Total synthesis, structure elucidation and expanded bioactivity of icosalide A: effect of lipophilicity and ester to amide substitution on its bioactivity.

The first total synthesis of icosalide A, an antibacterial depsipeptide that is unique in that it contains two lipophilic beta-hydroxy acids, has been achieved by following Fmoc solid-phase peptide synthesis in combination with solution-phase synthesis. The ambiguity in the absolute stereochemistry of icosalide A has been resolved by synthesizing the reported structures and other relevant diastereomers of icosalides and comparing their NMR data. NMR-based structure elucidation of icosalide A revealed a well-folded structure with cross-strand hydrogen bonds similar to the anti-parallel beta-sheet conformation in peptides and displayed a synergistic juxtaposition of the aliphatic sidechains. 12 analogues of icosalide A were synthesized by varying the constituent lipophilic beta-hydroxy acid residues, and their biological activities against Bacillus thuringiensis and Paenibacillus dendritiformis were explored. Most of these icosalide analogues showed an MIC of 12.5 µg mL-1 against both bacteria. Swarming inhibition by icosalides was least in B. thuringiensis (8.3%) compared to that in P. dendritiformis (33%). Furthermore, this is the first report of icosalides showing assured inhibitory action (MIC between 2 and 10 µg mL-1) against the active stage of Mycobacterium tuberculosis and cancer cell lines such as HeLa and ThP1. This study could help optimize icosalides for anti-TB, antibacterial, and anti-cancer activities.

Design and synthesis of piano-stool ruthenium(II) complexes and their studies on the inhibition of amyloid ß (1-42) peptide aggregation.

Misfolding and protein aggregation have been linked to numerous human neurodegenerative disorders such as Alzheimer's, prion, and Parkinson's diseases. Ruthenium (Ru) complexes have received considerable attention in studying protein aggregation due to their interesting photophysical and photo properties. In this study, we have synthesized the novel Ru complexes ([Ru(p-cymene)Cl(L-1)][PF6](Ru-1), and [Ru(p-cymene)Cl(L-2)][PF6](Ru-2)) and investigated their inhibitory activity against the bovine serum albumin (BSA) aggregation and the Aß1-42 peptides amyloid formation. Several spectroscopic methods were used to characterize these complexes, and the molecular structure of the complex was determined by X-ray crystallography. Amyloid aggregation and inhibition activities were examined using the Thioflavin-T (ThT) assay, and the secondary structures of the protein were analyzed by circular dichroism (CD) spectroscopy and transmission electron microscopy (TEM). The cell viability assay was carried out on the neuroblastoma cell line, revealing that the complex Ru-2 showed better protective effects against Aß1-42 peptide toxicity on neuro-2a cells than the complex Ru-1. Molecular docking studies elucidate the binding sites and interactions between the Ru-complexes and Aß1-42 peptides. The experimental studies revealed that these complexes significantly inhibited the BSA aggregation and Aß1-42 amyloid fibril formation at 1:3 and 1:1 molar concentrations, respectively. Antioxidant assays demonstrated that these complexes act as antioxidants, protecting from amyloid-induced oxidative stress. Molecular docking studies with the monomeric Aß1-42 (PDB: 1IYT) show hydrophobic interaction, and both complexes bind preferably in the central region of the peptide and coordinate with two binding sites of the peptide. Hence, we suggest that the Ru-based complexes could be applied as a potential agent in metallopharmaceutical research against Alzheimer's disease.

DNA binding, antitubercular, antibacterial and anticancer studies of newly designed piano-stool ruthenium(II) complexes.

