In-Silico Analysis of Coumarins for Neurodegenerative, Infectious and Metabolic Diseases

BackgroundHypercholesterolemia has posed a serious threat of heart diseases and stroke worldwide. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid biosynthesis, is regarded as the root of reactive oxygen species (ROS) that generate atherosclerosis and cholesterol crystals. β-Hydroxy β-methylglutaryl-coenzyme A reductase (HMGR) is a rate-limiting enzyme in cholesterol biosynthesis. Although some commercially available enzyme inhibiting drugs have effectively reduced cholesterol levels, most of them have failed to meet potential drug candidates’ requirements. Here, we have carried out an in-silico analysis of secondary metabolites that have already shown good inhibitory activity against XO and HMGR in a wet lab setup.MethodsOut of 118 secondary metabolites reviewed, sixteen molecules inhibiting XO and HMGR were selected based on the IC50 values reported in in vitro assays. Further, receptor-based virtual screening was carried out against secondary metabolites using GOLD Protein-Ligand Docking Software, combined with subsequent post-docking, to study the binding affinities of ligands to the enzymes. In-silico ADMET analysis was carried out to explore their pharmacokinetic properties, followed by toxicity prediction through ProTox-II.ResultsThe molecular docking of amentoflavone (GOLD score 70.54, ∆G calc. = − 10.4 Kcal/mol) and ganomycin I (GOLD score 59.61, ∆G calc. = − 6.8 Kcal/mol) displayed that the drug has effectively bound at the competitive site of XO and HMGR, respectively. Besides, 6-paradol and selgin could be potential drug candidates inhibiting XO. Likewise, n-octadecanyl-O-α-D-glucopyranosyl (6′ → 1″)-O-α-D-glucopyranoside could be potential drug candidates to maintain serum cholesterol. In-silico ADMET analysis has shown that these sixteen metabolites were optimal within the categorical range compared to commercially available XO and HMGR inhibitors, respectively. Toxicity analysis through ProTox-II revealed that 6-gingerol, ganoleucoin K, and ganoleucoin Z are toxic for human use.ConclusionThis computational analysis supports earlier experimental evidence towards the inhibition of XO and HMGR by natural products. Further study is necessary to explore the clinical efficacy of these secondary molecules, which might be alternatives for the treatment of hypercholesterolemia.

This article purposes to provide insights to piperazine based molecular designs that will facilitate drug discovery program in future. In our pursuit to summarize the reservoir of bioactive agents, and in line with the synthetic economy of new heterocycles, many new roles are being identified for the multiple biotargets of piperazine moieties. We mark out how series of different scaffolds provide an extensive range of various piperazine-based analogues displaying antimicrobial, antituberculosis, anticancer, antiviral and antimalarial activities. We believe that piperazine family of compounds, and their various co-components, highlight the existence of several potential leads for the furtherance of novel bioactive agents.

12 - Systems pharmacology and molecular docking strategies prioritize natural molecules as antiinflammatory agents

16-Hydroxy-ent-halima-5(10),13-dien-15,16-olide from Polyalthia longifolia targets adipogenesis by inhibiting mitotic clonal expansion and ameliorates dyslipidemia

Background: Carissa carandas L. (Apocynaceae), commonly known as Karanda, is a widely used medicinal plant. In Thailand, Karanda fruits are favorite fruits especially in central region due to attractive shape and color with health promoting activities. Aims: To evaluate its antimicrobial and anticancer activities for claim promoting activities. Cytotoxicity of extracts was also evaluated with normal cells to claim for health safety. Materials and Methods: Anticancer activities of Karanda fruits extracted with dichloromethane (KD) and methanol (KM) were performed by resazurin microplate assay and tested with five cell lines, including KB-oral cavity cancer, MCF7-breast cancer, NCI-H187-small lung cancer, HepG2-hepatocarcinoma, and Caco2-colon adenocarcinoma cell lines. Cytotoxicity of KD and KM were performed as above and used HDFn-neonatal dermal fibroblast as normal cells. Antimicrobial activities of KD and KM against herpes simplex virus type I (HSV-1) and Mycobacterium tuberculosis were tested according by green fluorescent protein-based assay; Candida albicans were tested according to resazurin microplate assay, and Plasmodium falciparum K1 strain was tested according to microculture radioisotope techniques. Results: Both extracts were not possessed anticancer activity to any cancer cell lines at maximum concentration = 100 µg/mL. In the same way to anticancer activity assays, both extracts were not inhibited HSV-1, P. falciparum K1 strain, and M. tuberculosis (maximum concentration = 50 µg/mL). Also, both extracts were nontoxic to normal cells. Conclusion: KD and KM extracts of ripped Karanda fruits had no significant anticancer and antimicrobial activities with noncytotoxicity.

