Synthesis, Molecular Docking and Biological Evaluation of 2-Aryloxy-N-Phenylacetamide and N'-(2-Aryloxyoxyacetyl) Benzohydrazide Derivatives as Potential Antibacterial Agents.

A new class of 2-aryloxy-N-phenylacetamide and N'-(2-aryloxyoxyacetyl) benzohydrazide derivatives with different active moieties were synthesized and screened for their antibacterial activity. Structural characterization of synthesized compounds was performed using HR-MS, 1 H-NMR, and 13 C-NMR spectral data. Amongst the synthesized compounds, 4-{2-[2-(2-chloroacetamido)phenoxy]acetamido}-3-nitrobenzoic acid (3h) and 2-chloro-N-(2-{2-[2-(2-chlorobenzoyl)hydrazinyl]-2-oxoethoxy}phenyl)acetamide (3o) have shown good antibacterial activity against a selected panel of bacteria. Besides, compounds also exhibited bactericidal activity against P. aeruginosa (3h, 0.69 µg/mL) and S. aureus (3o, 0.62 µg/mL) as evident by MBC and time-kill kinetics studies. In silico molecular docking and ADMET properties of newly synthesized compounds revealed that compounds could be considered as promising antibacterial agents.

Synthesis, molecular docking, binding free energy calculation and molecular dynamics simulation studies of benzothiazol-2-ylcarbamodithioates as Staphylococcus aureus MurD inhibitors.

A new series of benzothiazol-2-ylcarbamodithioate functional compounds 5a-f has been designed, synthesized and characterized by spectral data. These compounds were screened for their in vitro antibacterial activity against strains of Staphylococcus aureus (NCIM 5021, NCIM 5022 and methicillin-resistant isolate 43300), Bacillus subtilis (NCIM 2545), Escherichia coli (NCIM 2567), Klebsiella pneumoniae (NCIM 2706) and Psudomonas aeruginosa (NCIM 2036). Compounds 5a and 5d exhibited significant activity against all the tested bacterial strains. Specifically, compounds 5a and 5d showed potent activity against K. pneumoniae (NCIM 2706), while compound 5a also displayed potent activity against S. aureus (NCIM 5021). Compound 5d showed minimum IC50 value of 13.37 µM against S. aureus MurD enzyme. Further, the binding interactions of compounds 5a-f in the catalytic pocket have been investigated using the extra-precision molecular docking and binding free energy calculation by MM-GBSA approach. A 30 ns molecular dynamics simulation of 5d/modeled S. aureus MurD enzyme was performed to determine the stability of the predicted binding conformation.

Cytosolic lipid excess-induced mitochondrial dysfunction is the cause or effect of high fat diet-induced skeletal muscle insulin resistance: a molecular insight.

Mitochondria play a central role in the energy homeostasis in eukaryotic cells by generating ATP via oxidative metabolism of nutrients. Excess lipid accumulation and impairments in mitochondrial function have been considered as putative mechanisms for the pathogenesis of skeletal muscle insulin resistance. Accumulation of lipids in tissues occurs due to either excessive fatty acid uptake, decreased fatty acid utilization or both. Consequently, elevated levels cytosolic lipid metabolites, triglycerides, diacylglycerol and ceramides have been demonstrated to adversely affect glucose homeostasis. Several recent studies indicate that reduced insulin-stimulated ATP synthesis and reduced expression of mitochondrial enzymes and PPAR-γ coactivator, in high fat feeding (lipid overload) are associated with insulin resistance. Despite the fact, few notable studies suggest mitochondrial dysfunction is prevalent in type 2 diabetes mellitus; it is still not clear whether the defects in mitochondrial function are the cause of insulin resistance or the consequential effects of insulin resistance itself. Thus, there is a growing interest in understanding the intricacies of mitochondrial function and its association with cytosolic lipid excess. This review therefore critically examines the molecular cascades linking cytosolic lipid excess and mitochondrial dysfunction in the pathogenesis of high fat diet-induced insulin resistance in skeletal muscle. The sequential processes following the excess intake of high fat diet in skeletal muscle includes, accumulation of cytosolic fatty acids, increased production of reactive oxygen species, mutations and ageing, and decreased mitochondrial biogenesis. The consequent mitochondrial dysfunction is then leading to decreased ß-oxidation, respiratory functions and glycolysis and increased glucolipotoxicity. These events collectively induce the insulin resistance in skeletal muscle.