The chemotherapeutic potential of ruthenium(II) complexes has recently attracted researchers' interest as antibacterial and anticancer agents. In this study, two novel half-sandwich imine-based Ru complexes ([Ru(p-cymene)Cl(L-1)][PF6] (Ru-1) and [Ru(p-cymene)Cl(L-2)][PF6] (Ru-2)) were reported for their deoxyribonucleic acid (DNA) binding and antitubercular, antibacterial, and anticancer activities. The molecular structure of Ru-2 was obtained by single-crystal X-ray crystallography. DNA interaction studies were conducted by UV-Vis absorbance and fluorescence spectral titration which gave rise to DNA binding constants (Kb) of 1.32 × 106 and 1.82 × 106 for Ru-1 and Ru-2, respectively and the Stern-Volmer binding constant (KSV) values for Ru-1 and Ru-2 were 1.7763 × 104 M-1 and 7.6 × 103 M-1, respectively. The in vitro antitubercular activity was evaluated against Mycobacterium tuberculosis H37Ra. The antibacterial potential of both the Ru-complexes was examined against Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus and Bacillus subtilis) bacteria. The half-maximal inhibitory concentration (IC50) values for the antitubercular activity of Ru-1 and Ru-2 were 4.87 ± 1.32 µM and 5.78 ± 0.54 µM, respectively. A cytotoxic study of these complexes was performed against the human breast cancer cell line (MCF-7) and the human embryonic kidney cell line (HEK293) (normal cells). The study revealed meaningful activity of the Ru-1 complex against (cancer) MCF-7 cells, while the viability of HEK293 (normal) cells in the presence of Ru-2 was higher as compared to a reference drug 5FU. We suggest that these kinds of Ru-complexes could have potential for application in metallopharmaceuticals.

Conventional and microwave-assisted organic synthesis of novel antimycobacterial agents bearing furan and pyridine hybrids.

Drug resistance in tuberculosis poses a serious threat to humanity because currently available antitubercular drugs are ineffective against Mycobacterium tuberculosis (M. tuberculosis). As a result, the approval of Bedaquiline and Delamanid for the treatment of drug-resistant tuberculosis was accelerated. Still, there is an urgent need to search for new antitubercular drugs with novel mechanisms of action (MoA). Due to this, we have designed a synthetic strategy by utilizing microwave-assisted organic synthesis. We have compared our method with the conventional procedure, and the data show that our procedure is more effective in the preparation of title compounds. A unique series of 1-(2-(furan-2-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)-3-(aryl)-prop-2-en-1-ones (5a-o) was synthesized utilizing conventional and microwave-assisted techniques. Synthetic compounds were investigated for antitubercular activity against Mycobacterium TB H37 Ra and Mycobacterium bovis (M. bovis). Compound 5b was reported to be the most effective against M. tuberculosis H37 Ra (97.69 percent inhibition at 30 µg/ml) and M. bovis (97.09 percent inhibition at 30 µg/ml). An in silico binding affinity study of mycobacterial enoyl-acyl carrier protein reductase (InhA) reveals the binding mechanism and thermodynamic interactions that determine these molecule's binding affinity. Compound 5b had a high glide score of -8.991 and low glide energy of -49.893 kcal/mol.

In silico Studies, Synthesis and Antitubercular Activity of Some Novel Quinoline - Azitidinone Derivatives.

BACKGROUND: Diarylquinolines like Bedaquiline have shown promising antitubercular activity by their action of Mycobacterial ATPase. OBJECTIVE: The structural features necessary for a good antitubercular activity for a series of quinoline derivatives were explored through computational chemistry tools like QSAR and combinatorial library generation. In the current study, 3-Chloro-4-(2-mercaptoquinoline-3-yl)-1- substitutedphenylazitidin-2-one derivatives have been designed and synthesized based on molecular modeling studies as anti-tubercular agents. METHODS: 2D and 3D QSAR analyses were used to designed compounds having a quinoline scaffold. The synthesized compounds were evaluated against active and dormant strains of Mycobacterium tuberculosis (MTB) H37 Ra and Mycobacterium bovis BCG. The compounds were also tested for cytotoxicity against MCF-7, A549 and Panc-1 cell lines using MTT assay. The binding affinity of designed compounds was gauged by molecular docking studies. RESULTS: Statistically significant QSAR models generated by the SA-MLR method for 2D QSAR exhibited r2 = 0.852, q2 = 0.811, whereas 3D QSAR with SA-kNN showed q2 = 0.77. The synthesized compounds exhibited MIC in the range of 1.38-14.59(µg/ml). These compounds showed some crucial interaction with MTB ATPase. CONCLUSION: The present study has shown some promising results which can be further explored for lead generation.