Aims: The aim was to determine antimicrobial and anticancer activities for water and ethanol extracts of leaves and shooting parts of seablite. Materials and Methods: Anticancer activity tests of seablite extracts were performed by resazurin microplate assay (REMA) and tested with 3 cell lines including KB cell line, epidermoid carcinoma of the oral cavity (American Type Culture Collection [ATCC] CCL-17), MCF-7 cell line, breast adenocarcinoma (ATCC HTB-22) and NCI-H187 cell line, and small cell lung carcinoma (ATCC CRL-5804). Antimicrobial activities of seablite water and ethanol extracts against herpes simplex virus type-I (HSV-1) and Mycobacterium tuberculosis H 37 Ra strain were tested according by green fluorescent protein-based assay; Candida albicans (ATCC 90028) and Bacillus cereus (ATCC 11778 or TISTR 687) were tested according by REMA; and Plasmodium falciparum , K1 strain was tested according by micro-culture radioisotope techniques. Results: Both extracts were not possessed anticancer activity to KB-oral cavity cancer, MCF7-breast cancer and NCI-H187-small lung cancer cell lines at maximum concentration = 50 μg/mL. In the same way to anticancer activity assays, both extracts were not inhibited HSV-1, P. falciparum K1 strain, M. tuberculosis H 37 Ra strain and B. cereus at the same concentration. Conclusions: Ethanol and water extracts of leaves and shooting parts of seablite had no significant anticancer and antimicrobial activities.

Objective: Cashew nut is one of the major agriculture products in Southern of Thailand, and the volume of cashew nut shell is become increase as a by-product. Thus, cashew nut shell is attractive source for evaluation of antimicrobial activities as inexpensive source. This study was aimed to evaluates in vitro antimicrobial properties of the water extract (CW) and ethanol extract (CE) from cashew nut shell and to evaluate anticancer activity and cytotoxicity of extracts by in vitro screening test against cell lines and normal mammalian cells, respectively. Materials and Methods: CW and CE extracts were determined total phenolic compound by Folin-Ciocalteu reagent. Antibacterial activity of CW and CE against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii were evaluated by resazurin microplate assay (REMA). Antimicrobial activities of both extracts against herpes simplex virus Type I and Mycobacterium tuberculosis were tested according by green fluorescent protein (GFP)-based assay; Candida albicans was tested according by REMA; and Plasmodium falciparum was tested according by microculture radioisotope techniques. Anticancer activities of CW and CE were tested with MCF7, NCI-H187, HepG2-, and Caco2 cell lines; and cytotoxicity test was used Vero and human dermal fibroblasts, neonatal (HDFn) cells. Results: CW and CE were lack of in vitro antibacterial (maximum concentration = 100 μg/ml), antimicrobial, and anticancer activities (maximum concentration = 50 μg/ml). CW and CE (0-50 μg/ml) were lack of cytotoxicity against Vero cells and HDFn-neonatal dermal fibroblast. Conclusions: CW and CE extracts of cashew nut shell had no significant in vitro anticancer and antimicrobial activities with noncytotoxicity.

Several chromene derivatives have a wide variety of biological and pharmacological activity. They had anticancer activity, antimicrobial activity, antituberculosis activity, anticonvulsant activity, antidiabetic activity, antichlolinesterase activity, and inhibitor of monoamine oxidase activity. The above-mentioned activities directed us to synthesize novel chromene derivatives, chromeno[2,3-d][1,3]oxazines, and chromeno[2,3-d]pyrimidines. The starting material was 2- amino-8-(2-chlorobenzylidene)-4-(2-chlorophenyl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile. Several novel chromene derivatives had been synthesized. Compound 1 reacted with carbon disulfide, and ethyl chloroformate to afford chromene derivatives 2, 3. Chromene derivative 3 reacted with hydrazine dydrate to give compound 4. Chromene derivative 1 reacted with acetic acid and sulphuric acid to produce compounds 5, and 6. Amino derivative 5 reacted with chloroacyl derivative to afford compounds 7a-c which cycalized in dry xylene to afford compounds 8a-c. Chromene derivative 8a reacted with hydroxyl amine to afford compound 9. The structures of novel synthesized chromene derivatives had been confirmed using mass spectroscopy, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and elemental analysis. Most of the prepared compounds were screened against liver cancer cell lines (HepG-2), human colon cancer cell lines (HT-29), and breast adenocarcinoma cell lines (MCF-7). Chromene derivative 2 had anticancer activity against human colon cancer cell lines (HT-29) higher than the reference drug doxorubicin. The rest of the tested compounds had anticancer activity against human colon cancer cell lines (HT-29) lower than that of the reference drug doxorubicin. Chromene derivative 5 had anticancer activity against liver cancer cell lines (HepG-2) higher than the reference drug doxorubicin. Several chromene derivatives had been synthesized and their structures had been confirmed using different spectroscopic techniques. Some of the chromene derivatives that were screened against different cancer cell lines showed promising anticancer activity higher than the reference standard drug. For example, chromene derivative 2 had anticancer activity against human colon cancer cell lines (HT-29) higher than the reference drug doxorubicin. Chromene derivative 5 had anticancer activity against liver cancer cell lines (HepG-2) higher than the reference drug doxorubicin. Chromene derivative 6 had anticancer activity against breast adenocarcinoma cell lines (MCF-7) higher than the standard drug.

