SYNTHESIS AND ANTICANCER SCREENING OF TRIAZINE ANALOGUES

Objective: The study was aimed to investigate the cytotoxic effect of S-5H-[1,2,4]-triazino (5,6-b) indol-3-yl-3,4-phenylethane-thioate derivatives as epidermal growth factor Receptor (EGFR) inhibitors. Methods: In the present study 14 novel triazine analogues were synthesized and characterized using different spectroscopic techniques such as FT-IR, NMR and Mass Spectroscopy. The anticancer activity was performed using MCF-7 (breast cancer) and K-562 (leukaemia) cell lines. Further, molecular docking was carried out using Vlife Molecular Docking Software (MDS) on crystal structure of epidermal growth factor receptor (EGFR) to identify the binding mode of interaction with an active site. Results: Compounds MA-7, MA-8, MA-12, MA-13 and MA-14 show potent activity against cancer cell lines in the range of<10 to 84.4 µg/ml. Further molecular docking on EGFR also supports that there is a strong correlation between in silico and in vitro biological activity. The results of this study may be further useful for lead optimization process. Conclusion: The results of this study indicates that the synthesized triazine analogues can give a potential lead as an anticancer agent

IN SILICO MOLECULAR DOCKING AND PHARMACOKINETIC PREDICTION OF GALLIC ACID DERIVATIVES AS PPAR-γ AGONISTS

Objective: To perform molecular docking and pharmacokinetic prediction of gallic acid derivatives as Peroxisome proliferator-activated receptors-γ (PPAR-γ) agonist for the treatment of diabetes.Methods: Molecular docking study on gallic acid and different derivatives of gallic acid was performed using GOLD v5.2 software. In addition to this, all the derivatives were analysed for drug likeliness, Lipinski's rule and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties using online tools like admet SAR, Molinspiration and Medchem designer.Results: Molecular docking studies reveals that SSP-12, SSP-13 and SSP-40 demonstrated significant binding to the PPAR-γ receptor with good Gold score fitness (73.11, 69.86 and 75.51 respectively) and relative ligand energy (-8.26,-8.33 and-7.82, respectively) as compared to standard drugs i.e. rosiglitazone and pioglitazone, (64.10 and 66.72) and (-4.30 and-2.47) respectively.Conclusion: The final results of molecular docking along with information gathered from pharmacokinetic parameters of gallic acid derivatives may be utilised further for the development of newer PPAR-γ agonists having anti-diabetic potential with better pharmacokinetic and pharmacodynamic profile

Design of anti-fungal agents by 3D-QSAR

An increase in the number of invasive fungal infections especially in immunocompromised patients is increasing the mortality rate worldwide. Due to the emergence of drug-resistant fungi, the currently available antifungal drugs have become ineffective. Because no alternative treatment is available, some existing drugs are still used. Therefore, there is a need to design and develop novel and effective anti-fungal drugs. Molecular docking and 3-dimensional quantitative structure-activity relationship (3D-QSAR) methods have been useful approaches for the design of novel molecules. A set of 30 molecules reported in the literature containing azoles and non-azoles have been used in this study to derive 3D-QSAR.CoMFA and CoMSIA models for the most active compound and least active compounds have been developed. The structural requirements were obtained by analysing the contour maps. The partial least square analysis for CoMFA and CoMSIA showed a significant cross-validated correlation coefficient of 0.625 and 0.67 and a non-cross validated correlation coefficient of 0.991 and 0.99, respectively. The model was validated by observing the predicted correlation for test molecules with the value of 0.699 and 0.659, respectively

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Design of anti-fungal agents by 3D-QSAR

