Current Update of Phytotherapeutic Agents in the Treatment of COVID-19: In-Silico Based Virtual Screening Approach for the Development of Antiviral Drug.

COVID-19, caused by the severe acquired respiratory syndrome coronavirus-2 (SARS-CoV-2), is a highly contagious disease that has emerged as a pandemic. Researchers and the medical fraternity are working towards the identification of anti-viral drug candidates. Meanwhile, several alternative treatment approaches are being explored to manage the disease effectively. Various phyto-drugs and essential oils have been reported to have antiviral activity, but this has not been well studied in the context of SARS-CoV-2. The main focus of this review is on the biology of infection and the different therapeutic strategies involved, including drug repurposing and phytopharmaceuticals. The role of phytochemicals in treating COVID-19 and various other diseases has also been emphasized.

Formulation of a thermo-sensitive hydro-gel for ulcerative colitis treatment.

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that causes chronic intestinal inflammation in gastrointestinal (GI) tract, mainly in innermost lining of colonic mucosa. In any of the UC drug therapy regimens, maintaining remission is challenging and about 20-40% of patients don't respond to conventional UC medications, namely, amino salicylates, steroids and immunosuppressive drugs. These agents can weaken the patient's immune system thus enhancing the risk of infectious diseases. Therefore, in our exploration we probed to test marine-derived anti-inflammatory compounds as potential agents to treat UC. Fucoidan, a complex fucose-rich sulphated polysaccharide originated in edible brown algae with known anti-inflammatory properties was isolated from Turbinaria ornate. Collagen (Achillis tendon) is another agent that may provide a beneficial effect in wound healing and tissue regeneration. Collagen was also reported to possess anti-UC properties. Collagen has a limitation of being in solution form even at high concentrations. We therefore formulated fucoidan with collagen that underwent a sol-gel transition and yielded a gel like consistency in situ. This formulation showed sustained release of fucoidan for about 12 hours. The fucoidan, collagen and the fucoidan-collagen formulation were tested in the dextran sodium sulfate (DSS) induced colitis model in mice. In comparison to the vehicle treated group, fucoidan-collagen hydrogel formulation led to significant reduction in the clinical scores and rectal bleeding, which was higher than the reference standard, mesalamine and those seen with fucoidan and collagen given alone.

Non-carboxylic acid inhibitors of aldose reductase based on N-substituted thiazolidinedione derivatives.

In search of dually active PPAR-modulators/aldose reductase (ALR2) inhibitors, 16 benzylidene thiazolidinedione derivatives, previously reported as partial PPARγ agonists, together with additional 18 structural congeners, were studied for aldose reductase inhibitory activity. While no compounds had dual property, our efforts led to the identification of promising inhibitors of ALR2. Eight compounds (11, 15-16, 20-24, 30) from the library of 33 compounds were identified as potent and selective inhibitors of ALR2. Compound 21 was the most effective and selective inhibitor with an IC50 value of 0.95 ± 0.11 and 13.52 ± 0.81 µM against ALR2 and aldehyde reductase (ALR1) enzymes, respectively. Molecular docking and dynamics studies were performed to understand inhibitor-enzyme interactions at the molecular level that determine the potency and selectivity. Compound 21 was further subjected to in silico and in vitro studies to evaluate the pharmacokinetic profile. Being less acidic (pKa = 9.8), the compound might have a superior plasma membrane permeability and reach the cytosolic ALR2. This fact together with excellent drug-likeness criteria points to improved bioavailability compared to the clinically used compound Epalrestat. The designed compounds represent a novel group of non-carboxylate inhibitors of aldose reductase with an improved physicochemical profile.

In vitro and In silico Analysis of the Anti-diabetic and Anti-microbial Activity of Cichorium intybus Leaf extracts.

OBJECTIVE: To screen the selected phytochemicals against diabetes by docking studies in comparison with experimental analysis. METHODS: Ethanol crude extract was obtained from the leaves of C.intybus and its chemical compounds were identified using GC- MS. Docking studies were carried out for selected phytochemicals to find the binding affinity and H-bond interaction using Schrodinger suite. Dynamic simulations were carried out for protein-ligand complex up to 50ns using desmond OPLS AA forcefield and α- Amylase and α- Glucosidase assay were carried for the ethanolic extract to infer its inhibition. RESULTS: Four compounds were chosen for induced fit docking based on the docking score and glide energy obtained from GLIDE-XP docking. The compounds were docked with the protein target human aldose reductase (PDB ID: 2FZD) for checking the anti-diabetic nature. The molecular dynamics simulations were carried out for the most favorable compounds and stability was checked during the simulations. The ethanol extract exhibits significant α-amylase and α-glucosidase inhibitory activities with an IC50 value of 38µg and 88µg dry extract, respectively, and well compared with standard acarbose drug. The antimicrobial activity was also carried out for various extracts (Chloroform, Ethyl acetate, and Ethanol) of the same (C. intybus) screened against four selected human pathogens. Compared to other solvent extracts, ethanol and chloroform extracts show better inhibition and their minimal inhibitory concentration (MIC) value has been calculated. CONCLUSION: In silico studies and in vitro studies reveals that C. intybus plant compounds have more potent for treating diabetes.

Anti-Cancer Compounds from Terrestrial and Marine Resources -In silico and Experimental Studies.

