ANTIMICROBIAL POTENTIAL OF HYDROGEL INCORPORATED WITH PLGA NANOPARTICLES OF CROSSANDRA INFUNDIBULIFORMIS

Objective: Present study is aimed at formulation of Hydrogel containing Poly Lactic Glycolic Acid (PLGA) nanoparticles incorporated with ethanolic extract of Crossandra infundibuliformis (EECI) and investigate the efficacy of hydrogel nanoparticles as a carrier of antimicrobial constituents. Methods: Poly Lactic Glycolic Acid (PLGA) nanoparticles containing ethanolic extract of Crossandra infundibuliformis (EECI) were synthesized by an emulsion-evaporation method and their physicochemical properties were studied. Polymeric PLGA nanoparticles were then incorporated into gel matrix, using Hydroxy Propyl Methyl Cellulose (HPMC K4M) as a base. The antibacterial activity of nanoparticulated hydrogel formulations were evaluated by agar well diffusion method against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa. Results: Nanoparticulate hydrogel formulations exhibited high viscosity, neutral pH with good spreadability which is appropriate for transdermal application as well as showed prolonged drug release from optimized formulation up to 24 h. Nanoparticulate hydrogel formulations were effective inhibitors of all the micro-organisms with more promising activity against Staphylococcus aureus. Conclusion: Nanoparticulate hydrogel formulation can be used as a feasible alternative to conventional formulations of Crossandra infundibuliformis extract with advanced permeation characteristics of antimicrobial constituents for transdermal application

SYNTHESIS, IN SILICO PHYSICOCHEMICAL PROPERTIES AND BIOLOGICAL ACTIVITIES OF SOME PYRAZOLINE DERIVATIVES

Objectives: Nitrogen containing heterocyclic compounds plays an important role in medicinal chemistry. Among them, five-membered ring pyrazolines have found to possess many biological and pharmacological activities like anticancer, antitubercular, antimicrobial, anti-inflammatory etc. Objective is to determine the physicochemical and drug like properties of the synthesized pyrazolines by in silico methods and to screen their antidiabetic and antioxidant activities.Methods: Chalcones were synthesized from naphthaldehydes by condensing with various substituted acetophenones in ethanol and cyclized into pyrazolines using semicarbazides/thiosemicarbazides by conventional and microwave oven synthesis. The physicochemical and drug like properties were determined by using computational tools. Antidiabetic activity was evaluated by alpha amylase inhibition assay method. Antioxidant activity studies were done by DPPH and nitric oxide method.Results: Pyrazolines were synthesized from chalcones. Microwave irradiated synthesis of chalcone was carried out to get higher yield with less reaction time period as compared to conventional method. The synthesized pyrazolines produces yield around 68% (conventional) and 85% (microwave). In silico studies showed considerable values satisfying all the parameters of physicochemical and Lipinski's rule of five properties.  Among the compounds tested for antidiabetic and antioxidant studies, some showed promising activity.Conclusion: Physiochemical and drug like properties revealed that these compounds have good bioavailability and druglikeness properties. So these compounds are found to be interesting lead molecules for further synthesis as antidiabetic and antioxidant agents.Keywords: Chalcones, pyrazolines, in silico physicochemical properties, biological activities.Â

STRUCTURE-BASED MULTITARGETED MOLECULAR DOCKING ANALYSIS OF PYRAZOLE-CONDENSED HETEROCYCLICS AGAINST LUNG CANCER

Objective: The significant drawbacks of chemotherapy are that it destroys healthy cells, resulting in adverse effects. Hence, there is a need to adopt new techniques to develop cancer-specific chemicals that target the molecular pathways in a non-toxic fashion. This study aims to screen pyrazole-condensed heterocyclics for their anticancer activities and analyse their enzyme inhibitory potentials EGFR, ALK, VEGFR and TNKS receptors. Methods: The structures of the compounds were confirmed by IR, NMR and Mass spectral studies. The in silico techniques applied in this study were molecular docking and pharmacophore modeling to analyse the protein-ligand interactions, as they have a significant role in drug discovery. Drug-likeness properties were assessed by the Lipinski rule of five and ADMET properties. Anticancer activity was performed by in vitro MTT assay on lung cancer cell lines. Results: The results confirm that all the synthesised pyrazole derivatives interacted well with the selected targets showing docking scores above-5 kcal/mol. Pyrazole 2e interacted well with all the four lung cancer targets with its stable binding mode and was found to be potent as per the in vitro reports, followed by compounds 3d and 2d. Pharmacophore modeling exposed the responsible features responsible for the anticancer action. ADMET properties reported that all the compounds were found to have properties within the standard limit. The activity spectra of the pyrazoles predicted that pyrazolopyridines (2a-2e) are more effective against specific receptors such as EGFR, ALK and Tankyrase. Conclusion: Thus, this study suggests that the synthesised pyrazole derivatives can be further investigated to validate their enzyme inhibitory potentials by in vivo studies

