Al-Rashood Sara T, Alharbi Amal S, Alkahtani Hamad M
Novel series of pyrimidine derivatives (9a-o) were synthesized and evaluated for their antiproliferative activity against human colorectal carcinoma HCT-116, cervical carcinoma HeLa and breast carcinoma MCF-7 cell lines. Compounds 9b, 9k and 9h were the most active ones against HCT-116, HeLa and MCF-7 cell lines (IC50=2.46 ± 0.21, 1.81 ± 0.11 and 3.83 ± 0.27 µM, respectively) compared to doxorubicin (IC50=2.39 ± 0.16, 3.02 ± 0.18 and 5.56 ± 0.3 µM, respectively). Cell cycle analysis showed arrest at G1 /S phase upon treatment of HCT-116, HeLa cells with compounds 9b and 9k, respectively, and at G2 /M phase upon treatment of MCF-7 with 9h. Apoptotic effect of compounds 9b, 9k and 9h was showed through their pre G1 early and late apoptotic effects. Besides, compounds 9h and 9e displayed promising CDK2 and CDK9 inhibitory activities (IC50 values; 0.299 ± 0.02 and 0.396 ± 0.02 µM, respectively). Molecular docking study showed similar binding modes of the studied compounds to that attained by the native ligands either for CDK2 and or for CDK9 isoform. These findings recognized compound 9h as potent antiproliferative agents against MCF-7 cancer cells with pronounced CDK2 inhibition activity.
Kejia Jessy
Organic chemists must decide structures of the carbon-based compounds that they use in biochemical reactions, that form in these biochemical responses, and that they separate from living organisms. They complete this using several contributory methods collectively described as carbon-based spectrometry. Carbon-based spectrometry makes use of microelectronic gadgets called spectrometers that provide dynamism to particles and then measure how the particles respond to that applied energy.
Kejia Jessy
Organic chemists must decide structures of the carbon-based compounds that they use in biochemical reactions, that form in these biochemical responses, and that they separate from living organisms. They complete this using several contributory methods collectively described as carbon-based spectrometry. Carbon-based spectrometry makes use of microelectronic gadgets called spectrometers that provide dynamism to particles and then measure how the particles respond to that applied energy.
Arijit Nandi, Anwesha Das
An enormous number of articles hold up that the nuclear factor kappa B (NF-κB) pathway can modulate the pathophysiological conditions of cancer, inflammation, and numerous central nervous system diseases. Surprisingly, for such an important transcription factor, little progress has been made in uncovering the specific effects of the naturally occurring compounds in NF-κB pathway inhibitors. Several natural products and traditional medicines are extensively used by people worldwide in different disease conditions having unknown mechanisms. Among this undiscovered domain, a large number of compounds are isolated and showing their modulatory activity on the NF-κB pathway.
Kejia Jessy
An antimicrobial is an agent that kills microorganisms or stops their increase. Antimicrobial drugs may be grouped consistent with the microorganisms they act frequently towards. For example, antibiotics are used towards bacteria, and antifungals are used towards fungi. They also can be categorized consistent with their function. Agents that kill microbes are microbicides, whilst those who simply inhibit their increase are known as bacteriostatic agents. The use of antimicrobial drugs to deal with contamination is referred to as antimicrobial chemotherapy, whilst using antimicrobial drugs to save you contamination is referred to as antimicrobial prophylaxis. Antimicrobial chemotherapy has conferred large blessings on human health. A sort of microorganisms had been elucidated to motive infectious sicknesses with inside the latter 1/2 of the nineteenth century. Thereafter, antimicrobial chemotherapy made brilliant advances all through the 20th century, ensuing with inside the overly positive view that infectious sicknesses could be conquered with inside the close to future. However, in reaction to the improvement of antimicrobial retailers, microorganisms which have obtained resistance to pills thru loads of mechanisms have emerged and preserve to plague human beings. In Japan, as in different countries, infectious sicknesses due to drug resistant microorganism are one of the maximum crucial troubles in every day scientific practice
