Designing novel anti-plasmodial quinoline-furanone hybrids: computational insights, synthesis, and biological evaluation targeting Plasmodium falciparum lactate dehydrogenase.

To combat resistance against current antimalarials, modifying key pharmacophores and exploring novel parasite-specific drug targets remained one of the key drug design strategies. The resistance to quinoline-based antimalarials arises often due to the efflux of the drug. Hence, the development of newer agents containing bulkier pharmacophores will enable medicinal chemists to counteract drug resistance. In view of this, herein we designed bulkier quinoline-furanone hybrids. Initially, virtual drug-likeness and ADMET screening were conducted to optimize physicochemical properties followed by docking of the hybrids against the Plasmodium falciparum lactate dehydrogenase (PfLDH) enzyme. The most potent hybrids that emerged from the computational screening were synthesized and screened for their bioactivity against the resistant strain of Plasmodium through Schizont Maturation Inhibition assays. Among the compounds tested, 5g and 6e demonstrated the best activity, with IC50 values similar to chloroquine (CQ), and 5g exhibited superior LDH inhibition compared to CQ. Compounds 5f, 7a, and 7f showed IC50 values comparable to CQ and moderate LDH inhibition. Structure-activity relationship (SAR) analysis revealed that halogen substitutions, particularly Br and Cl, enhanced antimalarial activity, while strong electron-withdrawing (-NO2) or -donating (-OH) groups led to diminished activity. Additionally, bulkier aromatic substitutions were favoured for antimalarial activity and LDH inhibition. The investigation successfully found potent anti-plasmodial quinoline-furanone hybrids, demonstrating promising prospects for combating malaria.

Therapeutic Potential of Natural Compounds in Lung Cancer.

Lung cancer is a leading cause of cancer deaths worldwide. The management of lung cancer treatment is often ineffective as a result of the development of drug resistance, reactions to treatment, drug-drug interactions or non-specific targeting of the anticancer drugs. Natural compounds show promise and potential activity in lung cancer with very few side effects. While, the combinatorial action of an anti-cancer drug with a natural compound provides synergistic action which helps boost the overall therapeutic action against cancer cells. In cancer, there is a dysregulation of apoptosis which facilitates the cancer cell to survive, resulting in progression of cancer. Many cancer drugs cause mutations of genes that regulate cancer and should kill the cancer cell but lead to chemoresistance. There are many natural compounds that could specifically target different cell signalling pathways associated with cancer progression to provide a cytotoxic effect in the target cell. The importance of these compounds is emerging in many therapies developed with dual action often including a natural compound. In this review, we present a selection of these natural compounds and how they target lung cancer cells with a focus on the cell signalling pathways. Further work is required to delineate the potential action of natural compounds in the treatment against cancer.

Antimicrobial, Antitumor and Side Effects Assessment of a Newly Synthesized Tamoxifen Analog.

BACKGROUND: Tamoxifen citrate is a very prevalent drug marketed under several trade names like Apo-Tamox, Nolvadex, Tamec, Tamizam, and Tamoplex. This molecule is approved by the FDA for breast cancer treatment. Some studies have shown that tamoxifen has anti-tuberculosis and antiparasitic activities. Like any drug, tamoxifen possesses side effects, more or less dangerous. AIMS: Basically, this work is a comparative study that aims to: primarily compare the antimicrobial and antitumor activities of tamoxifen and a newly synthesized tamoxifen analog; and to determine the molecule with lesser side effects. METHODS: Three groups of mice were injected with tamoxifen citrate and compound 2(1,1-bis[4-(3- dimethylaminopropoxy)phenyl]-2-phenyl-but-1-ene dihydrochloride) at doses corresponding to C1 (1/10), C2 (1/50), and C3 (1/100) to compound 2 lethal dose (LD50 = 75 mg/kg) administered to adult mice. A group of noninjected mice served as a study control. RESULTS: Experimental results suggest that compound 2 has better antitumor and antimicrobial activity than tamoxifen citrate besides its lower toxicity effects. CONCLUSION: The results obtained from the present study confirmed the antitumor and antimicrobial effect of tamoxifen citrate and its hematological side effects. Compound 2 seems to be more effective than tamoxifen citrate for antitumor and antimicrobial treatment while having less hematological side effects and less disruption of the blood biochemical parameters. These findings encourage us to perform further studies on compound 2 and test it for other therapeutic uses for which tamoxifen was found effective.