MICROWAVE ASSISTED GREEN SYNTHESIS OF SILVER NANOPARTICLES USING COLEUS AMBOINICUS LEAF EXTRACT

Objective: Current study is aimed at the formulation of silver nanoparticles loaded with the extract of Coleus amboinicus leaf extract by microwave irradiation. A facile and green synthesis of silver nanoparticles by using a biological agent such as plant extracts with the aid of microwave irradiation is proposed as an economical and environmentally friendly approach alternative to chemical and physical methods. Methods: In order to fabricate silver nanoparticles by microwave irradiation, aqueous extract of leaves Coleus amboinicus (CA) were treated with aqueous silver nitrate solution and mixture was placed in the microwave oven for exposure to microwave. Optimizations of the process were carried out by varying the quantity of extract, silver nitrate concentration and duration of microwave irradiation. Formations of nanoparticles were confirmed by UV-visible spectroscopy observing for the presence of surface plasmon resonance (SPR) peak. Nanoparticles were characterized by scanning electron microscopy, transmission electron microscopy (TEM) and Fourier transform infrared (FTIR) spectroscopy. Results: Silver nanoparticle showed the SPR optical absorption band peak at 434 nm by UV-Visible spectrophotometer. Reaction mixture containing 2 mmol silver nitrate and 9 ml of extract subjected to microwave irradiation of 60 sec at a temperature of 60 °C was found to be optimised condition, which produced nanoparticles that were spherical in shape and had an average diameter of 15.685 nm. Conclusion: This research study opens an innovative design to progress our understanding of how silver nanoparticles behave can be optimized to improve their surface morphology, which is beneficial to improve its therapeutic effect

Synthesis of Functionalized Isoxazolines as New Acetylcholinesterase and Tyrosinase Inhibitors and Antioxidant Agents

In the search for new leads capable of interacting with multiple targets involved in NDD pathogenesis, a series of pyrazine-linked isoxazoline scaffolds were designed, synthesized and evaluated for their acetylcholinesterase and tyrosinase inhibitory potency and antioxidant activity. Isoxazolines 4a, 4d and 4h exhibited better molecular interaction with cholinesterases, tyrosinases and peroxiredoxin enzymes. Isoxazolines 4a, 4d and 4h interacted with acetylcholinesterase with the highest docking score of −9.083, −8.68 and −7.87 kcal/mol, respectively. Compound 4h ranked top when interacting with butyrylcholinesterase with a docking score of −7.926 kcal/mol, followed by 4a (−6.327 kcal/mol). 4a exhibited a robust interaction with 1HD2 with a docking score of −3.103 kcal/mol followed by 4d and 4h. 4a, 4d and 4h exhibited better docking scores of −5.47 kcal/mol, −4.63 kcal/mol and −5.157 kcal/mol with the enzyme tyrosinase. Based on the in-silico data, we have proceeded further to synthesis and in-vitro studies. Chalcones were synthesized by the Claisen-Schmidt reaction, which was cyclised to isoxazolines by the cycloaddition of hydroxylamine HCl. FTIR, 1HNMR, 13CNMR, and mass spectral studies further characterized the compounds. The prediction of pharmacokinetic parameters also supports the study, and all the compounds passed the screening. In-vitro studies were performed to evaluate acetylcholinesterase and tyrosinase inhibition. Compound 4h displayed excellent action against acetylcholinesterases and tyrosinase enzymes. Hydrogen peroxide assay determined the antioxidant effect, which found that 4h and 4d compounds exhibited higher strength as peroxide scavengers. Thus, the study shows that pyrazine-based isoxazolines with electron-withdrawing groups can be used as leads to develop a drug of choice for NDD, as it has excellent acetylcholinesterase and tyrosinase inhibitory action and tremendous peroxide scavenging effect.</p

Pharmacophore Modeling, 3D QSAR, Molecular Dynamics Studies and Virtual Screening on Pyrazolopyrimidines as anti-Breast Cancer Agents

