In-silico design and synthesis of N9-substituted ß-Carbolines as PLK-1 inhibitors and their in-vitro/in-vivo tumor suppressing evaluation.

A new series of ß-Carboline/Schiff bases was designed, synthesized, characterised and biologically evaluated as inhibitors of PLK-1. The synthesized compounds exhibited strong to moderate cytotoxic activities against NCI-60 panel cell assay. Compound SB-2 was the most potent, particularly against colon with GI50 of 3-45 µM on NCI-60 panel cell lines. SB-2 selectively inhibited PLK-1 at 15 µM on KinomeScan screening. It also showed a dose-dependent cell cycle arrest at S/G2 phase on HCT-116 and induced apoptosis by the activation of procaspase-3 and cleaved PARP. Further, the antitumor studies on DLA and EAC model revealed that SB-2, at 100 mg/kg/bd.wt significantly increased their average lifespan. Further, a decrease in the body weight of the tumor-bearing mice was also observed when compared to the tumor controlled mice. SB-2 thus shows good potential as antitumor agent.

Thiazolidinediones as antidiabetic agents: A critical review.

Thiazolidinediones (TZDs) or Glitazones are an important class of insulin sensitizers used in the treatment of Type 2 diabetes mellitus (T2DM). TZDs were reported for their antidiabetic effect through antihyperglycemic, hypoglycemic and hypolipidemic agents. In time, these drugs were known to act by increasing the transactivation activity of Peroxisome Proliferators Activated Receptors (PPARs). The clinically used TZDs that suffered from several serious side effects and hence withdrawn/updated later, were full agonists of PPAR-γ and potent insulin sensitizers. These drugs were developed at a time when limited data were available on the structure and mechanism of PPARs. In recent years, however, PPAR-α/γ, PPAR-α/δ and PPAR-δ/γ dual agonists, PPAR pan agonists, selective PPAR-γ modulators and partial agonists have been investigated. In addition to these, several non PPAR protein alternatives of TZDs such as FFAR1 agonism, GPR40 agonism and ALR2, PTP1B and α-glucosidase inhibition have been investigated to address the problems associated with the TZDs. Using these rationalized approaches, several investigations have been carried out in recent years to develop newer TZDs devoid of side effects. This report critically reviews TZDs, their history, chemistry, mechanism mediated through PPAR, recent advances and future prospects.

Inhibitors of histone deacetylase as antitumor agents: A critical review.

Histone deacetylase (EC 3.5.1.98 - HDAC) is an amidohydrolase involved in deacetylating the histone lysine residues for chromatin remodeling and thus plays a vital role in the epigenetic regulation of gene expression. Due to its aberrant activity and over expression in several forms of cancer, HDAC is considered as a potential anticancer drug target. HDAC inhibitors alter the acetylation status of histone and non-histone proteins to regulate various cellular events such as cell survival, differentiation and apoptosis in tumor cells and thus exhibit anticancer activity. Till date, four drugs, namely Vorinostat (SAHA), Romidepsin (FK-228), Belinostat (PXD-101) and Panobinostat (LBH-589) have been granted FDA approval for cancer and several HDAC inhibitors are currently in various phases of clinical trials, either as monotherapy and/or in combination with existing/novel anticancer agents. Regardless of this, today scientific efforts have fortified the quest for newer and novel HDAC inhibitors that show isoform selectivity. This review focuses on the chemistry of the molecules of two classes of HDAC inhibitors, namely short chain fatty acids and hydroxamic acids, investigated so far as novel therapeutic agents for cancer.

Incidence of biofilms among the multidrug resistant E. coli, isolated from urinary tract infections in the Nilgiris district, South India.