Understanding the microbiome: Emerging biomarkers for exploiting the microbiota for personalized medicine against cancer.

The human body is a home to more than 1 trillion microbes with a diverse variety of commensal microbes that play a crucial role towards the health of the individual. These microbes occupy different habitats such as gut, skin, vagina, oral etc. Not only the types and abundance of microbes are different in different organs, but also these may differ in different individuals. The genome of these microbiota and their ecosystem constitute to form a microbiome. Factors such as diet, environment, host genetics etc. may be the reason behind the wide microbial diversity. A number of studies performed on human microbiome have revealed that microbiota present in healthy and diseased individuals are distinct. Altered microbiome is many a times the reason behind the overexpression of genes which may cause complex diseases including cancer. Manipulation of the human microbiome can be done by microbial supplements such as probiotics or synbiotics, diet or prebiotics and microbial suppression strategies using antibiotics. Recent advances in genome sequencing technologies and metagenomic analysis provide us the broader understanding of these commensal microbes and highlighting the distinctive features of microbiome during healthy and disease states. Molecular pathological epidemiology (MPE) studies have been very helpful in providing insights into the pathological process behind disease evolution and progression by determining the specific etiological factors. New emerging field of research targets the microbiome for therapeutic purposes by which personalized medicines can be made for treating various types of tumors. Screening programmes might be helpful in identifying patients who are at the verge of developing cancer and in delivering appropriate approaches according to individual risk modes so that disease could be prevented.

Pyrazole Schiff Base Hybrids as Anti-Malarial Agents: Synthesis, In Vitro Screening and Computational Study.

BACKGROUND: Malaria is one of the most vital infectious diseases caused by protozoan parasites of the Plasmodium genus. As P. falciparum, the cause of most of the severe cases of malaria, is increasingly resistant to available drugs such as amodioquine, chloroquine, artemisinin, and antifolates, there is an urgent need to identify new targets for chemotherapy. OBJECTIVE: This study screened novel pyrazole derivatives carrying iminium & benzothiazole group for antimalarial potential against P. falciparum chloroquine sensitive (3D7) strain. MATERIALS & METHODS: Several pyrazole schiff base hybrids with a wide range of substitution have been synthesized via condensation of substituted aniline with substituted 4-formylpyrazole and evaluated for their in vitro antimalarial activity against asexual blood stages of human malaria parasite, Plasmodium falciparum. The interaction of these conjugate hybrids was also investigated by molecular docking studies in the binding site of P. falciparum cystein protease falcipain-2. The pharmacokinetic properties were also studied using ADME prediction. RESULTS: Among all compounds, 6bf and 6bd were found to be potential molecules with EC50 1.95µg/ml and 1.98µg/ml respectively. Docking study results reveal that the pyrazole schiff base derivatives occupy the PfFP binding sites and they show good interactions with significant values of binding energies. CONCLUSION: We provide evidence which implicates pyrazole Schiff base hybrids as potential prototypes for the development of antimalarial agents.

Role of Azoles in Cancer Prevention and Treatment: Present and Future Perspectives.

BACKGROUND: Cancer has gradually become one of the leading causes of death worldwide. The incidence of cancer among the population has increased alarmingly over the last two decades, primarily due to an increasing population of immune-compromised patients and the continuing rise in anti-cancer drug resistance. Azole found privileged structure in medicinal chemistry and pharmaceutical industry and also found to be showing antioxidant; antimicrobial, anthelmintic, anticancer, antiviral, anti-parasitic, anti-inflammatory, anti-HIV, and antihypertensive activities. OBJECTIVE: In this review, we highlight some areas of current interest in context to azoles and their derivatives as potential chemotherapeutic agents and inhibitors. METHOD: A comprehensive literature search was performed for writing this review. An updated view on different derivatives of azoles and use in cancer management has been discussed. RESULTS: Here we have discussed the present scenario of azoles and their derivatives as potential chemotherapeutic agents and inhibitors. Along with, the future perspectives of azoles in cancer prevention and treatment are also discussed. CONCLUSION: The information provided in this review might be useful to researchers in designing of novel and potent multifunctional azole analogues for the treatment of cancer and other multifactorial diseases.

