Yogendra Nayak

Design and synthesis of 2-quinolones as antioxidants and antimicrobials: a rational approach

As an important class of compounds, 2-quinolones are isomeric to 4-quinolones and isosteric to coumarins. The compounds that have 2-quinolone moiety are associated with interesting biologic activities such as antibacterial, anticancer, antiviral, cardiotonic, and N-methyl-D-aspartate receptor inhibitor functions, among others. In the current study, based on the rational approach, lead molecules of the 2-quinolone skeleton were designed for binding to the bacterial DNA gyrase subunit A. Docking simulations and quantitative structure activity relationship (QSAR) analysis were performed using the Molegro Virtual Docker and Sarchitech softwares. Based on these studies, the 7-amino-4-methylquinolin-2(1H)-one parent compound and its carboxamides (JST 1–15) were synthesized using Conrad Limpach synthesis. The synthesized test compounds then were characterized by thin-layer chromatography and melting point determination, as well as by ultraviolet, infrared (IR), 1H-NMR, and MS studies. All synthesized and purified compounds were tested for antioxidant and antibacterial activity.

Chronotherapeutic drug delivery for early morning surge in blood pressure: A programmable delivery system

The purpose of the study was to develop pulsatile capsule dosage form of valsartan for controlled delivery. In the majority of individuals blood pressure rises in the early morning hours, which lead to serious cardiovascular complications. Formulations with constant/programmable delivery rates make it possible to deliver drug at definite time or controlled rate in chronopharmacokinetic studies. The prepared system contained swellable polymer (l-hydroxypropyl cellulose (L-HPC), xanthan gum, polyethylene oxide or sodium alginate) together with drug tablet and erodible tablet (L-HPC or guar gum) in a pre-coated capsule. Various formulation factors were investigated through series of tests, in vitro dissolution and ex vivo continuous dissolution-absorption studies. We found that the type, amount of polymers and erodible tablet influenced the drug release. The formulation containing 200 mg sodium alginate and erodible tablet (150 mg) containing 50% guar gum and 46% lactose showed 5-6 h lag time and 10+/-2.1% drug release in initial 6 h following rapid release (99+/-1.7% release in 12 h) of drug was observed. The continuous dissolution-absorption study conducted using everted rat intestinal segment indicated delay in absorption of drug. Thus this approach can provide a useful means for timed release of valsartan and may be helpful for patients with morning surge.

Antidiabetic, Antihyperlipidemic and Antioxidant Effects of the Flavonoids

Environmental and lifestyle changes contribute to the increasing global incidence of metabolic pathologies. None of the available marketed drugs comprehensively tackle the complexities associated with the axis linking inflammation/insulin resistance with obesity/hyperlipidemia. Flavonoids, found ubiquitously in most edible vegetables and fruits and constituting a major portion of micronutrients in diet, have emerged as potential alternatives for treating diabetes, hyperlipidemia and oxidative stress, involving multiple signaling pathways. Active components in a flavonoid-rich diet act synergistically on different biochemical pathways, bringing about a comprehensive therapeutic effect. Clinical evidences support the usefulness of flavonoid-rich foods over supplementation with individual flavonoids in high doses. The pleiotropic nature of flavonoids demonstrates a strong basis for their multi-targeted action on metabolic pathology. As more and more drugs focusing on single targets are being withdrawn, possibly because they destabilize the delicate equilibrium in the complex metabolic network, research on flavonoids is pacing ahead towards targeting multiple pathways holistically, legitimizing the need for re-establishing the metabolic homeostasis.

Development of risperidone liposomes for brain targeting through intranasal route

The present paper is aimed at development of functionalized risperidone liposomes for brain targeting through nasal route for effective therapeutic management of schizophrenia. The risperidone liposomes were prepared by thin film hydration method. Various parameters such as lipid ratio and lipid to drug ratio were optimized by using Design-Expert(®) Software to obtain high entrapment with minimum vesicle size. The surface of the optimized liposomes was modified by coating stearylamine and MPEG-DSPE for enhanced penetration to the brain. The formulations were evaluated for vesicle size, zeta potential, and entrapment efficiency. The morphology was studied by Transmission Electron Microscopy (TEM). In vivo efficacy was assessed by performing pharmacokinetic study in Wistar albino rats following intranasal administration of the formulations in comparison to intravenous bolus administration of pure drug. The mean vesicle size of optimized liposomes ranged from 90 to 100nm with low polydispersity index (<0.5). The entrapment efficiency of optimized liposomes was between 50 and 60%, functionalized liposomes showed maximum entrapment. The TEM images showed predominantly spherical vesicles with smooth bilayered surface. All formulations showed prolonged diffusion controlled drug release. The in vivo results showed that liposomal formulations provided enhanced brain exposure. Among the formulations studied, PEGylated liposomes (LP-16) had shown greater uptake of risperidone into the brain than plasma. High brain targeting efficiency index for LP-16 indicating preferential transport of the drug to brain. The study demonstrated successful formulation of surface modified risperidone liposomes for nasal delivery with brain targeting potential.

