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A highly efficient protocol was developed for the ipso hydroxylation of arylboronic acids using citric acid as an effective organocatalyst. The sustainable methodology offers good to excellent yields with in the rapid reaction time in water as a solvent media and 30% H2O2 as an oxidant. The reaction proceeds without the aid of any metal catalyst or base and is simple, safe, and clean. The current protocol enables the access to variety of phenols and is found to be tolerable to the diverse electronic substrates. Even, the devised reaction conditions have been found to be effective in the gram-scale synthesis of an API, Mequinol.

Immunomodulators are substances that either enhance or suppress the immunity of the host. Immunomodulators have been used for ages in Ayurvedic Medicine and Traditional Chinese Medicine. In the surge of modern medicine, many chemically derived substances are used as immunomodulators. Historically, plants present a rich source of these therapeutic agents. Researchers have used these lead structures for exploring the underlying mechanisms of immunomodulation so that newer, safer agents can be designed and used clinically. Microbial sources have also been tried in search of immunomodulators. Chemically, these are a diverse group of substances that act on varied signaling pathways to cause immunomodulation. The involvement of the immune system in many diseases and disorders makes these agents essential in the treatment of these diseases, e.g., cancer. This chapter discusses the chemistry of a selected few commonly known plant-derived immunomodulators along with their biological evaluation methods and provides a broad overview of their therapeutic potential with particular emphasis on the mechanism of immunomodulation.

Introduction. Resistance to antibiotics is leading to challenges in the treatment of microbial diseases. One amongst the various approaches to control these pathogens is quorum sensing (QS), which is used to rectify resistance issues. Blocking the bacterial QS circuit is the most reliable anti-virulence therapy to control pathogenicity-associated genes. Pseudomonas aeruginosa is a contagious bacterium that proliferates in the host by using signalling molecules like acyl-homoserine lactones; these molecules generate and disseminate toxins and virulence factors for increasing host infection. Hypothesis. The herb Cassia fistula is known to have antimicrobial, antidiabetic, anti-inflammatory, antitumor medicinal properties amongst others. We hypothesize that its crude extracts will inhibit the QS circuit of Pseudomonas aeruginosa (P. aeruginosa). Aim. The research work was aimed at evaluating anti-quorum sensing and anti-biofilm activity of various crude extracts from Cassia fistula against P. aeruginosa . Methodology. Various extraction methods and solvents were availed for maximum separation, and the extracts were screened for anti-quorum sensing activity. The most potent Fruit Ethyl acetate (FEE) extract at non-inhibitory concentrations was found to interrupt both short-chain (RhlI/R) and long-chain (LasI/R) QS circuits and other virulence factors (P P. aeruginosa . Biofilm inhibitory properties of FEE were demonstrated using atomic force microscopy, scanning electron microscope and confocal laser microscope. Caenorhabditis elegans infection model (Paralytic assay) was developed to determine the protective role of FEE by reducing the pathogenicity of P. aeruginosa . Results. The study results suggest that hot crude FEE extract interfered in the QS circuit, leading to comprehensive debilitation of QS-controlled virulence factors. The extract reduced virulence factor production in P. aeruginosa at 4 mg ml-1 concentration whilst paradoxically promoting biofilm formation. Possibly, higher sugar content in the extract promoted clump formation of biofilm architecture by increasing exopolysaccharide production. Moreover, in vivo analysis of bacterial pathogenesis on Caenorhabditis elegans reveals a drastic increase in survival rates in FEE treated worms compared to untreated control. Conclusions. FEE showed promising QS inhibitory activity against P. aeruginosa . In the future, additional purification of crude FEE is required to remove carbohydrates, and pure isolated phytochemicals from FEE could be used as therapeutic agents to control QS-mediated infections in P. aeruginosa .

Surface-associated bacterial communities called biofilms are ubiquitous in nature. Biofilms are detrimental in medical settings due to their high tolerance to antibiotics and may alter the final pathophysiological outcome of many healthcare-related infections. Several innovative prophylactic and therapeutic strategies targeting specific mechanisms and/or pathways have been discovered and exploited in the clinic. One such emerging and original approach to dealing with biofilms is the use of human milk oligosaccharides (HMOs), which are the third most abundant solid component in human milk after lactose and lipids. HMOs are safe to consume (GRAS status) and act as prebiotics by inducing the growth and colonization of gut microbiota, in addition to strengthening the intestinal epithelial barrier, thereby protecting from pathogens. Moreover, HMOs can disrupt biofilm formation and inhibit the growth of specific microbes. In the present review, we summarize the potential of HMOs as antibacterial and antibiofilm agents and, hence, propose further investigations on using HMOs for new-age therapeutic interventions.