4-aryl/heteroaryl-4H-fused Pyrans as Anti-proliferative Agents: Design, Synthesis and Biological Evaluation.

AIMS: The current study is focused on the design and synthesis of 4-aryl/heteroaryl-4H-fused pyrans as anti-proliferative agents. All the synthesized molecules were screened against a panel of human carcinoma cell lines. DESCRIPTION: Significant inhibition was exhibited by the compounds against HCT-116 (Colon) and PC-3 (Prostate) cell lines while A-549 (Lung) cell lines, MiaPaCa-2 (Pancreatic) cell lines and HL-60 (Leukemia Cancer) cell lines were almost resistant to the exposure of the test compounds. Compound FP-(v)n displayed noteworthy cytotoxicity towards HCT-116 malignant cells with the IC50 value of 0.67 µM. It induces apoptosis as revealed by several biological endpoints like apoptotic body formation, through DAPI staining, phase contrast microscopy and mitochondrial membrane potential loss. Moreover FP-(v)n is a potent apoptotic inducer confirmed by cell cycle arrest and ROS generation. The cell phase distribution studies indicate an augment from 4.94 % (control sample) to 39.68 % (sample treated with 1.5 µM compound FP-(v)n) in the apoptotic population. Compound FP-(v)n inhibits the tumor growth in Ehrlich ascites carcinoma (EAC), Ehrlich Tumor (ET, solid) and sarcoma-180 (solid) mice models. Additionally, it was established to be non-toxic at maximum tolerated dose of 1000 mg/kg in acute oral toxicity in Swiss-albino mice. CONCLUSION: The current study provides an insight into anti-cancer potential of FP-(v)n, which might be valuable in the treatment of tumor.

Antibacterial, tyrosinase, and DNA photocleavage studies of some triazolylnucleosides.

In order to explore the biological potential, some synthesized triazolylnucleosides were evaluated for their antibacterial, tyrosinase and DNA photocleavage activities. Triazolylnucleosides (5-12) were screened against Staphylococcus aureus (ATCC 6538), gram-positive and Escherichia coli (ATCC 10536), gram-negative bacterial strains. Among the series, compound 9 exhibited a significant level of antibacterial activity against both strains at higher concentration in reference to the standard drug, Levofloxacin. Tyrosinase activity and inhibition of these compounds were also studied, and it has been found that compounds 8 and 11 displayed more than 50% inhibitory activity. In addition, six compounds (7-12) were evaluated for their DNA photocleavage activity. The compounds 8 and 12 exhibited excellent DNA photocleavage activity at a concentration of 10 µg and may be used as template for antitumor drugs in the future.

Antidepressant Flavonoids and Their Relationship with Oxidative Stress.

Depression is a serious disorder that affects hundreds of millions of people around the world and causes poor quality of life, problem behaviors, and limitations in activities of daily living. Therefore, the search for new therapeutic options is of high interest and growth. Research on the relationship between depression and oxidative stress has shown important biochemical aspects in the development of this disease. Flavonoids are a class of natural products that exhibit several pharmacological properties, including antidepressant-like activity, and affects various physiological and biochemical functions in the body. Studies show the clinical potential of antioxidant flavonoids in treating depressive disorders and strongly suggest that these natural products are interesting prototype compounds in the study of new antidepressant drugs. So, this review will summarize the chemical and pharmacological perspectives related to the discovery of flavonoids with antidepressant activity. The mechanisms of action of these compounds are also discussed, including their actions on oxidative stress relating to depression.

Protein Modeling and Molecular Dynamics Simulation of Cloned Regucalcin (RGN) Gene from Bubalus bubalis.