Antidiabetic activity of 3-hydroxyflavone analogues in high fructose fed insulin resistant rats.

Synthetic 3-hydroxyflavone analogues (JY-1, JY-2, JY-3, JY-4), were tested for antidiabetic activity in high-fructose-diet-fed (66 %, for 6 weeks) insulin-resistant Wistar rats (FD-fed rats). The fasting blood glucose, insulin, creatinine and AGEs were decreased to near normal upon treatment with test compounds. Insulin resistance markers such as HOMA-IR, K-ITT, plasma triglycerides, lipids, endogenous antioxidant defense and glycogen were restored in FD-fed rats after treatment with 3-hydroxyflavones. It is known that insulin resistance is partly because of oxidative stress and hence antioxidant activity was determined. They exhibited significant in vitro DPPH and ABTS radical scavenging activity (IC50: 10.66-66.63 µM). Test compounds inhibited ROS and NO production in RAW 264.7 cells (IC50: 10.39–42.63 µM) and they were found as potent as quercetin. Further, the test compounds inhibited lipid peroxidation at low concentrations (IC50: 99.61-217.47 µM). All test compounds at concentrations 100-200 µM protected calf thymus DNA-damage by Fenton reaction. In addition, test compounds inhibited protein glycation in different in vitro antiglycation assays. JY-2 showed maximum potency in all the stages of glycation which was comparable to the standard quercetin and aminoguanidine. Test compounds also enhanced the glucose uptake by L6 myotubes at an EC50 much lower than that of quercetin. Thus the synthetic 3-hydroxyflavones were found to have good antidiabetic activity by pleotropic and multimodal suppression of insulin resistance and enhancement of glucose uptake by skeletal muscles. These compounds are non-toxic at the doses tested. Further, the combined antioxidant and antiglycation activities of these molecules have complementary benefits in management of diabetes.

Biological Activity of a Small Molecule Indole Analog, 1-[(1H-indol-3- yl)methylene]-2-phenylhydrazine (HMPH), in Chronic Inflammation

A synthetic small molecule, 1-[(1H-indol-3-yl)methylene]-2-phenylhydrazine (HMPH) was conveniently synthesised by a one-step reaction, purified and characterised by chromatographic and spectroscopic methods. HMPH scavenged free radicals and inhibited lipopolysaccharide (LPS)-induced ROS generation and NO release in RAW-264.7 cells without signs of any detectable cytotoxicity. HMPH inhibited lipid peroxidation (LPO) with IC50 of 135 ± 9 as against 58 ± 8 μM for α-tocopherol. Further, HMPH (>50 μM) significantly reduced the LPS-induced TNF-α release in mouse peritoneal macrophages and in human peripheral blood mononuclear cells (PBMCs). HMPH did not show any visible signs of toxicity in rats up to 400 mg/kg/intraperitoneal and 2000 mg/kg/oral. HMPH at 25 and 50 mg/kg attenuated neutrophil infiltration in air-pouch lavage and bronchoalveolar lavage (BAL) in rat models. HMPH also reduced myeloperoxidase (MPO), nitrite and TNF-α in air-pouch lavage in addition to MPO in plasma. HMPH reduced acute paw-inflammation in carrageenan-induced paw-edema. HMPH consistently decreased both ipsilateral and contralateral paw inflammation, minimised the clinical scores of arthritis, prevented body weight (B.wt.) loss, attenuated serum C-reactive protein (C-RP) and rheumatoid factors (RF) in rat model of adjuvant-induced arthritis. Histopathology and radio-graphical reports show that HMPH reduced bone erosion in both ipsilateral and contralateral paw joints. Failure to inhibit COX suggests that effectiveness of HMPH in both acute and chronic inflammation is mediated by a multimodal mechanism involving modulation of immunity, attenuating TNF-α, protecting bone attrition and reducing oxidative stress.

