisopropylidene bridges were key determinants of the % inhibition of α - glucosidase and α -amylase. In particular, the diisopropylidene bridges are critical for achieving inhibition selectivity. Molecular docking studies of the FSEs corroborates the in vitro results. The molecular docking studies further reveal that the presence of free aromatic 'OH' groups and the substitution at position 3 on the sucrose core are critical for the inhibition of both the enzymes. From the in vitro and molecular docking studies, FSE 12 was selected as a lead candidate for validation in vivo. The oral co-administration of FSE 12 with starch abrogated the increase in post-prandial glucose and significantly reduced blood glucose excursion in STZ-treated mice compared to control (starch only) mice. CONCLUSION: Our studies reveal the potential of FSEs as selective AGIs for the treatment of diabetes, with a hypothetical reduction of side effects associated with commercial AGIs.

Cinnamoyl Sucrose Esters as Alpha Glucosidase Inhibitors for the Treatment of Diabetes.

Cinnamoyl sucrose esters (CSEs) were evaluated as AGIs and their enzyme inhibition activity and potency were compared with gold standard acarbose. The inhibition activity of the CSEs against α-glucosidase and α-amylase depended on their structure including the number of the cinnamoyl moieties, their position, and the presence or absence of the acetyl moieties. The inhibitory values of the CSEs 2-9 generally increases in the order of mono-cinnamoyl moieties < di-cinnamoyl ≤ tri-cinnamoyl < tetra-cinnamoyl. This trend was supported from both in vitro and in silico results. Both tetra-cinnamoyl CSEs 5 and 9 showed the highest α-glucosidase inhibitory activities of 77 ± 5%, 74 ± 9%, respectively, against acarbose at 27 ± 4%, and highest α-amylase inhibitory activities of 98 ± 2%, 99 ± 1%, respectively, against acarbose at 93 ± 2%. CSEs 3, 4, 6, 7, 8 showed desired higher inhibition of α-glucosidase than α-amylase suggesting potential for further development as AGIs with reduced side effects. Molecular docking studies on CSEs 5 and 9 attributed the high inhibition of these compounds to multiple π-π interactions and favorable projection of the cinnamoyl moieties (especially O-3 cinnamoyl) in the enzyme pockets. This work proposes CSEs as new AGIs with potentially reduced side effects.

Solid and liquid state characterization of tetrahydrocurcumin using XRPD, FT-IR, DSC, TGA, LC-MS, GC-MS, and NMR and its biological activities.

Tetrahydrocurcumin (THC) is one of the major metabolites of curcumin (CUR), an ancient bioactive natural polyphenolic compound. This research article describes both the solid and liquid state characterization of THC using advanced spectroscopic and thermo-analytical techniques. Anti-inflammatory, anti-oxidant, and neuroprotective activities of THC were investigated using in vitro cell lines. Liquid chromatography-mass spectrometry analysis revealed that our sample comprised 95.15% THC, 0.51% tetrahydrodemethoxycurcumin (THDC), 3.40% hexahydrocurcumin, and 0.94% octahydrocurcumin. Gas chromatography-mass spectrometry analysis indicated the presence of 96.68% THC and 3.32% THDC. THC in solution existed as keto-enol tautomers in three different forms at different retention time, but the enol form was found to be dominant, which was also supported by nuclear magnetic resonance analysis. THC was thermally stable up to 335.55 °C. THC exhibited more suppression of cytokines (TNF-α, IL-1ß, and MIP-1α) than CUR in a concentration-dependent manner in mouse splenocytes, while NK-cell and phagocytosis activity was increased in macrophages. THC showed a significant reduction of free radicals (LPO) along with improved antioxidant enzymes (SOD and catalase) and increased free radical scavenging activity against ABTS+ radicals in HepG2 cells. THC displayed higher protection capability than CUR from oxidative stress and neuronal damage by improving cell viability against H2O2 induced HepG2 cells and MPP+ induced SH-SY5Y cells, respectively, in a concentration-dependent manner. Thus, a variation of the biological activities of THC might rely on its keto-enol form and the presence of other THC analogs as impurities. The present study could be advantageous for further research on THC for better understanding its physicochemical properties and biological variation.

Structure-activity relationship of human carbonic anhydrase-II inhibitors: Detailed insight for future development as anti-glaucoma agents.

Human carbonic anhydrase-II (hCA-II) is the most dominant physiologic isoform amongst the sixteen reported hCA isoforms. Because of its high availability in the different anatomical, and cellular sites of the eye like retina and lens, it plays a more prominent role in the regulation of intraocular pressure than the other twelve catalytically active hCA isoforms. This isoform is also located in the brain, kidney, gastric mucosa, osteoclasts, RBCs, skeletal muscle, testes, pancreas, lungs, etc. Earlier, hCA-II inhibitors were designed based on the sulfonamides e.g. acetazolamide, dichlorphenamide, methazolamide, ethoxzolamide, etc. and they were used systemically in antiglaucoma therapy. Many successful attempts have been made by the researchers in order to design more potent and effective inhibitors by incorporating various moieties in sulphonamides. Some novel scaffolds like chalcones, thiophenes, organotellurium compounds, dithiocarbamate, selenide, and 2-benzylpyrazine, etc. were also designed as hCA-II inhibitors and their inhibitory efficacy was proved in the nanomolar range. In order to obtain relevant information from the insights of their structure-activity relationship, the reported hCA-II inhibitors from the year 1989 to 2019 were critically analysed. It gave a complete insight into the relationship between their structure-activity and hCA-II inhibition. The broad spectrum of our investigation may help researchers to summarize all the crucial structural information required for the development of more potent hCA-II inhibitors for glaucoma.