Multidrug resistant uropathogenic Escherichia coli (MDRUPEC) significantly correlates with recurrent, complicated, and persistent urinary tract infection (UTI). The leading cause of multidrug resistance is the ability of E. coli to form biofilms. The physiological heterogeneity, genetic incontinency, and putative events in gene expression of biofilms render them resistant to antimicrobials and the host immune system. Understanding the determinants of antimicrobial resistance and its correlation with biofilm formations will, therefore, help the development of a better strategy for treating biofilm-associated UTIs. The present study reports on the in vitro detection of biofilm formation among multidrug resistant E. coli strains isolated from urine, the major cause of communal, nosocomial, and food-borne uropathogenic UTI. This is a cross-sectional study conducted in and around Ooty, Nilgiris, India. From the 869 urine samples analyzed for UTI, 29.34% were found to be caused by E. coli. Among this about 23.92% were found to be multidrug resistant. Among the multidrug resistant E. coli isolates, 36.06% of them were potent biofilm producers. E. coli biofilms (n = 22) were resistant to the antibiotics used to treat UTI, namely, amikacin, amoxicillin, ampicillin, cefepime, cefoperazone, cefotaxime, ceftriaxone, cefuroxime, cephalotin, ciprofloxacin, co-trimoxazole, gentamicin, levofloxacin, and nalidixic acid, but sensitive to imipenem and meropenem. All the biofilm producers exhibited motility and hemaggultination but none were positive for hemolysin production. The isolated E. coli biofilms were confirmed by VITEK R2 Compact (bioMerieux, France) and 16S rRNA gene sequencing.

Targeting of ErbB1, ErbB2, and their Dual Targeting Using Small Molecules and Natural Peptides: Blocking EGFR Cell Signaling Pathways in Cancer: A Mini-Review.

Cancer is one of the deadliest diseases involving dysregulated cell proliferation and has been the leading cause of death worldwide. The chemotherapeutic drugs currently used for treating cancer have serious drawbacks of non-specific toxicity and drug resistance. The four members of the human epidermal growth factor receptor (EGFR), namely, ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4, the trans-membrane family of tyrosine kinase receptors, are overexpressed in many types of cancers. These receptors play an important role in cell proliferation, differentiation, invasion, metastasis and angiogenesis and unregulated activation of cancer cells. Overexpression of ErbB1 and ErbB2 occurs in several types of cancers and is associated with a poor prognosis leading to resistance to ErbB1 directed therapies. Heterodimerization with ErbB2/HER2 is a potent activator of Epidermal Growth Factor Receptor-Tyrosine kinase (EGFRTK) complex than EGFR alone. Though ErbB3/HER3 can bind to a ligand, its kinase domain is devoid of catalytic activity and hence relies on its partner (ErbB2/HER2) for initiation of signals, thus, ErbB2 is involved in the activation of ErbB3. However, recent evidence reveals that ErbB1 and ErbB2 are the most important targets for cancer therapy. By inhibiting these two important kinases, the cancer cell signaling transduction pathways can be inhibited. Lapatinib and monoclonal antibodies like trastuzumab have been used for the dual inhibition of ErbB1 and ErbB2 in the treatment of various cancers. Resistance, however, develops soon. The present report reviews the investigations that have been carried out by earlier workers for targeting ErbB1, ErbB2, and both using small molecules and novel peptides that could help/facilitate researchers to design and develop better cancer chemotherapy.

Plant Based Natural Products as Quorum Sensing Inhibitors in E. Coli: A Critical Review.

The existence of multidrug-resistant (MDR) E. coli (superbugs) is a global health issue confronting humans, livestock, food processing units, and pharmaceutical industries. The quorum sensing (QS) controlling ability of the E. coli to form biofilms has become one of the important reasons for the emergence of multidrug-resistant pathogens. Quorum signaling activation and formation of biofilm lead to the emergence of antimicrobial resistance of the pathogens increasing the therapy difficult for treating bacterial diseases. There is a crucial need, therefore, to reinforce newer therapeutic designs to overcome this resistance. As the infections caused by E. coli are attributed via the QSregulated biofilm formation, easing this system by QS inhibitors is a possible strategy for treating bacterial diseases. Plant based natural products have been reported to bind to QS receptors and interrupt the QS systems of pathogens by inhibiting biofilm formation and disrupting the formed biofilms, thus minimizing the chances to develop a resistance mechanism. The present report reviews critically the QS capability of E. coli to form biofilms leading to multidrug resistant pathogens and the investigations that have been carried out so far on plant acquired natural products as QS inhibitors.

In silico screening of FDA approved drugs against ACE2 receptor: potential therapeutics to inhibit the entry of SARS-CoV-2 to human cells.