Non-nucleoside reverse transcriptase inhibitors are the prime members of antiretroviral therapy that are presently employed for the management of the human immunodeficiency virus. It uses an enzyme i.e., reverse transcriptase to convert its ribonucleic acid into reverse transcription; these agents impede the function of reverse transcriptase and reverse transcription counter human immunodeficiency virus from replicating. Efavirenz is the first-generation non-nucleoside reverse transcriptase inhibitor agent. Similar to the other non-nucleoside reverse transcriptase inhibitor agents; it is prescribed with other inhibitors in combination for regimens antiretroviral therapy. To enhance survival and avoid aggressive infections in patients affected with human immunodeficiency virus infection, adequate antiretroviral therapy is the most significant treatment. Accordingly, the development and validation of such therapeutic agents are challenging work for the analysts. Therefore, the proposed review integrally addresses the analytical reports of efavirenz recorded in the literature databases like Scopus, Web of Science, Google Scholar, Pub-Med, and through many other sources. It has been remarked that for the development of efavirenz many analytical techniques were used for addressing the qualitative and quantitative estimation of efavirenz from various pharmaceutical and biological matrices. This review plan to review the stereochemistry, mechanism of action, resistance, pharmacokinetics, pharmacodynamics, safety and adverse reaction, and various analytical approaches assessed for the same. The hyphenated and chromatographic techniques are frequently used for analysis of cited drug.

A novel nanocarrier system of phospholipids complex loaded chitosan nanoparticles (FAPLC CNPs) was developed to improve the oral bioavailability and antioxidant potential of FA. FAPLC CNPs were optimized using a Box-Behnken Design (BBD). FAPLC CNPs were characterized using differential scanning calorimetry, Fourier transforms infrared spectroscopy, powder x-ray diffractometry, proton nuclear magnetic resonance, solubility, in vitro dissolution, ex vivo permeation, and in vivo antioxidant activity in carbon tetrachloride (CCl4)-induced albino rat model. The characterization studies indicated a formation of the complex as well as FAPLC CNPs. The FAPLC CNPs exhibited a lower particle size ~123.27 nm, PDI value ~0.31, and positive zeta potential ~32 mV respectively. Functional characterization studies revealed a significant improvement in the aqueous solubility, dissolution, and permeation rate of FAPLC and FAPLC CNPs compared to FA and FA CNPs. The FAPLC CNPs showed significant enhancement of in vivo antioxidant activity of FA by restoring the elevated marker enzymes in the CCl4-intoxicated rat model compared to FA CNPs. Moreover, the pharmacokinetic analysis demonstrated a significant enhancement of oral bioavailability of FA from FAPLC CNPs compared to FA CNPs. These findings show that FAPLC CNPs could be used as an effective nanocarrier for improving the oral delivery of FA.

Cancer stem cells (CSCs), a subpopulation of cancer cells endowed with self-renewal, tumorigenicity, pluripotency, chemoresistance, differentiation, invasive ability, and plasticity, reside in specialized tumor niches and are responsible for tumor maintenance, metastasis, therapy resistance, and tumor relapse. The new-age "hierarchical or CSC" model of tumor heterogeneity is based on the concept of eradicating CSCs to prevent tumor relapse and therapy resistance. Small-molecular entities and biologics acting on various stemness signaling pathways, surface markers, efflux transporters, or components of complex tumor microenvironment are under intense investigation as potential anti-CSC agents. In addition, smart nanotherapeutic tools have proved their utility in achieving CSC targeting. Several CSC inhibitors in clinical development have shown promise, either as mono- or combination therapy, in refractory and difficult-to-treat cancers. Clinical investigations with CSC marker follow-up as a measure of clinical efficacy are needed to turn the "hype" into the "hope" these new-age oncology therapeutics have to offer.

An alarming increase in global death toll resulting from cancer incidents, particularly due to multidrug resistance and reduced efficacy as a consequence of target mutations, has compelled us to look for novel anticancer agents. Cancer stem cells (CSCs), contributing majorly to the chemoresistance and tumor relapse, seem to the main culprits. In the present investigation, new chemical entities (NCEs) belonging to four novel chemical series (A: 4'-allyl-2'-methoxyphenoxymethyl-1,2,3-triazoles; B: 4'-acetamidophenoxymethyl-1,2,3-triazoles; C: naphthalene-1'-yloxymethyl-1,2,3-triazoles, and D: naphthalene-2'-yloxymethyl-1,2,3-triazoles) were synthesized via Copper (I)-catalyzed alkyne-azide cycloaddition reaction and evaluated for in vitro anticancer activity. A total of 30 NCEs (39-68) were screened at 10 µM concentration in cell viability assay against cancer cell lines such as breast (MDA-MB-231), prostate (PC-3), glioma (U87 MG), along with cervical (SiHa) and lung (A549). The NCEs from Series C (56-60) and D (61-68) were more potent than those in Series A (39-45) and Series B (46-55) at the tested concentration. Furthermore, NCEs with >80% inhibition at 10 µM were evaluated for dose response. A total of five NCEs, 48, 56, 61, 65 and 66, were further assessed in soft-agar assay and found to be relatively potent (IC50 < 10 µM). Finally, the hits were screened in sphere assay to identify potential CSC inhibitors against mammospheres (MDA-MB-231) and prostatospheres (PC-3). More so, the hits were also evaluated to understand in vitro cytotoxicity against normal cells using mouse embryonic fibroblast cell line (NIH/3T3) and human peripheral blood mononuclear cells (hPBMCs). Overall, hits 56 and 61 exhibited potent anticancer as well as CSC inhibitory activities with notably less toxicity toward NIH/3T3 and hPBMCs. On the whole, our arduous study led to the identification of potential hits with anticancer and CSC inhibitory activities, with minimal or no toxicity to normal cells.