An effective treatment approach of DPP-IV inhibitor encapsulated polymeric nanoparticles conjugated with anti-CD-4 mAb for type 1 diabetes.

Nanotechnology based biomedical approaches and surface modification techniques made it easier for targeting specific site and improving the treatment efficacy. The present study reports on targeted polymeric nanoparticles conjugated with antibody as a site-specific carrier system for effective treatment of type 1 diabetes. Sitagliptin (SP)-loaded Poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NP) were prepared by nanoprecipitation cum solvent evaporation method and were characterized in terms of morphology, size, surface charge, and entrapment efficiency. Optimized batch demonstrated a particle size of 105.24 nm, with significant entrapment efficacy. In vitro release studies exhibited a controlled release pattern of 67.76 ± 1.30% in 24 h, and a maximum of 96.59 ± 1.26% at the end of 48 h. Thiol groups were introduced on the surface of SP-NPs whose concentration on SP-NPs was 27 ± 2.6 mmol/mol PLGA-NPs, anti-CD4 antibody clone Q4120 was conjugated to the thiolated SP-NPs via a sulfo-MBS cross-linker, ∼70% conjugation was observed. The in vitro cytotoxicity studies performed on RIN-5 F cells for mAb-SP-NPs presented an IC50 of 76 µg/mL, and the insulin release assay had revealed an increased release at 5.15 ± 0.16 IU/mL. The results indicate that mAb-SP-NPs allowed a controlled release of SP and thereby produced insulin levels comparable with control. Therefore, mAb-SP-NPs system appears to be effective in the treatment of auto immune diabetes, subject to further analysis.

Activation of Cellular Immunity in Herpes Simplex Virus Type 1-Infected Mice by the Oral Administration of Aqueous Extract of Moringa oleifera Lam. Leaves.

Moringa oleifera Lam. is used as a nutritive vegetable and spice. Its ethanol extract has been previously shown to be significantly effective in alleviating herpetic skin lesions in mice. In this study, we evaluated the alleviation by the aqueous extract (AqMOL) and assessed the mode of its anti-herpetic action in a murine cutaneous herpes simplex virus type 1 (HSV-1) infection model. AqMOL (300 mg/kg) was administered orally to HSV-1-infected mice three times daily on days 0 to 5 after infection. AqMOL significantly limited the development of herpetic skin lesions and reduced virus titers in the brain on day 4 without toxicity. Delayed-type hypersensitivity (DTH) reaction to inactivated HSV-1 antigen was significantly stronger in infected mice administered AqMOL and AqMOL augmented interferon (IFN)-γ production by HSV-1 antigen from splenocytes of HSV-1-infected mice at 4 days post-infection. AqMOL administration was effective in elevating the ratio of CD11b(+) and CD49b(+) subpopulations of splenocytes in infected mice. As DTH is a major host defense mechanism for intradermal HSV infection, augmentation of the DTH response by AqMOL may contribute to their efficacies against HSV-1 infection. These results provided an important insights into the mechanism by which AqMOL activates cellular immunity. Copyright © 2016 John Wiley & Sons, Ltd.

Identification and characterization of a potent anticancer fraction from the leaf extracts of Moringa oleifera L.

Anticancer potential of Moringa oleifera L. extracts have been well established. However, there are no reports on the isolated molecules/fractions from these extracts which are responsible for the anticancer/cytotoxic activity. Thus, in the present study, we explored the same. The n-hexane, chloroform, ethyl acetate, methanol extracts of the M. oleifera leaves and 15 fractions (F1 to F15) of ethyl acetate extract were evaluated for their in vitro and in vivo anticancer activity using Hep-2 cell lines and Dalton's lymphoma ascites model in mice, respectively. Among the tested samples, the F1 fraction showed potential cytotoxic effect in Hep-2 cell lines with a CTC50 value of 12.5 ± 0.5 µg/ml. In vivo studies with the doses 5 and 10 mg/kg, p.o. demonstrated significant reduction in body weight and increased the mean survival time compared to the control group. These results were also comparable to the standard, 5-Fluorouracil, treated animals. We have also successfully isolated and characterized the anticancer fraction, F1 from the leaves of M. oleifera L.