Development and in vivo evaluation of functionalized ritonavir proliposomes for lymphatic targeting

Aims: The aim of the present work was to prepare, characterize, and evaluate proliposomes containing lipophilic prodrug ritonavir for targeting towards CD4 + T cells in the lymphatic system. Materials and methods: The liposomes were prepared by lipid thin film hydration method and lyophilized in the presence of cryoprotectant mannitol to obtain proliposomes. The optimized proliposomes by Central Composite Design, were surface modified with biotin. The proliposomes were evaluated for particle size, zeta potential, polydispersity index (PDI), entrapment efficiency, in vitro drug release, in vivo pharmacokinetics and biodistribution studies. Key findings: The mean particle size was found to be in the range of 126.6 to 306.2 nm with PDI of 0.340–1.00. The entrapment efficiency was found to be in the range of 18.9 to 86.2%. The formulations showed a zeta potential in the range of − 18.1 to − 20.2 mv. Biotinylated proliposomes (LIP‐5B) were in the size of 149.8 ± 6.8 nm with entrapment efficiency 61.6%. The % CDR of pure drug, conventional, biotinylated proliposome in 3 h was found to be 58.3, 82.04, and 95.9% respectively. In vitro drug release and in vivo pharmacokinetics of the pure drug, optimized conventional proliposomes (LIP‐5) and biotin proliposomes (LIP‐5B) were executed. Significance: The AUC for the liposomes were found to be much higher in the spleen and thymus compared to that in the plasma which indicated that the developed formulations enhance the bioavailability and target specificity compared to that of the pure drug thereby enhancing bioavailability at target site.

Lymphatic Delivery of Anti-HIV Drug Nanoparticles

BACKGROUND HIV infection persists for a longer time in AIDS patient compared to many other viral diseases. This is mainly because the HIV resides maximally in lymphatic system mainly the lymph nodes. Most of the present anti-HIV drugs have very poor bioavailability at lymphatic tissue. Hence, pharmaceutical scientists have made many efforts to formulate anti-HIV drugs for targeting lymphatic system. The exploration of nanoparticulate drug delivery systems have been popularly investigated for lymphatic targeting and for improving therapeutic efficacy. METHODS An electronic search was undertaken to review the recent publications and patents from the available resources on nanoformulations of anti-HIV drugs for lymphatic delivery. RESULTS Various carrier systems such as liposomes, polymeric nanoparticles, solid-lipid nanoparticles, nanostructured lipid carriers, polymeric micelles, dendrimers, and nanocrystals have been tried for lymphatic targeting. These nanoparticles are widely studied as passive targeting carriers for lymphatic systems. There is dearth of active targeting for anti-HIV drugs. The studies on surface modified nanoparticles have shown promising results for lymphatic targeting. CONCLUSION One of the reasons for low success rate in targeting the lymphatic tissue is poor-understanding of pharmacokinetic interactions of novel delivery systems in disease pathology. Apart from this, there are several hurdles in biological screening models and clinical trials. These issues should never be neglected in developing newer targeted delivery systems for treatment of AIDS.

Preparation, characterization and pharmacokinetic study of nelfinavir nanocrystals for oral bioavailability enhancement

The study is aimed at development of nanocrystals of Nelfinavir Mesylate, an anti-HIV drug to overcome the drawback associated with drug such as poor solubility and oral bioavailability. Nanocrystals were attempted by combination technique and ultrasonication method using polyvinyl alcohol (PVA) and poloxamer 407 as stabilizers at various concentrations. The solid-state characteristics of optimized nanocrystals were studied by XRD, FTIR, DSC and SEM analysis. The release behavior of the drug was studied by in vitro dissolution. The in vivo pharmacokinetics was assessed in Wister Albino rats by administering nanocrystals orally. Nelfinavir nanocrystals were obtained with the narrow size distribution and mean particle size was ranged from 216 to 360 nm for the nanocrystals obtained from combination technique. At 0.5% w/w of PVA, particle size was 236 ± 19.23 nm and zeta potential was 18.34 ± 2.0 mV. Freeze dried Poloxamer 407 and PVA nanocrystals showed very good solubility than the freeze dried powder with cryoprotectant and pure drug. However, nanocrystals with PVA (NC PVA) showed high dissolution velocity as compared to nanocrystals with Poloxamer 407 and were supported by high saturation solubility of NC PVA. SEM and other solid-state studies indicated the crystalline nature of developed nanocrystals. Compared to pure drug, NC PVA formulation had decreased Tmax and increased Cmax and AUC0-24. Thus pharmacokinetic study revealed significant increase in oral absorption of the drug with nanocrystals which could be attributed to the increase in dissolution velocity of the Nelfinavir in nanocrystal form.