Anticancer potential of AgNPs synthesized using Acinetobacter sp. and Curcuma aromatica against HeLa cell lines: A comparative study.

BACKGROUND: Biogenic nanoparticles are gaining attention due to their low toxicity and numerous biomedical applications. Present study aimed to compare the potential anticancer activity of two biogenic silver nanoparticles (bAgNPs and pAgNPs) against human cervical cancer cell lines (HeLa). METHODS: bAgNPs were synthesized using Acinetobacter sp. whereas pAgNPs were synthesized using aqueous root extract of Curcuma aromatica. Effect of these nanoparticles on HeLa cells viability was studied using MTT assay and colony formation assay. Anticancer potential was determined using fluorescence microscopy and flow cytometry studies. Bio-compatibility studies were performed against peripheral blood mononuclear cells (PBMCs). RESULTS: Both the nanoparticles showed 50 % viability of peripheral blood mononuclear cells (PBMCs) when used at high concentration (200 µg/mL). IC50 for bAgNPs and pAgNPs against HeLa cells were 17.4 and 14 µg/mL respectively. Colony formation ability of Hela cells was reduced on treatment with both nanoparticles. Acridine orange and ethidium bromide staining demonstrated that bAgNPs were cytostatic whereas pAgNPs were apoptotic. JC-1 dye staining revealed that the mitochondrial membrane potential was affected on treatment with pAgNPs while it remained unchanged on bAgNPs treatment. Flow cytometry confirmed cell cycle arrest in HeLa cells on treatment with nanoparticles further leading to apoptosis in case of pAgNPs. About 77 and 58 % HeLa cells were found in subG1 phase on treatment with bAgNPs and pAgNPs respectively. bAgNPs showed cytostatic effect on HeLa cells arresting the cell growth in subG1 phase, whereas, pAgNPs triggered death of HeLa cells through mitochondrial membrane potential impairment and apoptosis. CONCLUSION: Overall, bAgNPs and pAgNPs could be safe and showed potential to be used as anticancer nano-antibiotics against human cervical cancer cells.

Exploring the Pharmacological Potentials of Biosurfactant Derived from Planococcus maritimus SAMP MCC 3013.

Therapeutic potential of biosurfactant (BS) has been improved in recent years. Our present study deals with production of BS from Planococcus maritimus SAMP MCC 3013 in a mineral salt medium (MSM) supplemented with glucose (1.5% w/v). Further, BS has been purified and partially characterized as glycolipid type through our previous publication. Current research article aimed to evaluate biological potential of BS against Mycobacterium tuberculosis, Plasmodium falciparum and cancerous cell lines. Planococcus derived glycolipid BS was found to be a promising inhibitor of M. tuberculosis (MTB) H37Ra at IC50 64.11 ± 1.64 µg/mL and MIC at 160.8 ± 1.64 µg/mL. BS also showed growth inhibition of P. falciparum at EC50 34.56 ± 0.26 µM. Additionally, BS also displayed the cytotoxicity against HeLa (IC50 41.41 ± 4.21 µg/mL), MCF-7 (IC50 42.79 ± 6.07 µg/mL) and HCT (IC50 31.233 ± 5.08 µg/mL) cell lines. Molecular docking analysis was carried for the most popular glycolipid type BS namely Rhamnolipid (RHL) aiming to interpret the possible binding interaction for anti-tubercular and anti-cancer activity. This analysis revealed the involvement of RHL binding with enoyl reductase (InhA) of M. tuberculosis. Docking studies of RHL with tubulin directed several hydrophobic and Vander Waal interactions to exhibit anti-cancer potential. The present study will be helpful for further development of marine bioactive molecules for therapeutic applications. Their anti-tubercular, anti-plasmodial and cytotoxic activities make BS molecules as a noteworthy candidate to combat several diseases. To the best of our knowledge, this is the first report on projecting the pharmacological potential of Planococcus derived BS.

Using diphenyleneiodonium to induce a viable but non-culturable phenotype in Mycobacterium tuberculosis and its metabolomics analysis.