Insights into the Emerging Therapeutic Targets of Triple-negative Breast Cancer.

Triple-negative Breast Cancer (TNBC), the most aggressive breast cancer subtype, is characterized by the non-appearance of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Clinically, TNBC is marked by its low survival rate, poor therapeutic outcomes, high aggressiveness, and lack of targeted therapies. Over the past few decades, many clinical trials have been ongoing for targeted therapies in TNBC. Although some classes, such as Poly (ADP Ribose) Polymerase (PARP) inhibitors and immunotherapies, have shown positive therapeutic outcomes, however, clinical effects are not much satisfiable. Moreover, the development of drug resistance is the major pattern observed in many targeted monotherapies. The heterogeneity of TNBC might be the cause for limited clinical benefits. Hence,, there is a need for the potential identification of new therapeutic targets to address the above limitations. In this context, some novel targets that can address the above-mentioned concerns are emerging in the era of TNBC therapy, which include Hypoxia Inducible Factor (HIF-1α), Matrix Metalloproteinase 9 (MMP-9), Tumour Necrosis Factor-α (TNF-α), ß-Adrenergic Receptor (ß-AR), Voltage Gated Sodium Channels (VGSCs), and Cell Cycle Regulators. Currently, we summarize the ongoing clinical trials and discuss the novel therapeutic targets in the management of TNBC.

WZB117 Decorated Metformin-Carboxymethyl Chitosan Nanoparticles for Targeting Breast Cancer Metabolism.

The "Warburg effect" provides a novel method for treating cancer cell metabolism. Overexpression of glucose transporter 1 (GLUT1), activation of AMP-activated protein kinase (AMPK), and downregulation of mammalian target of rapamycin (mTOR) have been identified as biomarkers of abnormal cancer cell metabolism. Metformin (MET) is an effective therapy for breast cancer (BC), but its efficacy is largely reliant on the concentration of glucose at the tumor site. We propose a WZB117 (a GLUT1 inhibitor)-OCMC (O-carboxymethyl-chitosan)-MET combo strategy for simultaneous GLUT1 and mTOR targeting for alteration of BC metabolism. WZB117 conjugated polymeric nanoparticles were 225.67 ± 11.5 nm in size, with a PDI of 0.113 ± 0.16, and an encapsulation of 72.78 6.4%. OCMC pH-dependently and selectively releases MET at the tumor site. MET targets the mTOR pathway in cancer cells, and WZB117 targets BCL2 to alter GLUT1 at the cancer site. WZB117-OCMC-MET overcomes the limitations of MET monotherapy by targeting mTOR and BCL2 synergistically. WZB117-OCMC-MET activates AMPK and suppresses mTOR in a Western blot experiment, indicating growth-inhibitory and apoptotic characteristics. AO/EB and the cell cycle enhance cellular internalization as compared to MET alone. WZB117-OCMC-MET affects cancer cells' metabolism and is a promising BC therapeutic strategy.

GC-MS analysis of curculigo orchiodes and medicinal herbs with cytotoxic, hepatoprotective attributes of ethanolic extract from Indian origin.

OBJECTIVES: Liver illnesses are a major public health issue all over the world. Medicinal plants constituents a viable alternative for the development of phytopharmaceuticals with hepatoprotective activity in order to solve some of these health-related problems. The present study is focused on the phytochemical and biological investigation on Indian traditional medicinal plant extracts, for their cytotoxic and hepatoprotective activity. The isolated compounds showed the presence of phenolic constituents which lead to cytotoxicity and hepatoprotective activity of medicinal plant. Cancer causes about 13% of all human deaths in 2007 (7.6 million) (American Cancer Society and WHO December 2006-07). The American Cancer Society estimates that 12,990 new cases of cervical cancer will be diagnosed in the United States year 2016. Cancer-related deaths are expected to increase, with an estimated 11.4 million deaths in 2030. METHODS: The ethanolic extracts of Centella asiatica, Myristica fragrans, Trichosanthes palmata, Woodfordia fruticosa, Curculigo orchioides were evaluated against HEP-G2 cell lines for hepatoprotective activity and Curculigo orchioides was further promoted for the isolation of secondary metabolites based on inhibitory concentration. RESULTS: The ethanolic extracts of C. asiatica, M. fragrans, T. palmata, W. fruticosa, Curculigo orchioides shown significant cytotoxic activity (IC50≤100 µg/mL). The plant extracts also shown significant hepatoprotective activity in a dose dependent manner when tested against HEP-G2 cell lines and cytotoxicity studies against HeLa and HEP-G2 cells. CONCLUSIONS: The extract of Curculigo orchiodes rhizome showed significant cytotoxicity results. Hence the Curculigo orchiodes rhizome was selected for further phytochemical studies to isolate active compounds and their Characterization by GCMS.