An unknown coronavirus that emerged sometime at the end of 2019 in China, the novel SARS-CoV-2, now called COVID-19, has spread all over the world. Several efforts have been made to prevent or treat this disease, though not with success. The initiation of COVID-19 viral infection involves specific binding of SARS-CoV-2 to the host surface of the receptor, ACE2. The ACE2- SARS-CoV-2 complex then gets transferred into the endosomes where the endosomal acidic proteases cleave the S protein present in SARS-CoV-2, activating its fusion and release of the viral genome. We have carried out detailed and thorough in silico studies to repurpose FDA approved compounds to inhibit human ACE2 receptor so as to prevent the viral entry. Our study reveals that five compounds show good binding to the ACE2 receptor and hence are potential candidates to interact with ACE2 and prevent it's recognition by the virus, SARS-CoV-2. Communicated by Ramaswamy H. Sarma.

Coronavirus disease - COVID-19: new perceptives towards epidemic to pandemic.

The sudden outbreak and uncontrolled spread of the novel coronavirus disease 2019 (COVID-19) has shocked the world to a degree never seen before. Due to the wide spread transmission of the virus, the number of infected cases worldwide has surpassed 16,421,958 and global death toll has spiked up to 6,52,308 from December 2019 to 27 July 2020. The virus has been labelled as a pandemic by the WHO. Virologists have found that this virus outbreak is similar to past outbreaks of viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome that caused severe respiratory syndrome and transmitted rapidly in humans. These single stranded RNA viruses come under the genera of ß-coronaviruses which ultimately infect lungs and respiratory tract. Even though the origin, source and intermediate hosts of this virus is unknown, transmittance from human-to-human through various paths has been identified globally. As of today, there are no approved drugs and vaccines. Several clinical trials are being conducted today to evaluate vaccines against the virus. The aim of our present review is to furnish brief details about the statistics, diagnosis, epidemiology, pathogenesis, prevention and treatment of COVID-19 to assist researchers and the society at large to come to grip with the deadly disease.HighlightsCumbersome outbreak of the novel Coronavirus Disease 2019 (COVID-19) became a pandemicAt June 19, 2020, as per WHO report 8,618,787 infected cases and 457,275 dead were recorded globallyMajor spread was found to be human to human transmissionsPeople with positive COVID-19 were infected with severe respiratory syndromeMore animal and clinical studies have to be done to overcome this pandemic.

The Blood Brain Barrier and its Role in Alzheimer's Therapy: An Overview.

BACKGROUND: Alzheimer's disease (AD) is the most frequent age related neurodegenerative disorder. It represents 70% of all dementia. Millions of people have been affected by AD worldwide. It is a complex illness characterized pathologically by accumulation of protein aggregates of amyloid and neurofibrillary tangles containing hyperphosphorylated neuronal tau protein. AD requires drugs that can circumvent the blood-brain barrier (BBB) which is not a simple physical barrier between blood and brain, but acts as an iron curtain, allowing only selective molecules to enter the brain. Unfortunately, this dynamic barrier restricts transport of drugs to the brain; due to which, currently very few drugs are available for AD treatment. OBJECTIVE: The present review focuses mainly on strategies used for administration of drug to the CNS by-passing BBB for the treatment of AD. RESULTS: Many studies have proved to be effective in overcoming BBB and targeting drugs to CNS by using different strategies. Here we have discussed some of the most important drug permeability and drug targeting approaches. CONCLUSION: In conclusion, concentrating solely in development of drug discovery programs is not enough but it is important to maintain balance between the drug discovery and drug delivery systems that are more specific and effective in targeting CNS of AD patients.

Antioxidant activity of Caesalpinia digyna root.

The antioxidant properties of three successive extracts of Caesalpinia digyna Rottler root and the isolated compound, bergenin, were tested using standard in vitro and in vivo models. The amount of the total phenolic compounds present was also determined. The successive methanol extract of Caesalpinia digyna root (CDM) exhibited strong scavenging effect on 2,2-diphenyl-2-picryl hydrazyl (DPPH) free radical, 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulphonic acid) diammonium salt (ABTS) radical cation, hydrogen peroxide, nitric oxide, hydroxyl radical and inhibition of lipid peroxidation. The free radical scavenging effect of CDM was comparable with that of reference antioxidants. The CDM having the highest content of phenolic compounds and strong free radical scavenging effect when administered orally to male albino rats at 100, 200 and 400mg/kg body weight for 7 days, prior to carbontetrachloride (CCl(4)) treatment, caused a significant increase in the levels of catalase (CAT) and superoxide dismutase (SOD) and significant decrease in the levels of lipidperoxidation (LPO) in serum, liver and kidney in a dose dependent manner, when compared to CCl(4) treated control. These results clearly indicate the strong antioxidant property of Caesalpinia digyna root. The study provides a proof for the ethnomedical claims and reported biological activities. The plant has, therefore, very good therapeutic potential.