744-754An increase in the number of invasive fungal infections especially in immunocompromised patients is increasing the mortality rate worldwide. Due to the emergence of drug-resistant fungi, the currently available antifungal drugs have become ineffective. Because no alternative treatment is available, some existing drugs are still used. Therefore, there is a need to design and develop novel and effective anti-fungal drugs. Molecular docking and 3-dimensional quantitative structure-activity relationship (3D-QSAR) methods have been useful approaches for the design of novel molecules. A set of 30 molecules reported in the literature containing azoles and non-azoles have been used in this study to derive 3DQSAR. CoMFA and CoMSIA models for the most active compound and least active compounds have been developed. The structural requirements were obtained by analysing the contour maps. The partial least square analysis for CoMFA and CoMSIA showed a significant cross-validated correlation coefficient of 0.625 and 0.67 and a non-cross validated correlation coefficient of 0.991 and 0.99, respectively. The model was validated by observing the predicted correlation for test molecules with the value of 0.699 and 0.659, respectively

Clinical safety and tolerability evaluation of Withania somnifera (L.) Dunal (Ashwagandha) root extract in healthy human volunteers

Background: Withania somnifera (L.) Dunal, known as Ashwagandha, is an adaptogen with significant importance in Ayurveda for its potential health benefits in strength ('balavardhan') and muscle growth ('mamsavardhan'). Despite numerous studies on its efficacy, limited research is reported on its clinical safety and tolerability in healthy individuals. Objective: This research evaluated the tolerability and safety of standardized Withania somnifera root extract (WSE) capsules (AgeVel®/Witholytin®) at 1000 mg/day dose upon oral administration in healthy male participants. Method: A non-randomized, open-label, single-treatment clinical study included eighteen healthy male participants aged 18 to 60. The participants were administered a dose of 500 mg of the WSE capsules twice daily for four weeks. Each capsule contained not less than 7.50 mg of total withanolides. The study evaluated various indicators in a cohort of healthy participants throughout the trial, including vital signs, organ function tests, urine analysis, X-ray and ECG, cardiorespiratory endurance, body fat percentage, lean body weight, adverse events profile, and tolerability of the WSE capsules. Results: The participant's physical, hematological, and biochemical characteristics were normal, and no significant alterations or irregularities were observed in safety metrics like liver, kidney, and thyroid functions after administering AgeVel®/Witholytin®. Conclusion: This study found that healthy male participants could consume a standardized WSE at a daily dosage of 1000 mg for four weeks without any adverse effects. Future research should focus on long-term safety assessments in male and female participants

Pharmacokinetic Study of Withanosides and Withanolides from Withania somnifera Using Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS)

Withania somnifera is a traditional Indian herb described under the ‘Rasayana’ class in Ayurveda, which gained immense popularity as a dietary supplement in the USA, Europe, Asia, and the Indian domestic market. Despite enormous research on the pharmacological effect of withanosides and withanolides, bioanalytical method development and pharmacokinetics remained challenging and unexplored for these constituents due to isomeric and isobaric characteristics. In current research work, molecular descriptors, pharmacokinetic, and toxicity prediction (ADMET) of these constituents were performed using Molinspiration and admetSAR tools. A rapid, selective, and reproducible bioanalytical method was developed and validated for seven withanosides and withanolides as per USFDA/EMA guidelines, further applied to determine pharmacokinetic parameters of Withania somnifera root extract (WSE) constituents in male Sprague Dawley rats at a dose of 500 mg/kg. Additionally, an ex vivo permeability study was carried out to explore the absorption pattern of withanosides and withanolides from the intestinal lumen. In silico, ADMET revealed oral bioavailability of withanosides and withanolides following Lipinski’s rules of five with significant absorption from the gastrointestinal tract and the ability to cross the blood-brain barrier. Upon oral administration of WSE, Cmax was found to be 13.833 ± 3.727, 124.415 ± 64.932, 57.536 ± 7.523, and 7.283 ± 3.341 ng/mL for withanoside IV, withaferin A, 12-Deoxy-withastramonolide, and withanolide A, respectively, with Tmax of 0.750 ± 0.000, 0.250 ± 0.000, 0.291 ± 0.102, and 0.333 ± 0.129 h. Moreover, at a given dose, withanoside V, withanolide B, and withanone were detected in plasma; however, the concentration of these constituents was found below LLOQ. Thus, these four major withanoside and withanolides were quantified in plasma supported by ex vivo permeation data exhibiting a time-dependent absorption of withanosides and withanolides across the intestinal barrier. These composite findings provide insights to design a clinical trial of WSE as a potent nutraceutical