Depletion of oxygen levels is a well-accepted model for induction of non-replicating, persistent states in mycobacteria. Increasing the stress levels in mycobacterium bacilli facilitates their entry into a non-cultivable, dormant state. In this study, it was shown that diphenyleneiodonium, an inhibitor of NADH oxidase, induced a viable, but non-culturable state in mycobacteria, having similar features to dormant bacilli, like loss of acid-fastness, upregulation of stress-regulated genes and decreased superoxide levels as compared to actively growing bacilli. Comprehensive, untargeted metabolic profiling also confirmed a decrease in biogenesis of amino acids, NAD, unsaturated fatty acids and nucleotides. Additionally, an increase in the level of lactate, fumarate, succinate and pentose phosphate pathways along with increased mycothiol and sulfate metabolites, similar to dormant bacilli, was observed in the granuloma. These non-cultivable bacilli were resuscitated by supplementation of fetal bovine serum, regaining their culturability in liquid as well as on agar medium. This study focused on the effect of diphenyleneiodonium treatment in causing mycobacteria to rapidly transition from an active state into a viable, but non-cultivable state, and comparing their characteristics with dormant phenotypes.

A high content screening assay for identifying inhibitors against active and dormant state intracellular Mycobacterium tuberculosis.

The antitubercular drug development pipeline could start with an in vitro investigation of several compounds to examine their effect on active and dormant state Mycobacterium tuberculosis (Mtb). However, in vitro screening of dormant state bacilli cannot provide enough information on the simultaneous effect of a compound on the host. Therefore, we developed a live cell fluorescence based screening protocol by utilizing the high content system for determining the effect of inhibitors against active and dormant state intracellular mycobacteria. THP-1 macrophages infected with an actively growing and hypoxia derived dormant Mtb culture were standardized to develop the screening protocol. The signal to noise ratio and the Z' factor of this assay were found to be 7.5-29 and 0.6-0.8, respectively, which confirm the robustness of the protocol. The protocol was then validated with standard inhibitors. This newly developed drug screening assay offers an easy, safe, image based high content screening tool to search for novel antitubercular inhibitors against both active and dormant state intracellular mycobacteria. Therefore, this assay could fill in the gap between in vitro and in vivo latent tuberculosis drug screening programs.

Thiazolyl-pyrazole derivatives as potential antimycobacterial agents.

Mycobacterium tuberculosis (Mtb) is an obligate aerobe that is capable of long-term persistence under conditions of low oxygen tension. A series of thiazolyl-pyrazole derivatives (6a-f, 7a-f, 8c, 8e) were screened for antimycobacterial activity against dormant M. tuberculosis H37Ra (D-MTB) and M. bovis BCG (D-BCG). Nine thiazolyl-pyrazole analogs, 6c, 6e, 7a, 7b, 7c, 7e, 7f, 8c and 8e exhibited promissing minimum inhibitory concentration (MIC) values (0.20-28.25 µg/mL) against D-MTB and D-BCG strains of Mtb. Importantly, six compounds (7a, 7b, 7e, 7f, 8c and 8e) exhibited excellent antimycobacterial activity and low cytotoxicity at the maximum evaluated concentration of >250 µg/mL. Finally, the promising antimycobacterial activity and lower cytotoxicity profile suggested that, these compounds could be further subjected for optimization and development as a lead, which could have the potential to treat tuberculosis.

Click chemistry based multicomponent approach in the synthesis of spirochromenocarbazole tethered 1,2,3-triazoles as potential anticancer agents.