1,3-Thiazolidine-4-ones have been known to possess miscellaneous pharmacological activities such as antibacterial, antimycobacterial, antiviral, anticancer and anticonvulsant. Therefore, we synthesized some novel 1-[2-(benzoylamino)-4-(methylthio)butyryl]-4-alkyl/aryl alkyl thiosemicarbazides, N-{1-[[2-(3-Alkyl/arylalkyl-4-oxo-1,3-thiazolidin-2-ylidene) hydrazino] carbonyl-3-(methylthio)propyl}benzamides and N-{1-[[2-[5-benzylidene)-3-alkyl/arylalkyl-4oxo-1,3-thiazolidin-2-ylidene]hydrazino]carbonyl-3-(methyl-thio)propyl}-benzamide derivatives. Structures of the synthesized compounds were elucidated by IR, H/ CNMR and HR-MS spectral data. All of the compounds were tested for antibacterial and antituberculosis activity and some of the compounds exhibited marginal activity against Staphylococcus aureus ATCC 29213, Bacillus subtilis A57 and Candida albicans A177. Antiviral activity of the synthesized compounds was determined against various types of viruses in HEL, HeLa and Vero cell cultures. Anti-HIV and cytotoxicity data were also obtained with the compounds using the strains HIV-1 (IIIB) and HIV-2 (ROD) in an MT-4/MTT based assay. None of the tested compounds showed antiviral activity at subtoxic doses whereas some of them exhibited remarkable cytotoxic potential. Target compounds were also screened for their antituberculosis potency against Mycobacterium tuberculosis H37 Rv, and some of them showed varying degrees of inhibition. Among the compounds tested, compound 27 was found to be most potent with 90% inhibition of mycobacterial growth at 6.25 μg/ml. Compounds 8, 13, 14, 23, 25 were evaluated for their anticancer activity by the National Cancer Institute (NCI). † This work was partly presented at the 2 International Meeting on Medicinal and Pharmaceutical Chemistry, Antalya TURKEY, P9, 10-14 October 2004. General Papers ARKIVOC 2008 (xiv) 191-210 ISSN 1551-7012 Page 192 ©ARKAT USA, Inc.

A new series of pyrazolo[1,2-b]phthalazine derivatives (4a–p) bearing the 5-aryloxypyrazole nucleus was synthesized by one-pot, three-component, base-catalyzed cyclo condensation reaction of 3-methyl-5-aryloxy-1-aryl-1H-pyrazole-4-carbaldehyde (1a–d), malononitrile or ethyl cyanoacetate (2a–b) and 2,3-dihydro-1,4-phthalazinedione (3a–b) in ethanol containing an eco friendly base, NaOH, in good to excellent yields. All synthesized compounds (4a–p) were duly characterized by physico-chemical parameters, 1H NMR, 13C NMR, FT-IR and LCMS techniques. In vitro antimicrobial activity of the synthesized compounds was investigated against a representative panel of pathogenic strains. Compounds 4e, 4g, 4h, 4k and 4o exhibited excellent antimicrobial activity compared with first line drugs. In vitro antituberculosis activity was evaluated against Mycobacterium tuberculosis H37Rv, and compounds 4g and 4o emerged as the promising antimicrobial members with better antituberculosis activity. A brine shrimp bioassay was carried out to study the in vitro cytotoxic properties of the synthesized compounds. In vitro antioxidant activity was evaluated by the ferric-reducing antioxidant power method. Compounds 4c, 4d, 4g and 4h showed the highest antioxidant potencies.