Antineoplastic properties of zafirlukast against hepatocellular carcinoma via activation of mitochondrial mediated apoptosis.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwideand haslimited treatment options. In view of this, zafirlukast (ZAF) was administered orally to DEN-induced HCC rats to evaluate its antineoplastic properties. ELISA, qRT-PCR and Western blot were used to determine the molecular mechanism associated with ZAF therapy for HCC. We found that HCC developed as a result of lower expression of caspases 3 and 9, but their levels returned to normal when the expression of eNOS, BAX, BAD, and Cyt C was decreased and when the expression of iNOS, Bcl-xl, and Bcl-2 was increased. Again, ZAF (80 mg/kg dose) treatment normalized the expression of caspase-mediated apoptotic factors, i.e. BAX and Bcl-2 proteins, as established through Western blot analysis. Later, 1H NMR-based serum metabolomics study revealed that levels of perturbed metabolites in DEN-induced rat serum returned to normal after ZAF administration. Altogether, the antineoplastic potential of ZAF was found to be comparable, and to some degree better, than the marketed chemotherapeutic 5-flurouracil, which may be beneficial for anti-HCC treatment from a future drug design perspective.

A comprehensive physicochemical, thermal, and spectroscopic characterization of zinc (II) chloride using X-ray diffraction, particle size distribution, differential scanning calorimetry, thermogravimetric analysis/differential thermogravimetric analysis, ultraviolet-visible, and Fourier transform-infrared spectroscopy.

OBJECTIVE: Zinc chloride is an important inorganic compound used as a source of zinc and has other numerous industrial applications. Unfortunately, it lacks reliable and accurate physicochemical, thermal, and spectral characterization information altogether. Hence, the authors tried to explore in-depth characterization of zinc chloride using the modern analytical technique. MATERIALS AND METHODS: The analysis of zinc chloride was performed using powder X-ray diffraction (PXRD), particle size distribution, differential scanning calorimetry (DSC), thermogravimetric analysis/differential thermogravimetric analysis (TGA/DTG), ultraviolet-visible spectroscopy (UV-vis), and Fourier transform-infrared (FT-IR) analytical techniques. RESULTS: The PXRD patterns showed well-defined, narrow, sharp, and the significant peaks. The crystallite size was found in the range of 14.70-55.40 nm and showed average crystallite size of 41.34 nm. The average particle size was found to be of 1.123 (d10), 3.025 (d50), and 6.712 (d90) µm and average surface area of 2.71 m2/g. The span and relative span values were 5.849 µm and 1.93, respectively. The DSC thermogram showed a small endothermic inflation at 308.10°C with the latent heat (ΔH) of fusion 28.52 J/g. An exothermic reaction was observed at 449.32°C with the ΔH of decomposition 66.10 J/g. The TGA revealed two steps of the thermal degradation and lost 8.207 and 89.72% of weight in the first and second step of degradation, respectively. Similarly, the DTG analysis disclosed Tmax at 508.21°C. The UV-vis spectrum showed absorbance maxima at 197.60 nm (λmax), and FT-IR spectrum showed a peak at 511/cm might be due to the Zn-Cl stretching. CONCLUSIONS: These in-depth, comprehensive data would be very much useful in all stages of nutraceuticals/pharmaceuticals formulation research and development and other industrial applications.

In-depth investigation on physicochemical and thermal properties of magnesium (II) gluconate using spectroscopic and thermoanalytical techniques.

Magnesium gluconate is a classical organometallic pharmaceutical compound used for the prevention and treatment of hypomagnesemia as a source of magnesium ion. The present research described the in-depth study on solid state properties viz. physicochemical and thermal properties of magnesium gluconate using sophisticated analytical techniques like PXRD, PSA, FT-IR, UV-Vis spectroscopy, TGA/DTG, and DSC. Magnesium gluconate was found to be crystalline in nature along with the crystallite size ranging from 14.10 to 47.35 nm. The particle size distribution was at d(0.1)=6.552 µm, d(0.5)=38.299 µm, d(0.9)=173.712 µm and D(4,3)=67.122 µm along with the specific surface area of 0.372 m2/g. The wavelength for the maximum absorbance was at 198.0 nm. Magnesium gluconate exhibited 88.51% weight loss with three stages of thermal degradation process up to 895.18 °C from room temperature. The TGA/DTG thermograms of the analyte indicated that magnesium gluconate was thermally stable up to around 165 °C. Consequently, the melting temperature of magnesium gluconate was found to be 169.90 °C along with the enthalpy of fusion of 308.7 J/g. Thus, the authors conclude that the achieved results from this study are very useful in pharmaceutical and nutraceutical industries for the identification, characterization and qualitative analysis of magnesium gluconate for preformulation studies and also for developing magnesium gluconate based novel formulation.