BACKGROUND: Regucalcin (RGN), a calcium regulating protein having anti-prolific, antiapoptotic functions, plays important part in the biosynthesis of ascorbic acid. It is a highly conserved protein that has been reported from many tissue types of various vertebrate species. Employing its effect of regulating enzyme activities through reaction with sulfhydryl group (-SH) and calcium, structural level study believed to offer a better understanding of binding properties and regulatory mechanisms of RGN, was performed. MATERIAL AND METHOD: Using sample from testis of Bubalus bubalis, amplification of regucalcin (RGN) gene was subjected to characterization by performing digestion using different restriction endonucleases (RE). Alongside, cDNA was cloned into pPICZαC vector and transformed in DH5α host for custom sequencing. To get a better insight of its structural characteristics, three dimensional (3D) structure of protein sequence was generated using in silico molecular modelling approach. The full trajectory analysis of structure was achieved by the Molecular Dynamics (MD) that explains the stability, flexibility and robustness of protein during simulation in a time of 50ns. Molecular docking against 1,5-anhydrosorbitol was performed for functional characterization of RGN. RESULTS: Preliminary screening of amplified products on Agarose gel showed expected size of ~893 bp of PCR product corresponding to RGN. Following sequencing, BLASTp search of the target sequence revealed that it shares 91% similarity score with human senescence marker protein-30 (pdb id: 3G4E). Molecular docking of 1,5-anhydrosorbitol reveals information regarding important binding site residues of RGN. 1,5-anhydrosorbitol was found to interact with binding free energy of - 6.01 Kcal/mol. RMSD calculation of subunits A, B and D-F might be responsible for functional and conserved regions of modeled protein. CONCLUSION: Three dimensional structure of RGN was generated and its interactions with 1,5- anhydrosorbitol, demonstrates the role of key binding residues. Until now, no structural details were available for buffalo RGN proteins, hence this study will broaden the horizon towards understanding the structural and functional aspects of different proteins in cattle.

PI3K/Akt/mTOR Intracellular Pathway and Breast Cancer: Factors, Mechanism and Regulation.

BACKGROUND: The most recurrent and considered second most frequent cause of cancer-related deaths worldwide in women is the breast cancer. The key to diagnosis is early prediction and a curable stage but still treatment remains a great clinical challenge. Origin of the Problem: A number of studies have been carried out for the treatment of breast cancer which includes the targeted therapies and increased survival rates in women. Essential PI3K/mTOR signaling pathway activation has been observed in most breast cancers. The cell growth and tumor development in such cases involve phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) complex intracellular pathway. HYPOTHESIS: Through preclinical and clinical trials, it has been observed that there are a number of other inhibitors of PI3K/Akt/mTOR pathway, which either alone or in combination with cytotoxic agents can be used for endocrine therapies. CONCLUSION: Structure and regulation/deregulation of mTOR provides a greater insight into the action mechanism. Also, through this review, one could easily scan first and second generation inhibitors for PI3K/Akt/mTOR pathway besides targeted therapies for breast cancer and the precise role of mTOR.

Vitamin B12 functionalized layer by layer calcium phosphate nanoparticles: A mucoadhesive and pH responsive carrier for improved oral delivery of insulin.