The study was aimed at exploring the feasibility of LIPOID SPC-3 as a coprecipitate carrier to enhance the aqueous solubility and permeability of ranolazine, a BCS class II drug. LIPOID SPC-3-based coprecipitates of ranolazine (RNZ-SPC-CP) were developed using the solvent method. The developed formulation was physico-chemically characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), powder x-ray diffractometry (PXRD), and drug content. Functional evaluation of RNZ-SPC-CP formulations was carried out by solubility analysis, in vitro dissolution studies, fed vs. fasted state dissolution comparison, and ex vivo permeation studies. The SEM studies revealed dissimilar morphological characteristics of pure ranolazine, LSPC-3, and RNZ-SPC-CP formulations. The physico-chemical analysis confirmed the formation of the coprecipitate. Optimized RNZ-SPC-CP1 demonstrated a noteworthy increase (~ 18-fold) in water solubility (~ 92.23 ± 1.02 μg/mL) over that of pure ranolazine (~ 4.94 ± 0.06 μg/mL) and physical mixture (PM) (~ 30.21 ± 2.12 μg/mL). Optimized RNZ-SPC-CP1 appreciably enhanced the rate and extent of ranolazine dissolution (~ 85%), compared with that of pure ranolazine (~ 21%) and PM (~ 35%). Similarly, the permeation rate of ranolazine from optimized RNZ-SPC-CP1 formulation was found to be enhanced significantly (~ 83%) over that of pure ranolazine (~ 19%) and PM (~ 32%). In the fed state, the RNZ-SPC-CP1 improved the rate and extent of ranolazine dissolution, compared with those of fasted state dissolution. The results conclude that RNZ-SPC-CP could be used as a promising approach for enhancing the aqueous solubility and permeation rate of ranolazine.

In this study, self-assembled phytosomal soft nanoparticles encapsulated with phospholipid complex (MPLC SNPs) using a combination of solvent evaporation and nanoprecipitation method were developed to enhance the biopharmaceutical and antioxidant potential of MGN. The mangiferin-Phospholipon® 90H complex (MPLC) was produced by the solvent evaporation method and optimized using central composite design (CCD). The optimized MPLC was converted into MPLC SNPs using the nanoprecipitation method. The physicochemical and functional characterization of MPLC and MPLC SNPs was carried out by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FT-IR), powder X-ray diffractometer (PXRD), proton nuclear magnetic resonance (1H-NMR), solubility, in vitro dissolution, oral bioavailability, and in vivo antioxidant studies. A CCD formed stable MPLC with the optimal values of 1:1.76, 50.55 °C, and 2.02 h, respectively. Characterization studies supported the formation of a complex. MPLC and MPLC SNPs both enhanced the aqueous solubility (~ 32-fold and ~ 39-fold), dissolution rate around ~ 98% via biphasic release pattern, and permeation rate of ~ 97%, respectively, compared with MGN and MGN SNPs. Liver function tests and in vivo antioxidant studies exhibited that MPLC SNPs significantly preserved the CCl4-intoxicated liver marker and antioxidant marker enzymes, compared with MGN SNPs. The oral bioavailability of MPLC SNPs was increased appreciably up to ~ 10-fold by increasing the main pharmacokinetic parameters such as Cmax, Tmax, and AUC. Thus, MPLC SNPs could be engaged as a nanovesicle delivery system for improving the biopharmaceutical and antioxidant potential of MGN.

Folate receptors (FRs) are expressed in vast majority of cancers. Selective targeting of the FRs is, therefore, one of the most popular and sought-after strategies for improving the efficacy of cancer therapeutics. Variety of approaches involving folate conjugation to several well-known and novel, nontoxic, biodegradable, and biocompatible (co)polymers have been attempted and successfully applied to a large number of nanoparticulate drug delivery systems (micelles, liposomes, nanoparticles, quantum dots, mesoporous silica-based materials, and others) in the last decade-and-a-half. Standard and novel synthetic approaches were utilized for the conjugation, followed by the formulation of the drug delivery modality. In most of the cases, the targeted system lived up to its reputation, validating its usefulness in targeted cancer therapeutics. The present review summarizes the progress and state-of-the-art synthetic methodologies for folate conjugation to (co)polymers, drugs, and nucleic acids. The limitations of the FR targeting are discussed in brief to give the reader the other side of the story. Finally, the information on marketed folic acid conjugates highlight their industrial applications.