Various targets, such as estrogen receptor (ER), mammalian target ofrapamycin(mTOR), epidermal growth factor receptor (EGFR), androgen receptor (AR) andpoly adenosine diphosphate-ribose polymerase (PARP), are focused on the treatment of breast cancer. In this study, in silico tools such as pharmacophore modeling, 3D QSAR study, molecular docking, binding free energy determination and molecular dynamics were executed on a series of pyrazolopyrimidines derivatives. The pharmacophore modeling of forty-one anticancer derivatives was generated, and atom-based 3D QSAR was applied. Molecular docking, dynamics, binding energy and high-throughput virtual screening (HTVS) were conducted by the software Schrodinger. The best five featured pharmacophore hypotheses AHRRR_1 with a maximum survival score of 5.533 was subjected to rigorous scoring function analysis and 3D QSAR studies. Docking studies and binding free energy were carried out on 41 inhibitors for their anti-breast cancer activity against human estrogen, progesterone receptor, EGFR kinase and mammalian target of rapamycin mTOR. Molecular dynamics simulation of the docked complex-34/4WKQ validated the stability of this complex. HTVS was performed to determine the virtual hits with the best-fitted model AHRRR_1. New EGFR kinase inhibitors were designed based on the active compound templates. Molecular docking was carried out on virtual hits, and newly designed compounds and dynamics studies revealed that the binding modes obtained after MD simulation were more or less similar to that acquired post docking mode. Promiscuity assessments demonstrated that designed compounds would be specific rather than a promiscuous one. Based on these findings, we have designed four novel compounds as anti-breast inhibitors, with potent binding affinity and desirable ADME properties.</p

COMPUTATIONAL TOOLS ASSISTED FORMULATION OPTIMIZATION OF NEBIVOLOL HYDROCHLORIDE LOADED PLGA NANOPARTICLES BY 32 FACTORIAL DESIGNS

Objective: The aim of the present study was to formulate and optimize the PLGA polymeric nanoparticle of Nebivolol Hydrochloride for sustain release of drug Methods: The drug-excipients interaction was explored by molecular docking studies by in silico tools. The drug-loaded polymeric nanoparticles prepared by emulsion solvent evaporation method using 32 factorial design and characterized for particle size, zeta potential, and entrapment efficiency. Shape and surface morphology was analysed by SEM and TEM. In vitro drug release study was performed by using a diffusion membrane. Results: The docking analysis inferred that the drug has interacted well with PLGA and PF-68, which could prevent the drug crystal formation. The optimized polymeric nanoparticles had a particle size of 291 nm and entrapment efficiency of 83.4% and were found to be within 95% of CI of the predicted value, which is acceptable. SEM and TEM studies showed that the formed polymeric nanoparticles were smooth, spherical in shape and uniform in size. In vitro drug release study of optimized formulation showed sustained release for prolonged time period Conclusion: Based on the computational studies and in vitro release studies, the developed Nebivolol hydrochloride loaded in PLGA nanoparticles could be a promising formulation in oral drug delivery for the treatment of hypertension

Synthesis, Molecular Docking and Molecular Dynamic Studies of Thiazolidineones as Acetylcholinesterase and Butyrylcholinesterase Inhibitors

Neurodegenerative diseases are chronic, progressive, age-related, and characterized by the loss of function of neurons caused by the accumulation of free radicals and oxidative stress. Although the prevalence of neuro disorders is rising, therapeutic efficacy is still limited due to various variables, including the blood-brain barrier. Hence, to identify molecules targeting different enzymes like acetylcholinesterase, butyrylcholinesterase and peroxiredoxins, a series of thiazolidineone derivatives were designed and synthesized. Schiff base was synthesized and cyclised with thioglycolic acid to yield thiazolidineones (T1-T10). Structural characterization was performed by IR, Mass and 1H NMR spectral studies and then subjected to in silico analysis against acetylcholinesterase (6O4W) and butyrylcholinesterase (1P0P). Compound T-9 (–10.10 kcal/mol) and T-8 (–7.65 kcal/mol) have shown excellent binding with 6O4W and 1P0P, respectively, compared with other derivatives. In addition, the compounds were checked for antioxidant activity by analyzing the interactions with peroxiredoxins (1URM), and compound T-4 was active. According to the physicochemical and ADME properties of Qikprop, synthesized compounds can be considered druglike molecules. In vitro, acetylcholinesterase inhibitory activity reveals compound T-8 as the most potent AChE inhibitor. In vitro, antioxidant activity found that compound T-4 has significant antioxidant activity. The compound T-8, with better docking scores and decisive acetylcholinesterase inhibitory action, was further explored to validate the molecular interactions through molecular dynamics studies. It was observed that compounds with the benzyl sulfonyl group (T-6 to T-10) showed higher AChE inhibitory potency than derivatives with phenyl substituents in place of the benzyl sulfonyl group (T-1 to T-5). Therefore, it is inferred that the sulfonyl group and substituents at the para position are essential for the higher inhibitory activity of compounds. Thus, there is plenty of scope for further study in developing these as promising lead compounds.</p