3D QSAR based Virtual Screening of Flavonoids as Acetylcholinesterase Inhibitors.

In an attempt to develop therapeutic agents to treat Alzheimer's disease, a series of flavonoid analogues were collected, which already had established acetylcholinesterase (AChE) enzyme inhibition activity. For each molecule we also collected biological activity data (Ki). Then, 3D-QSAR (quantitative structure-activity relationship model) was developed which showed acceptable predictive and descriptive capability as represented by standard statistical parameters r2 and q2. This SAR data can explain the key descriptors which can be related to AChE inhibitory activity. Using the QSAR model, pharmacophores were developed based on which, virtual screening was done and a dataset was obtained which loaded as a prediction set to fit the developed QSAR model. Top 10 compounds fitting the QSAR model were subjected to molecular docking. CHEMBL1718051 was found to be the lead compound. This study is offering an example of a computationally-driven tool for prioritisation and discovery of probable AChE inhibitors. Further, in vivo and in vitro testing will show its therapeutic potential.

Field-based 3D-QSAR for tyrosine protein kinase JAK-2 inhibitors.

The present work aimed to develop a Field-based 3D-QSAR model with existing JAK-2 inhibitors. The JAK-STAT pathway is known to play a role in the development of autoimmune diseases, including rheumatoid arthritis, ulcerative colitis, and Crohn's disease. Dysregulation of JAK-STAT is also linked to the development of myelofibrosis and other myeloproliferative diseases. JAK antagonists can be used in many areas of medicine. There are many compounds that already show inhibition of Jak-2. We have developed a Field-based 3D QSAR model which showed good correlation values (r2 0.884 and q2 0.67) with an external test set regression pred_r2 0.562. Various properties, such as electronegativity, electro positivity, hydrophobicity, and shape features, were studied under the activity atlas to determine the inhibitory potential of ligands. These were also identified as important structural features responsible for biological activity. We performed virtual screening based on the pharmacophore features of the co-crystal ligand (PDB ID: 3KRR) and a dataset of NPS was selected with a RMSD value less than 0.8. The developed 3D QSAR model was used to screen ligands and calculate the predicted JAK-2 inhibition activity (pKi). The results of the virtual screening were validated using molecular docking and molecular dynamics simulations. SNP1 (SN00154718) and SNP2 (SN00213825) showed binding affinity of -11.16 and -11.08 kcal/mol, respectively, which were very close to the crystal ligand of 3KRR, -11.67 kcal/mol. The RMSD plot of the protein-ligand complex of SNP1 and 3KRR showed stable interactions with an average RMSD of 2.89 Å. Thus, a statistically robust 3D QSAR model could reveal more inhibitors and aid in the design of novel JAK-2 inhibitors.

Insilico Screening of Pentacyclic Triterpenoids against Vascular Dementia Target's.

Vascular dementia (VaD) accounts to 30% of cases and is predicted as second most common form of dementia after Alzheimer's disease by WHO. Earlier studies reported that plant-derived pentacyclic triterpenoids possess a wide range of pharmacological activities but these compounds are not extensively studied for their neuroprotective potential against VaD. This in silico approach was designed to screen 20 pentacyclic triterpenoid plant compounds against known targets of VaD using Flare software. S-Adenyl homocysteine hydrolase, Acetylcholinesterase, and Butyrylcholinesterase were selected as important VaD targets, and various parameters like intermolecular interaction energies, binding energy, and dock scores were analyzed and compared between selected ligands. Our results showed that Ursolic acid has lowest binding energy when docked with most of the target proteins, and among all 20 pentacyclic triterpenoids studied, only three ligands Betulinic acid, Ambolic acid, and Madecassic acid, showed better binding energy scores, and they can be shortlisted as lead compounds to further study their therapeutic potential against VaD using in vitro and in vivo animal models.

Development and validation of ultra performance liquid chromatography-tandem mass spectrometry method for the simultaneous estimation of dolutegravir, lamivudine and tenofovir in bulk and tablet dosage form.

A simple, selective and rapid ultra performance liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous estimation of dolutegravir, lamivudine and tenofovir in bulk and tablet dosage form. Chromatographic separation was attained on Acquity Ethylene Bridged Hybrid (BEH) C18 column (50 × 2.1 mm, 3.5 µm), using a mixture of acetonitrile and 0.1% formic acid in water (60:40, v/v) as a mobile phase at a flow rate of 0.12 mL/min. The total run time of analysis was 3.5 min. The analytes were detected using tandem mass spectrometry, operating in positive ionization and multiple reaction monitoring modes. The method's linearity was determined to be in the range of 10-150 ng/mL with r2 > 0.99. The proposed method was validated as per the International Council for Harmonization (ICH) guidelines, and the results were found well within the acceptance limits. The method was successfully applied for the simultaneous quantification of all the three analytes in the combined tablet dosage form.