Background: Aromatic amino acid-based surfactants have been found to have interesting biological properties such as antibacterial and hemolytic activities. Recently, we have reported the antibacterial activity of a range of ester hydrochloride surfactants derived from L-Phenylalanine and LTyrosine. This study aims at assessing the antioxidant, α-glycosidase inhibitory and cytotoxic activities of a series of L-Phenylalanine and L-Tyrosine ester hydrochlorides. Molecular docking and BSA binding studies were also carried out in order to investigate their potential therapeutic targets. Methods: L-Phenylalanine and L-Tyrosine surfactants were tested as potential lipophilic antioxidants using the DPPH and ABTS assays. These surfactants were also tested for their α-glycosidase inhibitory activity using 4-nitrophenyl α -D-glucopyranoside (pNPG) as substrate. Their cytotoxicity effects were screened using HeLa and KB cell lines. Glide version 5.7 as implemented in Schrödinger suite 2013-1, was used for performing docking studies of L-Phenylalanine and L-Tyrosine dodecyl esters. The interaction of the ester hydrochlorides of L-Phenylalanine and L-Tyrosine with bovine serum albumin (BSA) was investigated using fluorometric titration. Results: The presence of the phenolic moiety in L-Tyrosine-based surfactants was found to enhance the antioxidant and α-glucosidase inhibitory activities compared to the L-Phenylalanine derivatives. The α- glucosidase and anticancer activities of the phenylalanine surfactants were found to increase with chain length up to C12 above which the activities exhibited a downward trend. In the case of the tyrosine series, an increase in chain length from C8 to C14 was found to decrease the α-glucosidase inhibitory activity and increase the anticancer activity of the surfactants. Binding studies with bovine serum albumin showed that the tyrosine surfactants displayed greater affinity for the serum albumin, owing to the presence of the phenolic group which altered the orientation of the surfactant molecule within the hydrophobic core of BSA. Conclusion: L-Tyrosine esters having a phenolic moiety were found to possess enhanced biological activity in terms of both the antioxidant and antidiabetic activities as well as also bind more strongly to Bovine serum albumin. Molecular docking studies of the phenylalanine and tyrosine surfactants of similar chain length with target proteins showed direct correlation with their anticancer and antidiabetic activity. Therefore, the findings show that these aromatic based surfactants derived from L-Tyrosine can act as promising antioxidant, antidiabetic and anticancer agents, and they can also be efficiently transported and eliminated in the body, making them useful candidates for drug designs.

A novel series of quinoline benzamide derivatives have been synthesized and screened for their anticancer activity against a breast cancer cell line (MDA-MB-231) by MTT assay method. All the synthesized compounds were confirmed by spectral characterization viz. FTIR, 1H & 13C NMR and MS. All the molecules demonstrated potency less than 35 μM and were better than standard cisplatin but not comparable to doxorubicin. Compound 3i (IC50 = 6.86 μM) exhibited better promising anti-breast cancer activity among various synthesized molecules and in addition, docking of compound 3i into kinesin spindle protein (KSP) active site was performed in order to predict the affinity and the orientation at the enzyme active site.

System xc− (Sxc−), a cystine‐glutamate antiporter, is established as an interesting target for the treatment of several pathologies including epileptic seizures, glioma, neurodegenerative diseases, and multiple sclerosis. Erastin, sorafenib, and sulfasalazine (SSZ) are a few of the established inhibitors of Sxc−. However, its pharmacological inhibition with novel and potent agents is still very much required due to potential issues, for example, potency, bioavailability, and blood–brain barrier (BBB) permeability, with the current lead molecules such as SSZ. Therefore, in this study, we report the synthesis and structure–activity relationships (SAR) of SSZ derivatives along with molecular docking and dynamics simulations using the developed homology model of xCT chain of Sxc− antiporter. The generated homology model attempted to address the limitations of previously reported comparative protein models, thereby increasing the confidence in the computational modeling studies. The main objective of the present study was to derive a suitable lead structure from SSZ eliminating its potential issues for the treatment of glioblastoma multiforme (GBM), a deadly and malignant grade IV astrocytoma. The designed compounds with favorable Sxc− inhibitory activity following in vitro Sxc− inhibition studies, showed moderately potent cytotoxicity in patient‐derived human glioblastoma cells, thereby generating potential interest in these compounds. The xCT‐ligand model can be further optimized in search of potent lead molecules for novel drug discovery and development studies.

Nanocrystalline cellulose (NCC) has gained much popularity over the last decade as a preferred nanomaterial in varied applications, despite its laborious industrial production and higher cost. Its production methods have undergone a great deal of metamorphosis lately. The main emphasis has been on the environment-friendly and green processes, in addition to the sustainable and renewable feedstock. Globally, the researchers have explored biomass and waste cellulosic materials as renewable sources for NCC extraction. Newer and/or improved process alternatives, e.g., ultrasonication, enzymatic hydrolysis and mechanical treatments have been applied successfully for producing high-quality material. Detailed investigations on optimizing the overall yield from cheaper feedstock have yielded obvious benefits. This is still work in progress. The present review majorly focuses on the advances made in the NCC preparation field from biomass and waste cellulosic materials in last three years (2016 - till date). Collaborative efforts between chemical engineers and research scientists are crucial for the success of this really amazing nanomaterial.