This study employed a bottom-up technique to synthesize copper oxide (CuO) nanoparticles over hydrophilic graphene oxide (GO) nanosheets. The CuO/GO nanocomposite has been prepared using two selected precursors of copper nitrate and citric acid with an intermittent mixing of GO solutions. The synthesized Nanocomposites were characterized using different biophysical techniques like FT-IR, NMR, FE-SEM, and HR-TEM analyses. FT-IR analyses confirm the nanocomposites’ successful formation, which is evident from the functional groups of C=C, C-O, and Cu-C stretching vibrations. Morphological analyses reveal the depositions of CuO nanoparticles over the planar rough GO sheets, which has been elucidated from the FE-SEM and HR-TEM analyses supported by respective EDAX analyses. The antimicrobial activities have been evident from the surface roughness and damages seen from the FE-SEM analyses. The CuO/GO sheets were tested against Gram-positive (e.g., Staphylococcus aureus) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa). It is evident that the intrinsic antibacterial activity of CuO/GO sheets, when combined in equal proportions, elicited a robust antibacterial activity when tested over Gram –ve representative bacteria Escherichia coli. The antioxidant behaviour of synthesized CuO/GO nanocomposite was evaluated by scavenging the free radicals of DPPH and ABTS. Moreover, the cytotoxic activity was also studied against epidermoid carcinoma cell line A-431. A brief mathematical formulation has been proposed in this study to uncover the possibilities of using the nanocomposites as potential drug candidates in theranostic applications in disease treatment and diagnosis. This study would help uncover the electronic properties that play in the nano-scaled system at the material-bio interface, which would aid in designing a sensitive nano-electromechanical device bearing both the therapeutic and diagnostic attributes heralding a new horizon in the health care systems.

Neuroinflammation is increasingly recognized as a pivotal factor not only in neurodegenerative diseases such as Alzheimer and Parkinson, but also in the pathogenesis of metabolic disorders that influence or exacerbate these conditions. This review explores the intricate relationships between neuroinflammation, metabolic dysregulation and neurodegenerative diseases. We begin by detailing the fundamental mechanisms of neuroinflammation, focusing on the roles of astrocytes and microglia, and the molecular pathways that contribute to inflammatory processes in the CNS. The discussion then shifts to how metabolic abnormalities such as obesity, insulin resistance and dyslipidemia can initiate or perpetuate neuroinflammatory responses. Furthermore, we examine the evidence linking neuroinflammation to various neurodegenerative diseases, delineating how inflammatory processes can exacerbate neurodegeneration through feedback loops that impair neuronal function and survival. We also review clinical and preclinical studies that provide insights into the bi-directional interactions between neurodegeneration and metabolic health. This includes a critical evaluation of current therapeutic strategies targeting neuroinflammation, ranging from conventional anti-inflammatory treatments to innovative approaches aimed at modulating metabolic factors. Lastly, the review identifies promising therapeutic avenues, challenges in current treatment paradigms, and the potential for integrative interventions that address both metabolic and inflammatory components. Our goal is to emphasize the need for comprehensive strategies that consider the complexity of these intertwined systems in the treatment of neurodegenerative and metabolic diseases.

Structure-based discovery of a novel nuclear receptor PPARγ inhibitor: Implications for obesity and metabolic disease intervention.

Aegeline inspired synthesis of novel amino alcohol and thiazolidinedione hybrids with antiadipogenic activity in 3T3-L1 cells

The scourge of infectious diseases is one of the problems contending with humanity. All infectious diseases are caused by pathogens. A major problem in biological research is the creation of enormous and redundant amounts of genomic data. From this large volume of generated data, biologists select a subset of each sequence known as DNA nucleotide subsequences “words”, for extended scientific analysis. Computational biology aids this pruning process by providing computerized tools to generate vital information with biological significance from these data. This research aimed to develop new tools for extracting DNA repeats from the gene sequences and also to perform a comparative analysis with existing tools having similar or closely-related functions. We were able to develop BengaSaVex (GBenga Samuel Victor genetic sequence extraction tool) and provide a sequential in-silico genetic-sequence-filtering functionality to identify repeated DNA nucleotide subsequences within the genes of some microorganisms, evaluated the potential benefits and applications of identifying such repeated sequences, and finally, performed an in-silico comparative analysis between BengaSaVex and tandem repeat finder. Keywords: BengaSaVex , DNA, repetitive sequence, in-silico analysis, computational genomics. African Journal of Biotechnology, Vol 13(21) 2103-2112