The present study investigates the potential of layer by layer coated calcium phosphate nanoparticles - for oral delivery of insulin where Vitamin B12 grafted chitosan and sodium alginate have been used as cationic and anionic polyelectrolyte respectively. The major emphasis has been given on the role Vitamin B12 conjugated chitosan as cationic polyelectrolyte (VitB12-Chi) in the delivery system. VitB12-Chi conjugate was prepared by carbodiimide reaction. The formulated VirB12-Chi-CPNPs were tested for in vitro and in vivo efficacy studies carried out in Caco-2 monolayers and diabetic rats. VitB12-Chi-CPNPs with particle size <250nm and zeta potential+32.56(±2.34) exhibited pH responsive insulin release at simulated gastric fluid and simulated intestinal fluid. Fluorescence microscopy and flow cytometry studies revealed higher uptake of VitB12-Chi-CPNPs in Caco-2 monolayer in comparison to Chi-CPNPs. Further reduction in TEER supported paracellular transport of insulin because of opening of tight epithelial junctions. In vivo intestinal uptake of FITC tagged Vit-B12-Chi-CPNPs from different intestinal segments supported paracellular and receptor mediated uptake of VitB12-Chi-CPNPs. Plasma insulin and blood glucose levels were measured in diabetic rats and showed about four fold increases in insulin bioavailability and sustained hypoglycemic effects up to 12h of administration with VitB12-Chi-CPNPs in comparison to Chi-CPNPs. Results of the study revealed the potential of layer by layer nanoparticles for oral insulin delivery. The study also specifically highlighted the role of VitB12 as a pH sensitive and targeting ligand which significantly participated in enhancing insulin oral bioavailability. STATEMENT OF SIGNIFICANCE: Oral delivery of insulin is always the most desirable approach for diabetic patients however it's also the most challenging in respect to formulation development due to harsh gastrointestinal conditions. Several groups have been working from decades for oral delivery of insulin. However the beauty of this prototype formulation is that it exhibits the pH responsive behavior in natural condition of gastrointestinal tract. It resists the release of insulin at gastric condition however stimulate the release at intestinal conditions. Apart from pH responsive behavior it utilizes multiple pathways to improve the overall bioavailability of insulin including paracellular transport and receptor mediated endocytosis.

Synthesis and biological evaluation of some 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-arylethanones: antibacterial, DNA photocleavage, and anticancer activities.

In continuation of our efforts to find new biologically active agents, regioselective synthesis of a series of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-arylethanones 4a-k has been achieved under facile, extremely mild and greener reaction conditions with excellent yields. Moreover, one pot multicomponent reaction has also been reinvestigated under previously reported solvent conditions to prepare 4a-b and found that the reaction generates significant amount of side products. The chemical structures of 4a-k were established on the basis of a combined use of IR, NMR ((1)H, (13)C) spectroscopy, mass spectrometry and elemental analysis. All the compounds were evaluated for their antibacterial, DNA photocleavage and anticancer activities. Among all, 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-(naphth-2-yl)ethanone 4j displayed good inhibitory profile against Escherichia coli and Staphylococcus aureus which was about 50% and 25% of the Ampicillin (standard drug), respectively. The compounds, 4a and 4f showed relatively moderate inhibition against Psuedomonas aeruginosa and E. coli. In DNA photocleavage study, compounds 4c and 4d were found to be highly active and completely degraded both forms of DNA (SC and OC), even at a very low concentration of 1 µg (4c) under irradiation of UV light. However, 4h and 4f resulted in complete DNA degradation at 30 µg concentration. Moreover, 4h showed fluorescence at 15 µg concentration and increased the intensity of both bands of DNA (SC and OC) as compared to control. On the other hand, to valorize the biological potential, the compounds were screened for their cytotoxic activity on colon (HCT116 and HT29), prostate (DU145), ovarian (SKOV3) and lung (A549) cancer cell lines. The compound 4j was found to be cytotoxic to all the cancer cell lines, except SKOV3, with more selectivity towards the colon cancer cell lines (HCT116, HT29) and A549 lung cancer cell line. On A549 lung cancer cell line, 4j and 4k exhibited similar potency as carboplatin in inhibiting cell viability.

Isoxazoline containing natural products as anticancer agents: a review.

Isoxazolines are an important class of nitrogen and oxygen containing heterocycles that belong to the azoles family which have gained much importance in the field of medicinal chemistry as the anticancer agents. Moreover, natural products are always expectedly regarded as an important hoard of a large number of potential chemotherapeutic candidates. Therefore, this review mainly focuses on the existence of isoxazoline derivatives in natural sources, their isolation and uses there of as anticancer agents besides highlighting the synthetic pathways to achieve these compounds. Structural-activity relationship and the influence of stereochemical aspects on anticancer activity of such compounds have also been discussed. It covers the literature upto 2014 and would certainly provide a great insight to scientific community to accelerate further research for the development of some novel anticancer drugs.