Novel Applications of Nanotechnology in Controlling HIV and HSV Infections.

Infectious diseases have been prevalent for many decades and viral pathogens have caused global health crises and economic meltdown on a devastating scale. The high occurrence of novel viral infections in recent years, in spite of the progress achieved in the field of pharmaceutical sciences, defines the critical need for newer and more effective antiviral therapies and diagnostics. The incidence of multi-drug resistance and adverse effects due to the prolonged use of anti-viral therapy is also a major concern. Nanotechnology offers a cutting edge platform for the development of novel compounds and formulations for biomedical applications. The unique properties of nano-based materials can be attributed to the multi-fold increase in the surface to volume ratio at the nano-scale, tunable surface properties of charge and chemical moieties. Idealistic pharmaceutical properties such as increased bioavailability and retention times, lower toxicity profiles, sustained- release formulations, lower dosage forms and most importantly, targeted drug delivery can be achieved through the approach of nanotechnology. The extensively researched nano-based materials are metal and polymeric nanoparticles, dendrimers and micelles, nano-drug delivery vesicles, liposomes and lipid-based nanoparticles. In this review article, the impact of nanotechnology on the treatment of Human Immunodeficiency Virus (HIV) and Herpes Simplex Virus (HSV) viral infections during the last decade is outlined.

Repositioning of Drugs to Counter COVID-19 Pandemic - An Insight.

COVID-19 is a pandemic, caused by the novel coronavirus 2 (SARS-CoV-2) which is a severe acute respiratory syndrome. The devastating impact of this novel coronavirus outbreak has necessitated the need for rapid and effective antiviral therapies against SARS-CoV-2 to control the spread of the disease and importantly, alleviate the severe life-threatening symptoms and disorders. Drug repurposing strategy offers an attractive, immediate and realistic approach to tackle this growing pandemic of COVID-19. Due to the similarities with the SARS-CoV-1 virus and phylogenetic relation to the MERS-CoV virus, accelerated screening of approved drugs and the development of repositioning strategies have proved to be critical for the survival of many COVID-19 patients. Numerous scientific investigations from the initial years of the coronavirus outbreak along with upcoming advances of immunotherapy and vaccines, may prove to be beneficial. Currently, several repurposing strategies are under different phases of clinical trials and provide a definitive framework for the development of future therapies for the effective treatment of COVID-19. This review article summarizes the latest developments and trends in drug repurposing strategy for COVID-19 treatment.

Benzohydrazide and Phenylacetamide Scaffolds: New Putative ParE Inhibitors.

Antibacterial resistance (ABR) is a major life-threatening problem worldwide. Rampant dissemination of ABR always exemplified the need for the discovery of novel compounds. However, to circumvent the disease, a molecular target is required, which will lead to the death of the bacteria when acted upon by a compound. One group of enzymes that have proved to be an effective target for druggable candidates is bacterial DNA topoisomerases (DNA gyrase and ParE). In our present work, phenylacetamide and benzohydrazides derivatives were screened for their antibacterial activity against a selected panel of pathogens. The tested compounds displayed significant antibacterial activity with MIC values ranging from 0.64 to 5.65 µg/mL. Amongst 29 title compounds, compounds 5 and 21 exhibited more potent and selective inhibitory activity against Escherichia coli with MIC values at 0.64 and 0.67 µg/mL, respectively, and MBC at onefold MIC. Furthermore, compounds exhibited a post-antibiotic effect of 2 h at 1× MIC in comparison to ciprofloxacin and gentamicin. These compounds also demonstrated the concentration-dependent bactericidal activity against E. coli and synergized with FDA-approved drugs. The compounds are screened for their enzyme inhibitory activity against E. coli ParE, whose IC50 values range from 0.27 to 2.80 µg/mL. Gratifyingly, compounds, namely 8 and 25 belonging to the phenylacetamide series, were found to inhibit ParE enzyme with IC50 values of 0.27 and 0.28 µg/mL, respectively. In addition, compounds were benign to Vero cells and displayed a promising selectivity index (169.0629-951.7240). Moreover, compounds 1, 7, 8, 21, 24, and 25 (IC50: <1 and Selectivity index: >200) exhibited potent activity in reducing the E. coli biofilm in comparison with ciprofloxacin, erythromycin, and ampicillin. These astonishing results suggest the potential utilization of phenylacetamide and benzohydrazides derivatives as promising ParE inhibitors for treating bacterial infections.