Hydrochlorothiazide (HTZ) is a first-line drug used in the treatment of hypertension suffered from low oral bioavailability due to poor aqueous solubility and permeability. Hence, lyophilized egg white protein-based solid dispersion (HTZ-EWP SD) was developed to explore its feasibility as a solid dispersion carrier for enhanced aqueous solubility and permeability of HTZ. The HTZ-EWP SD was prepared using the kneading method. HTZ-EWP SD was characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transforms infrared spectroscopy (FT-IR), powder X-ray diffractometer (PXRD), solubility, in vitro dissolution, and ex vivo permeation studies. The physico-chemical evaluation suggested the formation of the solid dispersion. Optimized HTZ-EWP SD4 drastically enhanced (~32-fold) aqueous solubility (~16.12 ± 0.08 mg/mL) over to pure HTZ (~ 0.51 ± 0.03 mg/mL). The dissolution study in phosphate buffer media (pH 6.8) revealed that HTZ-EWP SD4 significantly enhanced the release rate of HTZ (~ 87 %) over to HTZ (~ 25 %). The permeation rate of HTZ from optimized HTZ-EWP SD4 was enhanced significantly (~ 84 %) compared to pure HTZ (~ 24 %). Optimized HTZ-EWP-SD4 enhanced the rate of HTZ dissolution (~ 86 %) in FeSSIF (fed state simulated intestinal fluid), compared to a low dissolution rate (~ 72 %) in FaSSIF (fasted state simulated intestinal fluid) state after 2-h study. Obtained results conclude that lyophilized egg white protein can be utilized as an alternative solid dispersion carrier for enhancing the solubility and permeability of HTZ.

The anxiolytic activity of Psidium guajava L. leaf ethanolic extract (PLE) and its effect on neurotransmitter systems was investigated. PLE, extracted using Soxhlet apparatus, was subjected to preliminary qualitative and quantitative (flavonoids and phenols) analyses. The anxiolytic activity at 100, 200, and 400 mg/Kg doses were assessed in mice using elevated plus maze (EPM) and light/dark transition (LDT) test models on days 1 and 16. Neurotransmitters such as monoamines (serotonin, norepinephrine, and dopamine), γ-aminobutyric acid (GABA), and glutamate were estimated in different regions of the brain (cortex, hippocampus, and cerebellum and brain stem). Phytoconstituents identified using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry were analyzed in silico to evaluate their potential binding mode(s) to GABAA and 5-HT1A receptors. Phytochemical studies showed the presence of alkaloids, tannins, flavonoids, saponins, anthraquinone glycosides, carbohydrates, and proteins, whereas total flavonoid and phenol contents were estimated to be 64.96 ± 0.95 and 206.58 ± 1.60 mg/g of dried extract, respectively. PLE treatment significantly enhanced exploratory activity of mice in EPM and LDT models with significant effects on monoamines, GABA and glutamate levels in the brain. The in silico studies suggested the interaction(s) of PLE component(s) with GABAA /5-HT1A receptors as a potential mechanism of its anxiolytic activity.

In this study, self-assembled phytosomal soft nanoparticles encapsulated with phospholipid complex (MPLC SNPs) using a combination of solvent evaporation and nanoprecipitation method were developed to enhance the biopharmaceutical and antioxidant potential of MGN. The mangiferin-Phospholipon® 90H complex (MPLC) was produced by the solvent evaporation method and optimized using central composite design (CCD). The optimized MPLC was converted into MPLC SNPs using the nanoprecipitation method. The physicochemical and functional characterization of MPLC and MPLC SNPs was carried out by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FT-IR), powder X-ray diffractometer (PXRD), proton nuclear magnetic resonance (

The emergence of multidrug-resistant (MDR) bacterial strains in the last decade is astonishingly alarming. Many of the widely used antibiotics have failed to exhibit clinical efficacy against such strains. Eventually we will exhaust all the resources in our antibiotic armamentarium. As a need of the hour, novel strategies are desperately required not only to curb, but also to reverse, the development of resistance in these pathogens, thereby maintaining their sensitivity towards current antibiotics. Intervention of bacterial virulence, rather than killing them, by inhibiting specific pathways/targets has emerged as a novel approach to tackle the drug resistance problem. The bacterial virulence is regulated via quorum-sensing, a cell–cell communication process precisely controlled by autoinducer molecules such as acyl homoserine lactone (AHL). The present study aimed at identifying promising quorum-sensing inhibitors in Pseudomonas aeruginosa, an opportunistic human pathogen especially associated with nosocomial infections, yielding four potential hits. Out of these, potassium 2-methoxy-4-vinylphenolate was the most potent quorum-sensing inhibitor targeting P. aeruginosa LasIR/RhlIR circuitry. It also inhibited biofilm formation, various virulence factors like LasA protease, LasB elastase and pyocyanin, and motility of bacteria like swarming and twitching.

A potential fluorescent probe, N'-acetyl-2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide (HMC1) was designed on the basis of photoinduced electron transfer (PET) and synthesized using cheap starting materials. HMC1 was found to be highly efficient as a Cu2+ ion quencher with a detection limit of 0.64 μM (~ 40 ppb). The binding mode of HMC1 towards Cu2+ was evaluated by 1H NMR, LC-MS and FT-IR techniques. In addition, cellular imaging studies further exhibited that HMC1 could be used an intracellular turn-off fluorescent chemosensor for Cu2+ in living cells.