A series of spirochromenocarbazole tethered 1,2,3-triazoles were synthesized via click chemistry based one-pot, five component reaction between N-propargyl isatins, malononitrile, 4-hydroxycarbazole, aralkyl halides and sodium azide using cellulose supported CuI nanoparticles (Cell-CuI NPs) as the heterogeneous catalyst. Antiproliferative activity of all the synthesized compounds was investigated against panel of cancer cell lines such as MCF-7, MDA-MB-231, HeLa, PANC-1, A-549, and THP-1. Many of the synthesized compounds exhibited good anti-proliferative activity against breast (MCF-7 and MDA-MB-231) and cervical (HeLa) cancer cells with IC50 values less than 10 µM. In case of MCF-7 cells, among the nine compounds that showed good anti-proliferative activity, compounds 6f and 6j were found to be highly potent (IC50 = 2.13 µM and 4.80 µM, respectively). In case of MDA-MB-231, three compounds (6k, 6j and 6s) showed antiproliferative activity amongst which 6k was the most potent one (IC50 = 3.78 µM). On the other hand, in cervical cancer HeLa cells, compounds 6b, 6g, 6s and 6u showed excellent antiproliferative activity (IC50 = 4.05, 3.54, 3.83, 3.35 µM, respectively). All the compounds were found to be nontoxic to the human umbilical vein endothelial cells (HUVECs). AO and EtBr staining and fluorescence microscopy studies of the active compounds (IC50 < 5 µM) suggested that these compounds induce cell death by apoptosis.

Novel Benzylidenehydrazide-1,2,3-Triazole Conjugates as Antitubercular Agents: Synthesis and Molecular Docking.

BACKGROUND & OBJECTIVE: Novel 1,2,3-triazole based benzylidenehydrazide derivatives were synthesized and evaluated for antitubercular activity against Mycobacterium tuberculosis (MTB) H37Ra, M. bovis BCG and cytotoxic activity. Most of the derivatives exhibited promising in vitro potency against MTB characterized by lower MIC values. METHODS: Among all the synthesized derivatives, compound 6a and 6j were the most active against active and dormant MTB H37Ra, respectively. Compound 6d was significantly active against dormant and active M. bovis BCG. RESULTS: The structure activity relationship has been explored on the basis of anti-tubercular activity data. The active compounds were also tested against THP-1, A549 and Panc-1 cell lines and showed no significant cytotoxicity. Further, the synthesized compounds were found to have potential antioxidant with IC50 range = 11.19-56.64 µg/mL. The molecular docking study of synthesized compounds was performed against DprE1 enzyme of MTB to understand the binding interactions. CONCLUSION: Furthermore, synthesized compounds were also analysed for ADME properties and the potency of compounds indicated that, this series can be considered as a starting point for the developement of novel and more potent anti-tubercular agents in future.

Rational design of coumarin derivatives as antituberculosis agents.

AIM: A series of coumarin derivatives was designed as potential antituberculosis agents. RESULTS: The compounds were screened against active and dormant Mycobacterium tuberculosis (Mtb). Compounds 3k and 3n were found to have the most promising activity against replicating MtbH37Rv exhibiting minimum inhibitory concentration of 4.63 and 9.75 µM respectively. The compounds were also effective against dormant MtbH37Rv exhibiting more potency than the standard drugs, isoniazid and rifampicin. The compounds were found to be non-cytotoxic against human cell lines. CONCLUSION: This study provides promising antituberculosis agents that are effective against replicating as well as dormant Mtb and can thus act as potential leads for further development.

Ultrasound Assisted Synthesis of 4-(Benzyloxy)-N-(3-chloro-2-(substitutedphenyl)-4-oxoazetidin-1-yl) Benzamide as Challenging Anti-Tubercular Scaffold.

A series of ten novel derivatives of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl) benzamide 6a⁻j were synthesized in good yield from the key compound 4-(benzyloxy)-N'-(substituted benzylidene) benzo hydrazide, called Schiff 's bases 5a⁻j, by Staudinger reaction ([2 + 2] ketene-imine cycloaddition reaction) with chloro acetyl chloride in the presence of catalyst tri ethylamine and solvent dimethyl formamide (DMF), by using ultra-sonication as one of the green chemistry tools. All the synthesised compounds were evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) and most of them showed promising activity with an IC50 value of less than 1 µg/mL. To establish the safety, all the synthesized compounds were further tested for cytotoxicity against the human cancer cell line HeLa and all 6a⁻j compounds were found to be non-cytotoxic in nature. The molecular docking study was carried out with essential enzyme InhA (FabI/ENR) of Mycobacterium responsible for cell wall synthesis which suggests that 6a and 6e are the most active derivatives of the series. The theoretical evaluation of cell permeability based on Lipinski's rule of five has helped to rationalize the biological results and hence the synthesized azetidinone derivatives 6a⁻j were also analyzed for physicochemical evaluation that is, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and the results showed that all the derivatives could comply with essential features required for a potential lead in the anti-tubercular drug discovery process.