Kejia Jessy
Nucleic acids are biopolymers, or huge biomolecules, important to all identified tactics of lifecycle. They are accrued of nucleotides, which can be the monomers fabricated from 3 mechanisms: A 5-carbon sugar, a phosphate organization and a nitrogenous base. The most important lessons of nucleic acids are Deoxyribonucleic Acid (DNA) and Ribonucleic Acid (RNA). If the sugar is ribose, the polymer is RNA; if the sugar is the ribose derivative deoxyribose, the polymer is DNA. If the sugar is ribose, the polymer is RNA; if the sugar is the ribose by-product deoxyribose, the polymer is DNA. Nucleic acids are evidently going on chemicals that function the number one data-wearing molecules in cells and make up the genetic material. Nucleic acids are determined in abundance in all residing things, wherein they create, encode, after which save data of each residing mobileular of each lifestyles-shape on Earth. In turn, they feature to transmit and explicit that data outside and inside the mobileular nucleus to the indoors operations of the mobileular and in the long run to the subsequent technology of every residing organism. The encoded data is contained and conveyed through the nucleic acid sequence, which gives the 'ladder-step' ordering of nucleotides in the molecules of RNA and DNA. They play a mainly vital position in directing protein synthesis. Strings of nucleotides are bonded to shape helical backbones-typically, one for RNA, for DNA and assembled into chains of base-pairs decided on from the 5 number one, or canonical, nucleobases, which can be: adenine, cytosine, guanine, thymine, and uracil. Thymine happens simplest in DNA and uracil simplest in RNA. Using amino acids and the system referred to as protein synthesis, the precise sequencing in DNA of those nucleobase-pairs allows storing and transmitting coded commands as genes. In RNA, base-pair sequencing gives for production new proteins that decide the frames and elements and maximum chemical approaches of all lifestyles forms.
Kejia Jessy
Antimicrobial specialists are fundamental for the treatment of dangerous diseases and for dealing with the weight of minor contaminations locally. Also, they assume a critical part in organ and bone marrow transplantation, disease chemotherapy, fake joint and heart valve medical procedure. In contrast to different classes of medications, they are defenceless against opposition from changes in target microorganisms, and their antagonistic impacts might stretch out to different patients (expanded danger of crosscontamination). As a result, there is a steady necessity for new specialists, just as practices that guarantee the proceeded powerful endorsing of authorized specialists.
Athina Geronikaki
This manuscript deals with the synthesis ,computational and experimental evaluation of the antimicrobial activity of twenty nine 4-(indol-3-yl) thiazole-2-amines and 4-ιndol-3-yl)thiazole acylamines. Evaluation of antibacterial activity against Gram (+) and Gram (-) bacteria revealed that MIC of indole derivatives being in range of 0.06-1.88 mg/ml, while among fourteen methylindole derivatives only only six were active with MIC at 0.47-1.88 mg/ml. S.aureus appeared to be the most resistant strain, while S. typhimurium the most sensitive.Compound 5x was the most promising with MIC in range of 0.06-0.12 mg/ml, followed by 5d and 5m. Evaluation of these three compounds against resistant strains , namely, MRSA P. aeruginosa and E. coli revealed that they were more potent against MRSA than ampicillin.Furthermore, compounds 5m and 5x were superior inhibitors of biofilm formation thanampicillin and streptomycin in concentration of MIC. Compounds 5d, 5m and 5x interact with streptromycin being additive. Antifungal activity of some compounds exceeded or was equipotent with those of the reference antifungal agents bifonazole and ketoconazole. The most potent as antifungal agent was found to be compound 5g. Drug likeness scores of compounds was in range of -0.63 to 0.29, being moderate to good. According to docking studies E.coli Mur B inhibition is probable responsible for the antibacterial activity of compounds, whereas CYP51 inhibition implicated in antifungal activity. Compounds appeared to be on toxic according to the cytotoxicity assessment in MRC-5 cells.