Tuberculosis remains a global concern. There is an urgent need of newer antitubercular drugs due to the development of resistant forms of Mycobacterium tuberculosis (Mtb). Inosine 5'-monophosphate dehydrogenase (IMPDH), guaB2, of Mtb, required for guanine nucleotide biosynthesis, is an attractive target for drug development. In this study, we screened a focused library of 73 drug-like molecules with desirable calculated/predicted physicochemical properties, for growth inhibitory activity against drug-sensitive MtbH37Rv. The eight hits and mycophenolic acid, a prototype IMPDH inhibitor, were further evaluated for activity on purified Mtb-GuaB2 enzyme, target selectivity using a conditional knockdown mutant of guaB2 in Mtb, followed by cross-resistance to IMPDH inhibitor-resistant SRMV2.6 strain of Mtb, and activity on human IMPDH2 isoform. One of the hits, 13, a 5-amidophthalide derivative, has shown growth inhibitory potential and target specificity against the Mtb-GuaB2 enzyme. The hit, 13, is a promising molecule with potential for further development as an antitubercular agent.

Boswellic acids (BAs) are a group of pentacyclic triterpenes present in gum-resin of Boswellia serrata . They are well known for their anti-inflammatory, hypolipidemic, immunomodulatory and anti-tumor activity, but they have poor aqueous solubility and limited bioavailability. In order to enhance their aqueous solubility, inclusion complexes of BAs with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) were synthesized and their drug release profiles were studied. Molecular associations of β-CD and HP-β-CD with BAs were investigated by phase solubility studies. The stability constants were found to be 380.2 and 145.9 M -1 for BA: β-CD and BA: HP-β-CD inclusion complexes, respectively with A N - type curve. BA: β-CD and BA: HP-β-CD inclusion complexes were synthesized using kneading (KN), co-precipitation (CP) and solvent evaporation (SE) methods in 1:1 as well as 1:2 ratios. Further these were characterized by Fourier transform infrared (FTIR) spectrophotometry, Powder X-ray Diffraction (P-XRD) and Differential scanning calorimetric (DSC) analysis. FTIR analysis showed shifting of frequencies in complexes as compared to CDs and BAs. P-XRD data obtained for BA: β-CD complexes synthesized by CP and SE methods showed amorphous pattern. Also, DSC analysis showed a change in thermal behaviour for synthesized complexes. In vitro drug release studies of BA: β-CD complexes showed enhanced release with 1:2 complexes than 1:1 complexes at pH 1.2 and pH 6.8. Similarly, drug release enhancement was observed more with BA: HP-β-CD complexes in 1:2 ratio than 1:1. To understand the interaction of BAs with CD cavity molecular modelling studies were performed which favored 1:2 complex formation over 1:1 complexes. The study thus highlights that CDs can be used for solubility and dissolution enhancement of BAs.

A novel coumarin chemosensor, 7-hydroxy-2-oxo-N-(pyridin-2-ylmethyl)chromene-3-carboxamide (Probe 1), demonstrated significant selectivity towards Fe3+ ions. Probe 1 exhibited high fluorescence emission profile at 447nm, excellent selectivity towards Fe3+ over other biologically important metal ions (Al3+, Ba2+, Co2+, Cu2+, Zn2+, Cd2+, Hg2+, Pb2+ and Sn2+). Interestingly, there was ~30-fold decrease in fluorescence intensity upon Fe3+ binding. The limit of detection of Fe3+ was found to be 0.76μM (~40ppb). Probe 1 also exhibited high potential as an intracellular chemosensor for Fe3+.

The anticancer properties of arsenic trioxide (As2O3) are accompanied by highly cytotoxic effects on normal cells. This necessitates developing modalities towards the targeted delivery of As2O3. Albumins, on account of their large structure and presence of several interacting groups, are ideal for encapsulating or carrying various drugs. In the present study, human serum albumin (HSA) was chosen as a coating agent to increase the biocompatibility of As2O3. An in situ chemical precipitation method was adopted for the synthesis of HSA-coated As2O3 nanoparticles (HSA-As2O3NPs) that were further characterized by Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), ultraviolet-visible (UV-vis) spectroscopy, inductively coupled plasma atomic emission spectrometry (ICP-AES), zeta potential and transmission electron microscopy (TEM). HSA-As2O3NPs were assessed for their biocompatibility using mouse fibroblast cells (NIH-3T3) and human dermal fibroblast (HDF) cells by a time- and dose-dependent cytocompatibility MTT assay. The safety of the HSA-As2O3 nanoparticles was assessed using haemolysis and blood cell aggregation studies. Molecular simulation studies provided evidence of interaction between HSA and As2O3. Herein, we report the development of a protein-based delivery system for As2O3 with improved biocompatibility.

Gymnema sylvestre (GS) is a medicinal herb used for diabetes mellitus (DM). Herbs are gaining popularity as medicines in DM for its safety purpose. The aim of the present study was to evaluate in vivo pharmacokinetic (PK) interaction between allopathic drugs tolbutamide (TOLBU), amlodipine (AMLO), and phenacetin (PHENA) at low (L) and high (H) doses with ethanolic extract (EL) from GS. EL was extracted and subjected to TLC, total triterpenoid content (19.76 ± 0.02 W/W) and sterol content (0.1837 ± 0.0046 W/W) estimation followed by identification of phytoconstituents using HRLC-MS and GC-MS. PK interaction study with CYP2C9, CYP3A4 and CYP1A2 enzymes were assessed using TOLBU, AMLO and PHENA respectively to index cytochrome (CYP) mediated interaction in rats after concomitant administration of EL extract (400 mg/kg) from GS for 7 days. The rats were divided into four groups for each PK study where, group I and II were positive control for low and high dose of test drugs (CYP substrates) while group II and IV were orally administered EL. The PK study result of PHENA indicated that area under the plasma concentration–time curve (AUC0-24) was significantly (P

Hybrids of 16E-arylidene steroids and nitrogen mustard have been synthesized and evaluated for their in vitro cytotoxic activity to develop tissue specific antineoplastic agents from steroids. These hybrids displayed specificity towards leukemia cell lines, however somewhat reduced potency was observed in comparison with the earlier reported 16E-arylidene steroids. The in silico reverse screening experiments were employed to find out the probable pharmacological mechanism of these hybrids. Molecular docking studies suggested glucocorticoid receptors as a probable target for the antileukemic action of these steroid-nitrogen mustard hybrids.