Repurposing of Benzimidazole Scaffolds for HER2 Positive Breast Cancer Therapy: An In-Silico Approach.

BACKGROUND: A newer trend has been seen recently to reuse the conventional drugs with distinct indications for the newer applications to speed up the drug discovery and development based on earlier records and safety data. Most of the non-cancerous agents could afford a little or tolerable side effects in individuals. However, the repositioning of these non-cancerous agents for successful anticancer therapy is an outstanding strategy for future anti-cancer drug development. Since more diverse and selective cancer drug targets are being discovered and developed, the approved drug collections are particularly useful to quickly identify clinically advanced anticancer drugs against those targets. OBJECTIVE: Antihelminthic drugs such as Mebendazole and Albendazole (Benzimidazole class) have been reported to exhibit cytotoxicity (or anticancer activities) against several types of cancer. Therefore, this study aims to repurpose the benzimidazole scaffold for breast cancer treatment. METHODS: In the present study, three hydrazone analogs having a benzimidazole motif in their structural frame were synthesized. Their in-silico binding studies against HER2 receptor (PDB ID: 4LQM) and ADMET studies were carried out using Accelrys drug discovery studio 4.1. Cytotoxicity of the synthesized compounds against HER2 overexpressed MCF-7 cell lines was determined by MTT assay. RESULTS: One of the compounds 2-[2-(2,4-dinitrophenyl)hydrazinylidene]-2,3-dihydro-1H-benzimidazole (U1) has shown good cytotoxicity when compared to the standard Lapatinib, which is a well known HER2 inhibitor. CONCLUSIONS: Thus, the designed benzimidazole scaffold might serve as the best leads for treating breast cancer, which is additionally confirmed by performing their docking study via Accelrys discovery studio.

Dual Modulators of p53 and Cyclin D in ER Alpha Signaling by Albumin Nanovectors Bearing Zinc Chaperones for ER-positive Breast Cancer Therapy.

CDATA[The inherited mutations and underexpression of BRCA1 in sporadic breast cancers resulting in the loss or functional inactivation of BRCA1 may contribute to a high risk of breast cancer. Recent researchers have identified small molecules (BRCA1 mimetics) that fit into a BRCA1 binding pocket within Estrogen Receptor alpha (ERα), mimic the ability of BRCA1 to inhibit ERα activity, and overcome antiestrogen resistance. Studies indicate that most of the BRCA1 breast cancer cases are associated with p53 mutations. It indicates that there is a potential connection between BRCA1 and p53. Most p53 mutations are missense point mutations that occur in the DNA-binding domain. Structural studies have demonstrated that mutant p53 core domain misfolding, especially p53-R175H, is reversible. Mutant p53 reactivation with a new class of zinc metallochaperones (ZMC) restores WT p53 structure and functions by restoring Zn2+ to Zn2+ deficient mutant p53. Considering the role of WT BRCA1 and reactivation of p53 in tumor cells, our hypothesis is to target both tumor suppressor proteins by a novel biomolecule (ZMC). Since both proteins are present in the same cell and are functionally inactive, this state may be a novel efficacious therapeutic regime for breast cancer therapy. In addition, we propose to use Albumin Nanovector (ANV) formulation for target drug release.

Development of Novel Rhodanine Analogs as Anticancer Agents: Design, Synthesis, Evaluation and CoMSIA Study.