Metabolite Profiling in Withania somnifera Roots Hydroalcoholic Extract Using LC/MS, GC/MS and NMR Spectroscopy.

Ashwagandha (Withania somnifera) is a very well-known herbal medicine and it was well studied for its active metabolites throughout the World. Although, nearly 40 withanolides were isolated from W. somnifera root extract, still there is remaining unidentified metabolites due to very low abundance and geographical variation. Advanced separation technology with online identification by mass and nuclear magnetic resonance (NMR) are nowadays used to find out the new compounds in the crude herbal extract. This article described the metabolite profiling of ashwagandha root hydroalcoholic extract using ultra-performance liquid chromatography coupled with a positive ion electrospray ionization tandem mass spectrometry through gas chromatography mass spectrometry (GC/MS) and NMR spectroscopy. A total of 43 possible withanolides was identified and proposed their structures based on the mass of molecular and fragment ions. GC/MS and NMR analysis indicated the presence of several known withanolides including withaferin A, withanolide D, withanoside IV or VI, withanolide sulfoxide, etc. To the best of our knowledge, dihydrowithanolide D at m/z 473 (tR 7.86 min) and ixocarpalactone A at m/z 505 (tR 8.43 min) were first time identified in the ashwagandha root hydroalcoholic extract. The current study that described the identification of withanolides with summarized literature review might be helpful for designing the experiment to identify of the new chemical constituents in Withania species.

Synthesis and antiproliferative activity of helonioside A, 3',4',6'-tri-O-feruloylsucrose, lapathoside C and their analogs.

The first total synthesis of natural phenylpropanoid sucrose esters (PSEs) helonioside A 1, 3',4',6'-tri-O-feruloylsucrose 2 and lapathoside C 3 along with 17 unnatural PSE analogs has been successfully accomplished in a short and simple synthetic route. A selected set of 17 synthesized PSEs were evaluated for the antiproliferative activity against human cervical epithelioid carcinoma (HeLa) cell lines using MTS assay method. Eleven (11) compounds showed significant antiproliferative activity with their IC(50)values ranging from 0.16 to 6.01 µM. The structure-activity-relationship studies revealed that the antiproliferative activity is influenced by the lipophilicity and number of feruloyl substituents on these compounds. The preliminary screening indicated that these compounds are potentially very valuable source for new lead chemotherapeutics.

Synthesis and antitumor activity of lapathoside D and its analogs.

Phenylpropanoid sucrose esters are important class of plant-derived natural products and have greater potential to be leads for new drugs because of their structural diversity and broad-array of pharmacological and biological activities. Regio- and chemo-selective acylation of 2,1':4,6-O-di-isopropylidene sucrose 4 with cinnamoyl chloride 5 and p-acetoxycinnamoyl chloride 6 afforded mono-, di-, tri- and tetra- variant PSEs in moderate yields. The first total synthesis of di-substituted PSE, lapathoside D 1' has been achieved successfully in short and simple synthetic steps from sucrose 3 as an inexpensive starting material. Lapathoside D 1 and a set of selected synthesized PSEs were tested for in vitro cytotoxicity against human cervical epithelioid carcinoma (HeLa) cell lines. Most of the compounds exhibited significant antitumor activity with their IC(50) values ranging from 0.05 to 7.63 µM. The primary screening results indicated that PSEs might be valuable source for new potent anticancer drug candidates.

Possible anticancer agents: QSAR analogs of glutamamide: synthesis and pharmacological activity of 1,5-N,N'-disubstituted-2-(substituted benzenesulphonyl) glutamamides.

Based on our earlier QSAR prediction, a series of designed QSAR analogs of 1,5-N,N'-disubstituted-2-(substituted benzenesulphonyl) glutamamides were synthesized as possible anticancer agents. Inhibitions of tumor cell proliferation of the compounds were tested in tumor cell line IMR-32. Anticancer activities of these compounds were also evaluated on Swiss Albino mice against Ehrlich Ascites Carcinoma (EAC) cells. Tumor weight inhibition and tumor cell inhibition were considered as anticancer activity parameters. QSAR analysis of these compounds was performed on the basis of a set of descriptors like physicochemical, topological, quantum chemical and DRAGON whole molecular descriptors. The study showed that the increase of length of substituent at R(2) position and the increase of dipole moment of the molecule decrease the anticancer activity of these compounds, presence of bromine atom at R(3) position and hydrophilic substitution at R(2) position are advantageous to the activity. Nucleophilic attack at atom number 14 is advantageous and electrophilic attack at atom number 15 is detrimental to anticancer activity. Atom number 2 is important and may be involved in dispersive interactions of the compounds with enzymes. The results offer an opportunity for further tailoring of these analogs for an active member.