Aim The study is aimed at evaluating the chemosensitization and apoptotic effect of aglycone rich extracts of dietary phytoestrogens (derived from soybean and flaxseed) on estrogen receptor positive, MCF-7 and estrogen receptor negative, MDA-MB-231 cells. The extracts show potent activity on both the cell lines, hence, in silico studies have been carried out to find the possible reason for their activity. Main methods MTT assay was carried to assess chemosensitization effect and activated caspase-3/7 activity was studied using flow-cytometry and western blotting. In silico studies were carried out using PharmMapper and the top hits were taken up for docking using the Schrodinger software. Top molecular targets were subjected to gene expression studies by qPCR and protein expression using Western blot analysis. Key findings This study reports the apoptotic activity and chemosensitization effect of the phytoestrogens. Molecular docking studies predict AKR1B1 (aldose reductase), HRAS (Harvey rat sarcoma) and GSTP1 (glutathione s-transferase pi) as potential molecular targets for genistein, daidzein and secoisolariciresinol, respectively. Gene and protein expression studies show down-regulation of AKR1BI, HRAS and GSTP1 by the extracts. Significance The qPCR and western blot analysis results support the computational analyses, and hence genistein, daidzein and secoisolariciresinol may be considered as good candidates for future development into potent inhibitors of the respective protein targets through medicinal chemistry optimization.

Cancer stem cells (CSCs) mediate tumor initiation and maintenance. These cells are chemoresistant and possess characteristics such as self-renewal, pluripotency, plasticity and differentiation. They have aberrant or altered signaling pathways depending on tumor microenvironment, tumor type, etc. CSCs are responsible for highly aggressive and invasive form of the disease following chemo- and/or radiotherapy. Eliminating CSCs is likely to improve the survival rate in patients. Several anti-CSC strategies and associated targets have been proposed and validated till date. Areas covered: The main emphasis is on the patent applications/patents filed/granted in the last few years (2012-2015). The anti-CSC agents are discussed under two broad headings - small- and macromolecules. Different subclasses are further elaborated, e.g., kinase inhibitors, polypeptides, etc. Expert opinion: Clinical development of small- and macromolecular anti-CSC therapeutics is underway. Few of these agents act on validated targets such as kinases. Potential problems with these agents can be envisaged based on our understanding of target biology. Other issues governing the choice of small- versus macromolecules include druggability of the target, ease of its modulation and the presence of compensatory mechanisms. Drug repurposing can be attempted to discover newer anti-CSC drugs quickly.

Kinases remain one of the major attractive therapeutic targets for a large number of indications such as cancer, rheumatoid arthritis, cardiac failure and many others. Design and development of kinase inhibitors (ATP-competitive, allosteric or covalent) is a clinically validated and successful strategy in the pharmaceutical industry. The perks come with limitations, particularly the development of resistance to highly potent and selective inhibitors. When this happens, the cycle needs to be repeated, i.e., the design and development of kinase inhibitors active against the mutated forms. The complexity of tumor milieu makes it awfully difficult for these molecularly-targeted therapies to work. Every year newer and better versions of these agents are introduced in the clinic. Several computational approaches such as structure-, ligand-based or hybrid ones continue to live up to their potential in discovering novel kinase inhibitors. New schools of thought in this area continue to emerge, e.g., development of dual-target kinase inhibitors. But there are fundamental issues with this approach. It is indeed difficult to selectively optimize binding at two entirely different or related kinases. In addition to the conventional strategies, modern technologies (machine learning, deep learning, artificial intelligence, etc.) started yielding the results and building success stories. Computational tools invariably played a critical role in catalysing the phenomenal progress in kinase drug discovery field. The present review summarized the progress in utilizing computational methods and tools for discovering (mutant-)selective tyrosine kinase inhibitor drugs in the last three years (2017-2019). Representative investigations have been discussed, while others are merely listed. The author believes that the enthusiastic reader will be inspired to dig out the cited literature extensively to appreciate the progress made so far and the future prospects of the field.