Synthesis and biological evaluation of some new tricyclic pyrrolo[3,2-e]tetrazolo[1,5-c]pyrimidine derivatives as potential antitubercular agents.

A series of new tricyclic pyrrolo[3,2-e]tetrazolo[1,5-c]pyrimidines 8a-l were synthesized and characterized by IR, NMR (1 H and 13 C), and mass spectral analysis. The newly synthesized compounds 8a-l were inspected for their in vitro antitubercular activity against Mycobacterium tuberculosis (MTB) H37 Ra using an established XTT reduction menadione assay (XRMA). The title compounds exhibited minimum inhibitory concentrations (MIC90 ) ranging from 0.09 to >30 µg/mL. Five compounds (8c, 8i-l) were further confirmed for their dose-dependent effect against MTB. These compounds were evaluated in the THP-1 infection model, where 8i (MIC90 = 0.35 µg/mL), 8j (MIC90 = 1.17 µg/mL), 8k (MIC90 = 2.38 µg/mL), and 8l (MIC90 = 1.17 µg/mL) demonstrated significant antitubercular activity. All the ex vivo active compounds showed insignificant cytotoxicity against the human cancer cell lines, HeLa, MCF-7, and THP-1. Inactivity of all these compounds against Gram positive and Gram negative bacteria indicates their specificity. Molecular docking studies in the active site of the sterol 14alpha-demethylase (CYP51) enzyme revealed a similar binding mode to the native ligand in the crystal structure, thereby helping to understand the ligand-protein interactions and to establish a structural basis for inhibition of MTB. The results suggest novel pharmacophores as selective and specific inhibitors against MTB that can be explored further to synthesize lead compounds against tuberculosis. In summary, the results clearly indicate the identification of some novel, selective, and specific inhibitors against MTB that can be explored further for potential antitubercular drugs.

Design, synthesis, and pharmacological evaluation of fluorinated azoles as anti-tubercular agents.

Design, synthesis, and biological screening of 2,2-dimethyl-2,3-dihydrobenzofuran tethered 1,3,4-oxadiazole derivatives as anti-tubercular agents were described. The synthesis of the target compounds was conducted by a series of reaction schemes. All the synthesized compounds were characterized by IR, 1 H NMR, 13 C NMR, and mass spectrometry. The therapeutic potential of the synthesized compounds was confirmed by molecular docking studies. Among the synthesized compounds, 12a, 12c, 12d, 12e, 12g, and 12j were found to be more active against non-replicating than against replicating cultures of Mycobacterium tuberculosis H37Ra ex vivo and in vitro. These compounds exhibit minimum inhibitory concentration (MIC) values in the range of 2.31-23.91 µg/mL. The cytotoxicity study was conducted against the cell lines THP-1, A549 and PANC-1, and the compounds were observed to be non-toxic to host cells. Molecular docking was conducted with InhA (FabI/ENR) and suggested the antimycobacterial potential of the synthesized compounds. The investigation presented here was found to be adventitious for the development of new therapeutic agents against Mycobacterium infection.

Synthesis, biological evaluation, and molecular docking studies of novel 3-aryl-5-(alkyl-thio)-1H-1,2,4-triazoles derivatives targeting Mycobacterium tuberculosis.

A small library of new 3-aryl-5-(alkyl-thio)-1H-1,2,4-triazoles was synthesized and screened for the antimycobacterial potency against Mycobacterium tuberculosis H37 Ra strain and Mycobacterium bovis BCG both in active and dormant stage. Among the synthesized library, 25 compounds exhibited promising anti-TB activity in the range of IC50 0.03-5.88 µg/ml for dormant stage and 20 compounds in the range of 0.03-6.96 µg/ml for active stage. Their lower toxicity (>100 µg/ml) and higher selectivity (SI = >10) against all cancer cell lines screened make them interesting compounds with potential antimycobacterial effects. Furthermore, to rationalize the observed biological activity data and to establish a structural basis for inhibition of M. tuberculosis, the molecular docking study was carried out against a potential target MTB CYP121 which revealed a significant correlation between the binding score and biological activity for these compounds. Cytotoxicity and in vivo pharmacokinetic studies suggested that 1,2,4-triazole analogues have an acceptable safety index, in vivo stability and bio-availability.