Plant miRNAome and antiviral resistance: a retrospective view and prospective challenges.

MicroRNAs (miRNAs) are small regulatory RNAs that play a defining role in post-transcriptional gene silencing of eukaryotes by either mRNA cleavage or translational inhibition. Plant miRNAs have been implicated in innumerable growth and developmental processes that extend beyond their ability to respond to biotic and abiotic stresses. Active in an organism's immune defence response, host miRNAs display a propensity to target viral genomes. During viral invasion, these virus-targeting miRNAs can be identified by their altered expression. All the while, pathogenic viruses, as a result of their long-term interaction with plants, have been evolving viral suppressors of RNA silencing (VSRs), as well as viral-encoded miRNAs as a counter-defence strategy. However, the gene silencing attribute of miRNAs has been ingeniously manipulated to down-regulate the expression of any gene of interest, including VSRs, in artificial miRNA (amiRNA)-based transgenics. Since we currently have a better understanding of the intricacies of miRNA-mediated gene regulation in plant-virus interactions, the majority of miRNAs manipulated to confer antiviral resistance to date are in plants. This review will share the insights gained from the studies of plant-virus combat and from the endeavour to manipulate miRNAs, including prospective challenges in the context of the evolutionary dynamics of the viral genome. Next generation sequencing technologies and bioinformatics analysis will further delineate the molecular details of host-virus interactions. The need for appropriate environmental risk assessment principles specific to amiRNA-based virus resistance is also discussed.

Pyrazole containing natural products: synthetic preview and biological significance.

A large number of structurally diverse natural compounds containing azole nucleus constitute an important class of biologically active heterocycles that are gaining more attention in the field of medicinal chemistry. Among azoles, pyrazoles are rarely found in nature probably due to difficulty in the formation of N-N bond by living organisms. However, they exhibit numerous biological activities, including anti-diabetic, antiviral, anticancer, anti-inflammatory, antibacterial and antifungal activities. The present review is an attempt to understand the chemistry along with medicinal importance of pyrazole containing natural products reported till date which would certainly help the scientific community to bring further developments in the isolation and synthetic methodologies for pyrazole based novel bioactive compounds.

Management of diabetic complications: a chemical constituents based approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Long term hyperglycemia leads to development of complications associated with diabetes. Diabetic complications are now a global health problem without effective therapeutic approach. Hyperglycemia and oxidative stress are important components for the development of diabetic complications. Over the past few decades, herbal medicines have attracted much attention as potential therapeutic agents in the prevention and treatment of diabetic complications due to their multiple targets and less toxic side effects. This review aims to assess the current available knowledge of medicinal herbs for attenuation and management of diabetic complications and their underlying mechanisms. MATERIAL AND METHODS: Bibliographic investigation was carried out by scrutinizing classical text books and peer reviewed papers, consulting worldwide accepted scientific databases (SCOPUS, PUBMED, SCIELO, NISCAIR, Google Scholar) to retrieve available published literature. The inclusion criteria for the selection of plants were based upon all medicinal herbs and their active compounds with attributed potentials in relieving diabetic complications. Moreover, plants which have potential effect in ameliorating oxidative stress in diabetic animals have been included. RESULTS: Overall, 238 articles were reviewed for plant literature and out of the reviewed literature, 127 articles were selected for the study. Various medicinal plants/plant extracts containing flavonoids, alkaloids, phenolic compounds, terpenoids, saponins and phytosterol type chemical constituents were found to be effective in the management of diabetic complications. This effect might be attributed to amelioration of persistent hyperglycemia, oxidative stress and modulation of various metabolic pathways involved in the pathogenesis of diabetic complications. CONCLUSION: Screening chemical candidate from herbal medicine might be a promising approach for new drug discovery to treat the diabetic complications. There is still a dire need to explore the mechanism of action of various plant extracts and their toxicity profile and to determine their role in therapy of diabetic complications. Moreover, a perfect rodent model which completely mimics human diabetic complications should be developed.