In Silico and In Vivo Studies on Quercetin as Potential Anti-Parkinson Agent.

Parkinson's disease (PD) is a major cause of morbidity and mortality among older individuals. Several researchers have suggested that iron chelators which cross the blood-brain barrier (BBB) might have clinical efficacy in treating PD. Therefore, efforts are made not only in order to improve the effect of L-dopa but also to introduce drugs which provide anti-parkinsonian and neuroprotective effects. In this study, quercetin, a flavonoid, exhibited noticeable neuroprotective effects via iron induced-oxidative stress-dependent apoptotic pathways. Our results suggested that quercetin significantly decreased the catalepsy and exhibited neuroprotective effects in rotenone-induced Parkinson. A model of rotenone-induced Parkinsonism in rats produced the decrease in glutathione, SOD, catalase, and serum iron concentration and the increase in H2O2 and lipid peroxidation activity. Quercetin efficiently halted the deleterious toxic effects of L-dopa, revealing normalization of catalepsy and rotarod score, in addition to amelioration of neurochemical parameters, indicating benefit of both symptomatic and neuroprotective therapies. In silico molecular docking studies have also shown that quercetin could be an ideal potential drug target for aromatic L-amino acid decarboxylase and human catechol-O-methyltransferase. In conclusion, quercetin possesses strong iron-chelating abilities and could be recommended as a disease-modifying therapy when administered in combination with L-dopa, early on in the course of Parkinson's disease.

Ocimum Sanctum Linn: A Potential Adjunct Therapy for Hyperhomocysteinemia-Induced Vascular Dementia.

Vascular dementia (VaD) is well recognized as the second most familiar form of dementia in the aged population. The present study is aimed to investigate the neuroprotective effects of ethanolic extract of leaves of Ocimum sanctum (EEOS) against hyperhomocysteinemia (HHcy)-induced vascular dementia (VaD) in Wistar rats. HHcy was induced by administering L-methionine (1.7 g/kg, p.o) for 4 weeks. Donepezil (0.1 mg/kg, p.o.) and EEOS (100 mg/kg, 200 mg/kg, 400 mg/kg, p.o.) were administered from the 14th day of L-methionine treatment. The behavioral impairment caused due to HHcy in rats was assessed by the Morris water maze (MWM) and Y-maze tests using a video tracking system. Biochemical estimations and aortic ring assay were also performed followed by a molecular docking analysis of active chemical constituents present in the leaves of Ocimum sanctum Linn. In this study, the EEOS treatment in hyperhomocysteinemic rats has showed significant improvement in spatial learning and working memory performance. The EEOS treatment further increased nitric oxide bioavailability and significantly altered all serum and brain biochemical parameters in a dose-dependent manner. The docking analysis revealed that among all the phytoconstituents of Ocimum sanctum compound (IX), molludistin has showed good inhibitory activity against S-adenosyl homocysteine, thus preventing homocysteine formation and may be responsible for potential effects of EEOS against HHcy-induced VaD. From our results, we conclude that EEOS can be used as a promising adjunct therapy for treatment of HHcy-induced VaD and oxidative stress.

Design, One Pot Synthesis and Molecular Docking Studies of Substituted-1H-Pyrido[2,1-b] Quinazolines as Apoptosis-Inducing Anticancer Agents.

OBJECTIVE: The present study focused to build pyridine and quinazoline rings in a single molecule and designed a new fused Pyrido[2,1-b] quinazoline to have a better pharmacological activity. MATERIAL AND METHODS: A three component, one-pot synthesis of substituted-1H-Pyrido[2,1-b] quinazoline derivatives has been described by conventional and microwave synthesis using triflic acid as catalyst. These compounds were screened for in vitro cytotoxic activity against the panel of cancer cell lines A549, NCI-H460, HT-29, HCT-15, DU-145, and HFL. RESULTS: Among the tested compounds, 11-(1-benzyl-1H-indol-3-y1)-2, 3, 4, 11-tetrahydro-1H-pyrido[2,1-b] quinazoline (4i) showed most potent cytotoxicity against A549 and NCI-H460 lung cancer cell lines with IC50 values 4.57±0.25 and 5.53±0.49 µM, respectively. Moreover, compound 4i was found to be most potent considerable cell growth inhibition with GI50 values of 2.70±0.18 and 3.24±0.40 µM against A549 and NCI-H460 cell lines, respectively. In addition, induction of apoptosis for compound 4i on A549 was investigated by morphological changes, Acridine orange/ethidium bromide (AO/EB) and DAPI staining. Furthermore, a strong anti-clonogenic effect of compound 4i on lung cancer cells was observed. The flow cytometric analysis investigation reveals that compound 4i arrests the A549 cancer cell lines at the G0/G1 phase of the cell cycle. Molecular docking were also performed on 4i, 4j, and erlotinib to predict the binding mode towards the EGFR kinase (PDB code: 1M17) and the compounds have displayed similar interactions and compared with erlotinib. CONCLUSION: Overall, these findings could suggest that the compound 4i would be an ideal lead as an anticancer agent.