INTRODUCTION: In both developing and developed countries, cancer is among the leading causes of millions of deaths. The incidence of cancer is increasing due to environmental changes and modernization of life style. Lung and breast cancer deaths lead in number compared to other cancer deaths. Although the cause of cancer due to external factors like tobacco use, chemicals, radiation, infectious organisms and internal factors like immune conditions and genetic modification are known, the occurrence and deaths due to cancer cannot be controlled. METHODS: It is expected that the incidence of cancer after two decades will increase by 70% and the death rate will also increase by 50%, which is an alarming situation globally. Although synthetic compounds are being used in the control of cancer as chemopreventive agents, about 50% of these are related to natural products as the origin. There is an emerging evidence to show that in the past 50 years, natural products derived from plants and marine sources had beneficial effects in the treatment and prevention of cancer. Taxol, vincristine, vinblastine, cytarabine, eribulin mesylate and trabectidine are some of the anti-cancer compounds isolated from terrestrial and marine sources. RESULTS: This review highlights mainly the role of natural compounds isolated from terrestrial and marine sources as anti-cancer agents through the docking of these compounds with the related macromolecular targets. CONCLUSION: Cell line studies for some of the compounds isolated from natural products are also reported.

Phytochemical constituents from dietary plant Citrus hystrix.

Chemical investigation of the fruit peel of dietary plant Citrus hystrix offered two new flavones 5,6,4'-trihydroxypyranoflavone I and 5,4'-dimethyl-6-prenylpyranoflavone XIII besides 11 known compounds. The structures of all compounds were elucidated with the aid of suitable analytical methods like 1D, 2D-NMR, mass and single crystal X-ray analysis. An X-ray crystal study of compound II was done for the first time and the compounds I-VI, XI and XII are hitherto not reported from this plant. Biological studies revealed that compound I found to have a good antidiabetic and antiacetylcholinesterase activities meanwhile compounds II, III and V showed a significant free radical scavenging ability as well as antioxidant capacity. In addition, compounds I, IV, V and VI showed cytotoxicity against U87, A549 and MCF-7 cells. Overall, the new compound I showed valuable bioactive properties. Due to insufficient quantity of compound XIII, biological studies were not done.

Novel Benzylidene Thiazolidinedione Derivatives as Partial PPARγ Agonists and their Antidiabetic Effects on Type 2 Diabetes.

Peroxisome proliferator-activated receptor γ (PPARγ) has received significant attention as a key regulator of glucose and lipid homeostasis. In this study, we synthesized and tested a library of novel 5-benzylidene-thiazolidin-2,4-dione (BTZD) derivatives bearing a substituent on nitrogen of TZD nucleus (compounds 1a-1k, 2i-10i, 3a, 6a, and 8a-10a). Three compounds (1a, 1i, and 3a) exhibited selectivity towards PPARγ and were found to be weak to moderate partial agonists. Surface Plasmon Resonance (SPR) results demonstrated binding affinity of 1a, 1i and 3a towards PPARγ. Furthermore, docking experiments revealed that BTZDs interact with PPARγ through a distinct binding mode, forming primarily hydrophobic contacts with the ligand-binding pocket (LBD) without direct H-bonding interactions to key residues in H12 that are characteristic of full agonists. In addition, 1a, 1i and 3a significantly improved hyperglycemia and hyperlipidaemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats at a dose of 36 mg/kg/day administered orally for 15 days. Histopathological investigations revealed that microscopic architecture of pancreatic and hepatic cells improved in BTZDs-treated diabetic rats. These findings suggested that 1a, 1i and 3a are very promising pharmacological agents by selectively targeting PPARγ for further development in the clinical treatment of type 2 diabetes mellitus.

Liquid/Single Crystal Structure Analysis: Synthesis and Characterization of a Trimethylsilyl Derived Rod Shaped Mesogen.

4-[4'-Cyanophenoxy-carbonyl-phenyl-4-(trimethylsilyl)ethynyl]benzoate a rod shaped liquid crystal (SmA) is synthesized and characterized. The single-crystals were grown in triclinic crystal system in the space group of Pi - with unit cell parameters a = 5.9577(2) Å, b = 8.0398(3) Å, c = 25.8842(9) Å, α = 86.096(2)o, ß = 89.912(2)o, γ = 2.919(2)o, Z = 2, and V = 1182.16(7). The crystal structure is stabilized by C-H···O intra-molecular interactions. Further, the structure also involves C-H···π interactions and weak π-π stacking interactions [centroid-centroid separation = 3.806 (3) Å].

Synthesis and molecular modelling studies of novel sulphonamide derivatives as dengue virus 2 protease inhibitors.

Development of antivirals for dengue is now based on rational approach targeting the enzymes involved in its life cycle. Among the targets available for inhibition of dengue virus, non-structural protein NS2B-NS3 protease is considered as a promising target for the development of anti-dengue agents. In the current study we have synthesized a series of 4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)benzene-1-sulphonamide derivatives and screened for DENV2 protease activity. Compounds 16 and 19 showed IC50 of DENV2 Protease activity with 48.2 and 121.9µM respectively. Molecular docking and molecular dynamic simulation studies were carried out to know the binding mode responsible for the activity. MD simulations revealed that, NS2B/NS3 protease was more stable when it binds with the active compound. Structure optimization of the lead compounds 16 and 19 and their co-crystallization studies are underway.