The emergence of multidrug-resistant (MDR) bacterial strains in the last decade is astonishingly alarming. Many of the widely used antibiotics have failed to exhibit clinical efficacy against such strains. Eventually we will exhaust all the resources in our antibiotic armamentarium. As a need of the hour, novel strategies are desperately required not only to curb, but also to reverse, the development of resistance in these pathogens, thereby maintaining their sensitivity towards current antibiotics. Intervention of bacterial virulence, rather than killing them, by inhibiting specific pathways/targets has emerged as a novel approach to tackle the drug resistance problem. The bacterial virulence is regulated

The field of computational prediction of various toxicity end-points has evolved over last two decades significantly. Availability of newer modelling techniques, powerful computational resources and good-quality data have made it possible to generate reliable predictions for new chemical entities, impurities, chemicals, natural products and a lot of other substances. The field is still undergoing metamorphosis to take into account molecular complexities underlying toxicity end-points such as teratogenicity, mutagenicity, carcinogenicity, etc. Expansion of the applicability domain of these predictive models into areas other than life sciences, such as environmental and materials sciences have received a great deal of attention from all walks of life, fuelling further development and growth of the field. The present chapter discusses the state-of-the-art computational prediction of toxicity end-points of small organic molecules to balance the trade-off between the molecular complexity and the quality of such predictions, without compromising their immense utility in many fields.

Cancer kills, irrespective of geographical and cultural origin. Novel modalities for treating cancer are desperately needed. Cancer stem cells (CSCs), main culprits behind chemoresistance and tumor relapse, are one of the few logical choices. Herein, we report the synthesis and biological evaluation of small molecules with chloroacetamide war-head. These molecules were screened for viability against various breast, prostate, and oral cancer cell lines using MTT and soft-agar assays. Further, promising hits were screened in sphere-forming assay with the aim of discovering potential anti-CSC agents. Our optimism yielded four hits inhibiting self-renewal of cancer cells with stem-like characters in vitro. Finally, the hits were evaluated for in vitro toxicity against human peripheral blood mononuclear cells and mouse embryonic fibroblast cell line. Overall, these preliminary investigations yielded three hits exhibiting promising anti-CSC potential with little or no toxicity against normal cells.

H-Ras oncogene plays a critical role in the transformation of normal cells to a malignant phenotype through constitutive activation of the GTP bound protein leading to uncontrolled cell proliferation in several human cancers. Thus, H-Ras oncoprotein serves as an excellent target for anticancer drug discovery. To identify novel H-Ras inhibitors, we performed structure-based virtual screening of the Maybridge HitFinder (TM) library using Schrodinger suite. Thirty ligands from the chemical library were identified as they showed preferential in silico binding initially to H-Ras proteins with Gly12Val, Gly13Asp, and Gly12Val-Gly13Asp mutations. Absorption, distribution, metabolism, excretion, and toxicity profile confirmed drug-like properties of the compounds. Three representative molecules were tested for antiproliferative effect on T24 urinary bladder carcinoma cell line, MCF-7 breast cancer cell line and HDF-7 normal dermal fibroblast cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Two compounds (Cmpds) showed antiproliferative activity exclusively in the cancer cell lines with minimal effect on the control HDF-7 cells. The effect of compound treatment on cell cycle progression, assessed by propidium iodide (PI) staining, depicted increased arrest of T24 cell line in the sub G1 phase. Further, Annexin-V PI dual staining and pan caspase inhibitor Z-VAD-fmk indicated caspase-dependent apoptotic activity of Cmpds 1 and 3. Our findings demonstrate caspase-dependent apoptotic activity of Cmpds 1 and 3 selectively against Gly12Val mutated T24 cancer cell line implicating a potential for treatment of bladder cancer. We envisage that these molecules may be promising candidates with potential therapeutic value in H-Ras mutation-associated cancers.

The design, synthesis and antimicrobial evaluation of a novel series of azaspiro analogues of linezolid (1) have been described. Linezolid comprises of a morpholine ring which is known for its metabolism-related liabilities. Therefore, the key modification made in the linezolid structure was the replacement of morpholine moiety with its bioisostere, 2-oxa-6-azaspiro[3.3]heptane. Furthermore, the replacement of N-acetyl terminal of 1 with various aromatic or aliphatic functionalities was carried out. The title compounds were evaluated against a panel of Gram-positive and Gram-negative bacteria and Mycobacterium tuberculosis. Subsequent structure-activity relationship (SAR) studies identified several compounds with mixed antibacterial and antitubercular profiles. Compound 22 (IC50 0.72, 0.51, 0.88, 0.49 μg/mL for Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, respectively) exhibited similar antibacterial profile as 1. The N-acetyl derivative 18 was similar to 1 in antitubercular profile. Thus, the present study successfully demonstrated the use of azaspiro substructure in the medicinal chemistry of antibacterial and antitubercular agents.

5th Virtual Conference on Computational Science (VCCS) -- AUG 01-31, 2017 -- ELECTR NETWORK, WOS: 000462568100002, Density functional theory (DFT) method was used to compute the structural and vibrational parameters of favipiravir (T-705) in the gas phase. The functional used was B3LYP in conjuction with the 6-311++G(d,p) basis set. We also computed these parameters for unsubstituted T-705 and derivatives of T-705 by substituting fluorine by chlorine, bromine and the cyanide group. There is a good comparison between the computed and experimental parameters for T-705 and therefore, the predicted data should be reliable for the other compounds for which experimental data is not available. We extended our DFT study to include molecular docking involving the Ebola virus viral protein 35 (VP35). The docking results indicate that the T-705 and its chlorine and bromine analogues have comparable free energy of binding with VP35. [GRAPHICS] .