Phaedra Eleftheriou
Introduction: Although, inflammation is a process involved in the natural defence of the organism, anti-inflammatory treatment is needed in many cases to inhibit unregulated, life threatening or chronic inflammatory response. Arachidonic acid derivatives, prostaglandins(PG), produced via the cyclooxygenase(COX) pathway and leukotrienes(LT), produced by the 5-lipoxygenase(5-LOX) pathway are involved in inflammation. Lipoxins(LX), produced by the sequential action of 5-LOX and 15- or 12-LOX, exhibit both pro- and anti-inflammatory action. Particularly in asthma, a limited amount of lipoxins seems to be mandatory for the anticipation of inflammation. Most anti-inflammatory drugs are mainly COX inhibitors. Although, leukotrienes are important mediators of inflammation, only one LOX inhibitor has been approved till now for the treatment of asthma. Research for finding novel effective and safe LOX inhibitors continuous. In the present study, twelve quercetin derivatives were synthesised and evaluated in vitro for LOX inhibitory action. The contribution of substituents to the mode of binding to human 5-LOX was investigated using docking analysis. Methods: Docking analysis was performed using human 5-LOX 3V99. Soybean 1-LOX, broadly used in drug development, was used for in vitro activity evaluation. Results: All compounds exhibited activity with IC50 values between 4μΜ and 18µΜ. Competitive inhibitors with increased inhibition at low substrate concentrations and uncompetitive inhibitors with increased inhibition at high substrate concentrations were among the active compounds. Docking analysis was in accordance with the in vitro results. Compound 1 bearing N-isobutyl, 6-MeO, 2-quinolinone substituent showed the best action exhibiting competitive inhibition, while compound 6 bearing a tricyclic 1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one moiety was the best uncompetitive inhibitor(IC50 =7μΜ). Conclusions: The best inhibitor exhibited improved activity compared to quercetin, while five of the compounds exhibited IC50 values lower or equal to 7μΜ. The presence of compounds with uncompetitive inhibitory action may be of interest for the development of novel inhibitors targeting to balanced inhibition.
Douglas McCloskey
Technological advances in high-resolution mass spectrometry (MS) vastly increased the number of samples that can be processed in a life science experiment, as well as volume and complexity of the generated data. To address the bottleneck of high-throughput data processing, we present SmartPeak (https://github. com/AutoFlowResearch/SmartPeak), an application that encapsulates advanced algorithms to enable fast, accurate, and automated processing of capillary electrophoresis–, gas chromatography–, and liquid chromatography (LC)–MS(/MS) data and high-pressure LC data for metabolomics, lipidomics, and fluxomics experiments. The application allows for an approximate 100-fold reduction in the data processing time compared to manual processing while enhancing quality and reproducibility of the results.
Asiful H Seikh
In this current investigation, aliphatic amine-cured diglycidyl ether of bisphenol-A (DGEBA) based epoxy coating was mixed with certain weight % hardener polyaminoamide (1:2) and was coated on carbon steel panels with and without 1% nano crystalline Al powder. The corrosion behavior of the coated samples were investigated by exposing them in the salt spray chamber, for 500 hours. According to ASTM-B-117, the bath was kept at 35 °C and 5% NaCl containing mist was sprayed at 1.3 bars pressure. Composition of coatings was confirmed using Fourier-transform infrared spectroscopy (FTIR). Electrochemical characterization of the coated samples was done using potentiodynamic polarization technique and electrochemical impedance spectroscopy (EIS) technique. All the experiments were done in 3.5% NaCl solution. The nano Al coated sample shows good corrosion resistance property compared to bare Al sample. In fact after salt spray exposure no pitting or local damage was observed for nano coated sample and the coating gloss was negligibly affected. The surface morphology of coated and corroded samples were studied using scanning electron microscopy (SEM). Keywords: DGEBA, Salt spray, FTIR, Nano Aluminium, Potentiodynamic polarization, EIS, SEM
Adrián Ochoa-Terán