BACKGROUND: A series of novel 5-substituted benzylidene rhodanine derivatives using four different amines were designed based on our previously developed CoMSIA (Comparative molecular similarity indices analysis) model for the anticancer activity. METHODS: The designed rhodanines were synthesized via dithiocarbamate formation, cyclization and Knoevenagel condensation. The structures of the synthesized compounds were confirmed and analyzed by spectral studies. RESULTS: The synthesized rhodanines were investigated for in vitro anticancer activities and the analogs have displayed mild to significant cytotoxicity against MCF-7 breast cancer cells. The compounds with benzyloxy substitution at the fifth position of rhodanine ring (Compounds 20, 33 and 38) system showed significant cytotoxic activity against MCF-7 cells. CoMSIA, a three-dimensional quantitative structureactivity relationship (3D-QSAR) technique was accomplished to elucidate structure-activity relationships. CONCLUSION: Based on the information derived from CoMSIA contour plots, some key features for increasing the activity of compounds have been identified and used to design new anti-cancer agents. The present developed CoMSIA model displayed good external predictability, r2pred of 0.841 and good statistical robustness.

Synthetic enzyme-based nanoparticles act as smart catalyst for glucose responsive release of insulin.

BACKGROUND: Earlier studies have attempted to create electronic free insulin delivery systems using different glucose sensing mechanism, no successful clinical translation as hitherto been made. This study aimed to assess the faster responsiveness of the insulin release from this enzyme based nanoparticles which is a self-regulated insulin delivery system constructed by loading with insulin, enzyme glucose oxidase into hyaluronic acid and 2-nitroimidazole forming enzyme-based nanoparticles which works in accordance to the blood glucose level. MATERIALS AND METHOD: Enzyme-based nanoparticles were prepared by ionic gelation method. Insulin content in the nanoparticles kept for stability study was estimated by human insulin enzyme based immunosorbent assay. In in-vitro studies; different concentrations of glucose were taken and the release study of insulin was recorded. RESULTS: This enzyme-based nanoparticles were having average diameter of around 193 nm and stability studies showed that nanoparticles were stable upto 30 days at 4 °C. In-vitro studies showed the release of insulin from nanoparticle conjugates which was effectively correlated with the external glucose concentration created where different concentrations of glucose taken thus facilitating the stabilization of blood glucose levels in the hyperglycemia state which was achieved within 10 min. (400 mg/dL) wherein drug release rate remarkably increased in hyperglycemia state and no specific changes or small amount of release was observed in normoglycemia state (100 mg/dL). CONCLUSION: Overall, this preliminary study of this enzyme-based nanoparticles formulation showed excellent rapid responsiveness towards hyperglycemia which might act as a potential biomimetic system in triggering the release of insulin in sustained manner.

Isolation and characterization of flavonoids from the roots of medicinal plant Tadehagi triquetrum (L.) H.Ohashi.

Three flavonoid compounds were isolated from the roots of medicinal plant Tadehagi triquetrum (L.) H.Ohashi, also known as Desmodium triquetrum (Fabaceae). On the basis of the chemical and spectral analysis, the compounds were identified as baicalein (Flavone), naringin and neohesperidin (Flavonone). To the best of our knowledge and based on the literature survey all three compounds were first time reported from this medicinal plant.[Formula: see text].

A New Class of Coumate Benzimidazole Hybrids as BRCA 1 Mimetics Through Unconventional Binding Mode; Synthesis and Preliminary Cytotoxicity Screening.

BACKGROUND: It was found that breast cancer susceptibility protein 1 (BRCA 1) binds to estrogen receptor alpha (ERα) and inhibits its activity by direct interaction between domains within the amino terminus of BRCA 1 and the carboxy terminus of ER alpha. OBJECTIVES: The present work focuses to identify a new class of BRCA 1 mimetics that work differently from conventional anti-estrogens. METHODS: A novel class of hybrids having coumate and benzimidazolone scaffolds were designed to mimic BRCA 1 protein, suppressing the tumor activity of breast cancer cells. In silico molecular docking studies of the designed ligands were performed on BRCA 1 binding cavity of ER alpha. RESULTS: The designed hybrids which gave significant docking scores and had optimum binding interactions with key residues were selected for synthesis and in vitro assay. CONCLUSION: The compounds NY1 and NY2 exhibited significant effects on suppressing MDAMB- 231 cells in the concentration of 24 µg/ml and 44 µg/ml, respectively.