Design, synthesis, molecular modelling, ADME prediction and anti-hyperglycemic evaluation of new pyrazole-triazolopyrimidine hybrids as potent α-glucosidase inhibitors.

The aim of the present study is to design and synthesis of new pyrazole-triazolopyrimidine hybrids as potent α-glucosidase inhibitors. The target compounds 4a-n were synthesized by one-pot multicomponent approach with good yields and were characterized by various spectroscopic techniques and finally by single crystal X-ray diffraction method (4j). All the newly-synthesized derivatives have been screened for their α-glucosidase enzyme inhibition activity and acarbose taken as a standard drug. Among all the tested compounds, 4h has displayed excellent α-glucosidase enzyme inhibition activity with IC50 value 12.45 µM to the standard drug acarbose (IC50: 12.68 µM). Similarly, the compounds 4f and 4l have exhibited potent activity with IC50 values 14.47 µM and 17.27 µM respectively. Structure-activity relationship (SAR) studies of all the title compounds were established. The mode of binding interactions between the α-glucosidase enzyme and the compounds were studied. The drug-likeness properties (Lipinski parameters and in silico ADME properties) have predicted for the target compounds. The α-glucosidase inhibition, molecular docking and drug-likeness properties of the compounds 4h, 4f and 4l were suggested that these are promising hits for anti-diabetic activity.

Synthesis and Antibacterial Activity of 3-(Substituted)-2-(4-oxo-2-phenylquinazolin-3(4H)-ylamino)quinazolin-4(3H)-one.

A series of novel 3-(substituted)-2-(substituted quinazolinylamino)quinazolin-4(3H)-ones were synthesized by the reaction of 3-(substituted)-2-hydrazino-quinazoline-4(3H)-ones with 2-phenyl-3,1-benzoxazin-4-one. The starting materials 3-(substituted)-2-hydrazino-quinazolin-4(3H)-ones were synthesized from various primary amines by a multistep synthesis. All the title compounds were tested for their antibacterial activity using ciprofloxacin as reference standard. Compounds 3-(4-fluorophenyl)-2-(4-oxo-2-phenylquinazolin-3(4H)-ylamino)quinazolin-4(3H)-one (9a) and 3-(4-chlorophenyl)-2-(4-oxo-2-phenylquinazolin-3(4H)-ylamino)quinazolin-4(3H)-one (9h) emerged as the most active compounds of the series. These compounds have shown most potent antibacterial activity against the tested organisms of Proteus vulgaris and Bacillus subtilis having zone of inhibition values of 1.1 cm and 1.4 cm for compound 9a 1.2 cm and 1.0 cm for compound 9h, respectively.

Synthesis, In Vivo Anti-Inflammatory Activity, and Molecular Docking Studies of New Isatin Derivatives.

A novel synthesis of 2-hydroxy-N'-(2-oxoindolin-3-ylidene) benzohydrazide derivatives was synthesized by the condensation of 2-hydroxybenzohydrazide with substituted isatins. The synthesized compounds were characterized by FT-IR, (1)H-NMR, and mass spectral data. Further, the compounds were screened for in vivo anti-inflammatory activity by carrageenan induced paw edema method. The tested compounds have shown mild-to-moderate anti-inflammatory activity. The compounds VIIc and VIId exhibited 65% and 63% of paw edema reduction, respectively. The molecular docking studies were also carried out into the active site of COX-1 and COX-2 enzymes (PDB ID: 3N8Y, 3LN1, resp.) using VLife MDS 4.3. The compounds VIIc, VIId, and VIIf exhibited good docking scores of -57.27, -62.02, and -58.18 onto the active site of COX-2 and least dock scores of -8.03, -9.17, and -8.94 on COX-1 enzymes and were comparable with standard COX-2 inhibitor celecoxib. A significant correlation was observed between the in silico and the in vivo studies. The anti-inflammatory and docking results highlight the fact that the synthesized compounds VIIc, VIId, and VIIf could be considered as possible hit as therapeutic agents.

Synthesis of thiocarbohydrazide and carbohydrazide derivatives as possible biologically active agents.

ABSTRACT: A series of new ß-isatin aldehyde-N,N'-thiocarbohydrazone, bis-ß-isatin thiocarbohydrazones, bis-ß-isatin carbohydrazones was synthesized by condensation of 5-substituted isatin with thiocarbohydrazide or carbohydrazide. The chemical structures of the newly synthesized compounds were confirmed by FT-IR, 1H NMR, and mass spectral analysis. The synthesized compounds were evaluated for in vitro antiviral activity against various strains of DNA and RNA viruses, but exhibited moderate antiviral activity compared with the reference compounds. Among all the compounds 6c exhibited the highest chemoprevention activity in a two-stage mouse-skin carcinogenesis test.