Multifunctional inulin tethered silver-graphene quantum dots nanotheranostic module for pancreatic cancer therapy.

Cancer nanotechnology is an emerging area of cancer diagnosis and therapy. Although considerable progress has been made for targeted drug delivery systems to deliver anticancer agents to particular site of interest, new nanomaterials are frequently being developed and explored for better drug delivery efficiency. In the present work, we have explored a novel nanoformulation based on silver-graphene quantum dots (Ag-GQDs) nanocomposite for its successful implementation for pancreatic cancer specific drug delivery in wistar rats. Carboxymethyl inulin (CMI); a modified variant of natural polysaccharide inulin is tethered with the nanocomposite via carbodiimide coupling to enhance the biocompatibility of nanoformulation. Experiments are performed to investigate the cytotoxicity reduction of silver nanoparticles after inulin tethering as well as anticancer efficacy of the system using 5-Fluorouracil (5-FU) as model drug. SEM, TEM, FT-IR, UV-vis, photoluminescence and anti proliferative assays (MTT) are performed for characterisation of the nanocomposite. Hyaluronic acid (HA) is conjugated as targeting moiety for CD-44 (cancer stem cell marker) to fabricate a complete targeted drug delivery vehicle specific for pancreatic cancer. In the present work two prime objectives were achieved; mitigation the toxicity of silver nanoparticles by inulin coating and it's in vivo application for pancreatic cancer.

Synthesis and antimycobacterial screening of new thiazolyl-oxazole derivatives.

In the present study a series of 4-methyl-2-aryl-5-(2-aryl/benzyl thiazol-4-yl) oxazole (4a-v) have been synthesized and evaluated for their preliminary antitubercular, antimicrobial and cytotoxicity activity. Among all the synthesized compounds, 4v reported comparable activity against dormant M. tuberculosis H37Ra and M. bovis BCG strains with respect to standard drug rifampicin. The active compounds from the antitubercular study were further tested for anti-proliferative activity against HeLa, A549 and PANC-1 cell lines using MTT assay and showed no significant cytotoxic activity at the maximum concentration evaluated. Further, the synthesized compounds were found to have potential antibacterial activities with MIC range of 2.1-26.8 µg/mL. High potency, lower cytotoxicity and promising antimycobacterial activity suggested that these compounds could serve as good leads for further optimisation and development.

Anti-proliferative effect of novel primary cetyl alcohol derived sophorolipids against human cervical cancer cells HeLa.

Sophorolipids (SLs) are glycolipid biosurfactants that have been shown to display anticancer activity. In the present study, we report anti-proliferative studies on purified forms of novel SLs synthesized using cetyl alcohol as the substrate (referred as SLCA) and their anticancer mechanism in human cervical cancer cells. Antiproliferative effect of column purified SLCA fractions (A, B, C, D, E and F) was examined in panel of human cancer cell lines as well as primary cells. Among these fractions, SLCA B and C significantly inhibited the survival of HeLa and HCT 116 cells without affecting the viability of normal human umbilical vein endothelial cells (HUVEC). The two fractions were identified as cetyl alcohol sophorolipids with non-hydroxylated tail differing in the degree of acetylation on sophorose head group. At an IC50 concentration SLCA B (16.32 µg ml-1) and SLCA C (14.14 µg ml-1) blocked the cell cycle progression of HeLa cells at G1/S phase in time-dependent manner. Moreover, SLCA B and SLCA C induced apoptosis in HeLa cells through an increase in intracellular Ca2+ leading to depolarization of mitochondrial membrane potential and increase in the caspase-3, -8 and -9 activity. All these findings suggest that these SLCAs could be explored for their chemopreventive potential in cervical cancer.