In vitro anti-HIV activity of some Indian medicinal plant extracts.

BACKGROUND: Human Immunodeficiency Virus (HIV) persists to be a significant public health issue worldwide. The current strategy for the treatment of HIV infection, Highly Active Antiretroviral Therapy (HAART), has reduced deaths from AIDS related disease, but it can be an expensive regime for the underdeveloped and developing countries where the supply of drugs is scarce and often not well tolerated, especially in persons undergoing long term treatment. The present therapy also has limitations of development of multidrug resistance, thus there is a need for the discovery of novel anti-HIV compounds from plants as a potential alternative in combating HIV disease. METHODS: Ten Indian medicinal plants were tested for entry and replication inhibition against laboratory adapted strains HIV-1IIIB, HIV-1Ada5 and primary isolates HIV-1UG070, HIV-1VB59 in TZM-bl cell lines and primary isolates HIV-1UG070, HIV-1VB59 in PM1 cell lines. The plant extracts were further evaluated for toxicity in HEC-1A epithelial cell lines by transwell epithelial model. RESULTS: The methanolic extracts of Achyranthes aspera, Rosa centifolia and aqueous extract of Ficus benghalensis inhibited laboratory adapted HIV-1 strains (IC80 3.6-118 µg/ml) and primary isolates (IC80 4.8-156 µg/ml) in TZM-bl cells. Methanolic extract of Strychnos potatorum, aqueous extract of Ficus infectoria and hydroalcoholic extract of Annona squamosa inhibited laboratory adapted HIV-1 strains (IC80 4.24-125 µg/ml) and primary isolates (IC80 18-156 µg/ml) in TZM-bl cells. Methanolic extracts of Achyranthes aspera and Rosa centifolia, (IC801-9 µg/ml) further significantly inhibited HIV-1 primary isolates in PM1cells. Methanolic extracts of Tridax procumbens, Mallotus philippinensis, Annona reticulate, aqueous extract of Ficus benghalensis and hydroalcoholic extract of Albizzia lebbeck did not exhibit anti-HIV activity in all the tested strains. Methanolic extract of Rosa centifolia also demonstrated to be non-toxic to HEC-1A epithelial cells and maintained epithelial integrity (at 500 µg/ml) when tested in transwell dual-chamber. CONCLUSION: These active methanolic extracts of Achyranthes aspera and Rosa centifolia, could be further subjected to chemical analysis to investigate the active moiety responsible for the anti-HIV activity. Methanolic extract of Rosa centifolia was found to be well tolerated maintaining the epithelial integrity of HEC-1A cells in vitro and thus has potential for investigating it further as candidate microbicide.

Coumarin-Fatty Acid Conjugates as Potential ERα/AKT-1 Antagonists for ER Positive Breast Cancer.

BACKGROUND: Current drugs used for the treatment of hormone-dependent breast cancer function as anti-estrogens in the breast, in addition to Estrogen Receptor (ER) agonists in the uterus, thus elevate a woman's risk of developing uterine cancer. This is due to the lack of selective binding and partial agonistic effect of these drugs towards estrogen receptors. In recent years, therefore, researchers have turned their attention towards antiestrogens devoid of these agonist properties and thus have a mechanism of action different from the existing drugs. OBJECTIVE: In this context, we report here the design, development and in vitro evaluation of some novel pharmacophores containing coumarin and fatty acid scaffolds for their anti-breast cancer activity. METHODS: A library of coumarin-fatty acid conjugates was designed using structure-based drug design approach. The conjugates which have shown good in silico results were then synthesized, characterized and evaluated for their anti-breast cancer activity by MTT assay, Apoptotic assay, Cell proliferation assay, Estrogen binding assay and Gene expression study. RESULTS: Out of the fifteen compounds screened, two compounds, SAC-2 and LNAC-2, showed good activity with IC50 values 22µg/ml, 25µg/ml, respectively. These compounds suppressed the proliferation of ER overexpressed MCF-7 cells, increased ERα degradation and hence inactivate the ERα pathway. ER binding assay and gene expression RT-PCR study reveal that SAC-2 downregulated the expression of ERα receptor and AKT-1 gene. CONCLUSION: Compound SAC-2 is a good antagonist to ER and hence has a potential for treating breast cancer and other cancers where AKT plays an important role.