In vitro and in vivo studies on HPMC-K-100 M matrices containing naproxen sodium.

Controlled release (CR) matrix tablets of naproxen sodium were prepared by wet granulation using hydroxypropyl methyl cellulose (HPMC-K-100 CR) as the hydrophilic rate controlling polymer. The effect of the concentration of the polymer and different fillers on the in vitro drug release rate was studied. The studies indicated that the drug release can be modulated by varying the concentration of the polymer and the fillers. An optimized formulation subjected to accelerated stability studies for 3 months revealed that the developed CR tablets are stable. A complete cross-over bioavailability study of the optimized formulation of the developed CR tablets and marketed immediate release tablets was performed in 6 healthy male volunteers. The extent of absorption of drug from the CR tablets was significantly higher than that for the marketed naproxen sodium tablet due to lower elimination rate and longer half-life.

Poly(malic acid) bearing Doxorubicin and N-Acetyl Galactosamine as a site-specific prodrug for targeting hepatocellular carcinoma.

In the past, several systems of drug delivery carriers have been designed with a high capacity to target specific cells and/or tissues and a reduced non-specific toxicity. In this context, we synthesized and characterized novel poly(malic acid) derivatives bearing Doxorubicin (Dox), Poly(ethylene glycol) (PEG) and/or N-Acetyl Galactosamine (NAcGal) for drug delivery. These poly(malic acid) derivatives were obtained by chemical modification of the carboxylic acid lateral groups of poly(malic acid) (PMLA). The resulting nanoplatforms were evaluated for their in vitro cytotoxicity using the human HepaRG hepatoma cell line. Results reveal that the PMLA nanoplatform modified with PEG and Dox has an IC50 of 936 nM corresponding to a Dox concentration of 47 nM, while the grafting of NAcGal onto the nanoplatform reduced the IC50 to 527 nM corresponding to a Dox concentration of 26 nM. The presence of the targeting moiety, NAcGal, thus improves the cellular toxicity of the Dox.

Novel HDAC8 inhibitors: A multi-computational approach.

Abnormal HDAC function triggers irregular gene transcription that hampers the essential cellular activities leading to tumour activation and progression. HDAC inhibition has, therefore, been reported as a potential target for cancer treatment. In the present study, a sequential computational framework was carried out to discover newer lead compounds, namely HDAC8 inhibitors for cancer therapy. Pharmacophoric hypotheses were generated based on hydroxamic acid derivatives reported earlier for HDAC inhibition. The model AAADR.122, demonstrated statistical significance (r2 = 0.93, Q2 = 0.81) and proved robust on validation with a cross-validated correlation coefficient of 0.89. It was utilized to arrive at novel hits through a virtual screening workflow. The specificity of the process was enhanced further by analysing the crucial interactions of the ligands with key catalytic residues, achieved by induced fit docking (PDB ID: 1T64). On assessment, the filtered leads displayed optimal drug like features. Investigations using density functional theory (DFT) also facilitated the recognition of molecular spots in the leads beneficial for HDAC8 interaction. Overall, two leads were proposed for HDAC8 inhibition with potential anti-cancer activity.

Targeting strategies for Human immunodeficiency virus: a combinatorial approach.

The battle between human and the Human immunodeficiency virus (HIV) is on, with both of them rapidly improving their attacking and defense strategies. Many therapeutic agents for HIV infection have been designed and developed, However there are various aspects, like novel targets against HIV, which are yet to be unfolded with a goal of designing and developing novel drug molecules against HIV. This article reviews the current status and innovative new options for antiretroviral therapy for HIV and also discusses the various mechanisms of action for each class of drugs, and the problems yet to be solved with respect to HIV as a target for improvised treatment against AIDS.

Isolation and evaluation of a polysaccharide from Prunus amygdalus as a carrier for transbuccosal delivery of Losartan potassium.

An oral buccoadhesive drug delivery system for Losartan potassium using a hydrophilic polysaccharide, isolated from Prunus amygdalaus (Badam gum), was developed and evaluated for its potential to overcome the drawbacks associated with the conventional drug therapy. The results of the study indicate that the isolated polysaccharide has good physicochemical and morphological characteristics and is suitable for use as a mucoadhesive sustain release polymer in pharmaceutical dosage forms, to alleviate the drawbacks of the conventional drug therapy of Losartan potassium.

Poly(HEMA-Zidovudine) conjugate: a macromolecular pro-drug for improvement in the biopharmaceutical properties of the drug.

A macromolecular pro-drug of a known anti-viral agent Zidovudine (AZT) was synthesized and evaluated as a sustained drug delivery system. The pro-drug was synthesized by coupling the drug to 2-hydroxyethyl methacrylate (HEMA) through a succinic spacer to get a monomeric drug conjugate which was polymerized to obtain the polymeric pro-drug. The pro-drug was subjected for in-vitro drug release study in buffers of pH 1.2 and 7.4. The hydrolytic stability of the pro-drug to pepsin was assessed in simulated gastric fluid (SGF, pH 1.2) and to α-chymotrypsin in simulated intestinal fluid (SIF, pH 7.4). The results showed that the drug release from the polymeric backbone takes place in a sustained manner over a period of 24 h, and the amount of drug released was comparatively higher at pH 7.4. Plasmatic hydrolysis studies of succinylzidovudine showed nearly complete release of AZT. At all pH conditions in the presence and absence of α-chymotrypsin, AZT was released preferentially in comparison with the succinyl derivative. The in-vivo release studies in rabbits after oral administration of AZT conjugate demonstrated a sustained release of parent drug over a period of 24 h. The pro-drug provided a significant increase in the area under the plasma concentration time curve as compared to free drug and extended the plasma half-life from 1.06 h to 8.08 h. This study suggested that, after oral administration, the drug-polymer conjugate can release AZT for prolonged periods, thus improving the pharmacokinetics of AZT and decreasing the fluctuation in plasma drug levels that can lead to toxicity.

Synthesis, characterization, and in vitro drug release study of methacrylate diclofenac conjugate as macromolecular prodrug.

Diclofenac was covalently coupled to 2-hydroxyl ethyl methacrylate (HEMA) to get a monomeric drug derivative of diclofenac. This monomer was subjected to radicular polymerization to get poly(diclo-EMA) conjugate. The in vitro drug release study of the polymeric prodrug was carried out in buffers of pH 1.2 and 7.4 mimicking the upper and lower gastrointestinal tract (GIT). The hydrolytic stability of the prodrug to pepsin was assessed in an acid buffer of pH 1.2 (simulated gastric fluid) and to α-chymotrypsin in an alkaline buffer of pH 7.4 (simulated intestinal fluid). The synthesized prodrug was also analyzed for analgesic activity, anti-inflammatory activity, and ulcerogenic index. The results showed that the drug release from the polymeric backbone takes place in a sustained manner over a period of 12 h and that the amount of drug released was comparatively higher at pH 7.4, indicating that the drug release should take place predominantly in the alkaline environment of the lower GIT rather than in the acidic environment of the upper GIT. This drug release behavior could be an ideal behavior as it may avoid or minimize the direct damage to the upper GIT caused by diclofenac. Moreover, a marked reduction of the ulcerogenic index and comparable analgesic and anti-inflammatory activities were observed with the synthesized prodrug as compared to diclofenac.

Evaluation of Anti -Inflammatory Activity of Eclipta alba in rats.

The anti-inflammatory effect of the plant of Eclipta alba (Family - Asteraceae) was evaluated using carrageenin, mediators such as histamine and serotonin induced paw oedema, and cotton pellet induced granuloma tests for their effect on acute and chronic phase inflammation models in rats. Maximum inhibition (55.85%) was noted at the dose of 500 mg/kg after 3 hr of drug treatment in carrageenin induced paw oedema, whereas the Indomethacin (standard drug ) produced 61.30% of inhibition. In the chronic model (cotton pellet induced granuloma) the CEEA and standard drug showed decreased formation of granuloma tissue by 49.7,41.5,22.1% and 53.48 % respectively. The results indicate the potent anti-inflammatory effect and therapeutic efficacy of Eclipta alba extract on animal models, which is compared with Indomethacin.