Worldwide studies towards development of new drugs with a lower rate in emergence of bacterial resistance have been conducted. The molecular docking analysis gives a possibility to predict the activity of new compounds before to perform their synthesis. In this work, the molecular docking analysis of 64 Linezolid dipeptide type analogues was performed to predict their activity. The most negative scores correspond to six Fmoc-protected analogues where Fmoc group interacts in PTC for Linezolid. Twenty-six different Fmoc-protected Linezolid dipeptide-type analogues were synthesized from the chemical modification of ?-aminoacids and tested in antimicrobial experiments. Some of the tasted compounds show significant activity against group A Streptococcus clinical isolated and ATCC 25923 Staphylococcus aureus strain, as well as clinical isolated methicillin resistant Staphylococcus aureus strains, with MIC values lower than Linezolid. The activity of these analogues also was tasted against multidrug-resistant clinical isolates of Mycobacterium tuberculosis with moderate results
Beksisa Urge*, Temegen Kasa, Eyob Gebregziabhear, Getu Kitaw, Yigardu Mulatu
The objective of this experiment was to evaluate the effect of feeding bamboo leaf alone or in mixture with hay as basal diet on physiological and Blood eosinophil values in high grade crossbred milking cows. Five milking cows were grouped randomly into five treatments consisting of hay and bamboo leaves at the proportion of 100:0 (T1), 75:25 (T2), 50:50 (T3), 25:75 (T4) and 0:100% (T5) respectively. A prospective study was undertaken to study the effects of bamboo leaves on the response of eosinophils in experimental crossbred cows. In this experiment, mean rectal temperature of crossbred milking cows that had fed 25% (T2), 50% (T3) and 75% (T4) inclusion of bamboo leaves replacement over cows that received the control diet (T1) was 39.06 ± 0.64, 38.02 ± 0.70 and 39.04 ± 0.62 respectively. Similarly, mean blood eosinophil responses (55.33±3.90), mean packed cell volume indices (23.75 ± 0.66) and milk yield (7.9 ± 0.25) had dropped significantly (p<0.05) in crossbred cows that were fed with bamboo leaf replacement of the pasture hay at the ratio of 100% (T5). Mean Milk yield (8.3± 0.23), mean packed cell volume volume indices (30.5 ± 2.10) and mean blood eosinophils (118.75 ± 9.71) were significantly (P<0.05) increased for crossbred cows that had fed bamboo leaf at the ratio of 25% (T2) and 50% (T3) as compared to T1 values. Change of body weight of cows that were fed with 75% (T4) was significantly declined and lost in 100% (T5) which was negatively correlated with complete substitution (p<5%). The Eosinophil index of milking cows was generally greater in T2 and T3 values. Outputs of the experiment showed that Bamboo leaf supplementation had linearly improved blood eosinophil responses significantly (p<5%) at 25 percent and 50 percent inclusion levels over crossbred cows that had received the control diet (T1). Based on the result of this experiment, blood eosinophils of crossbred cows were effective and responsive when bamboo leaves had replaced the pasture hay at the ratio of 25% (T2) and 50%(T3) levels. On the other hand, bamboo leaf supplementation at the rate of 75% (T4) and 100%(T5) inclusion levels had resulted in poor performances of blood eosinophils and depressed milk yield that had adversely induced profuse diarrhea, weight loss, gait disorders, convulsions, toxic and other adverse effects in the experimental lactating cows. In conclusion, Bamboo leaves had better blood response values as compared to pasture hay in this experiment and hence can be a good substitute to hay at the rate of 25% and 50% in the long dry season when conventional roughages are in short supply without any adverse health effect on the cows.
Rajesh Kumar Das*, and Sahin Reja
2-(3-(Dimethylamino)Propyl)Isoindoline-1,3-Dione (DAPID) derivatives have been obtained by the reaction of the phthalic acid anhydride derivatives with N, N dimethyl propyl amine derivatives. The yield of DAPID type derivative was 60% by classical way which was carried out in our laboratory. But when this reaction was carried out by modern way i.e. microwave enhance method, then the yield was 85% to 91% with short time. 3-(1,3-dioxoisoindolin-2-yl)-N,N-dimethylpropan-1-ammonium perchlorate (DIDAP) derivatives have been obtained by the reaction of 2-(3-(Dimethylamino)Propyl)Isoindoline-1,3-Dione (DAPID) derivatives with salt. The DIDAP compound was synthesized in a different route followed by able to show it’s excellent anticancer activity against hepatomas Hep G2 Cell line.
Julie Owen*, Vijay Shahani, Serah Kimani, Alice Li, Albina Bolotokova, Ashley Hutchinson, Peter Loppnau, Santha Santhakumar, Almagul Seitova, Suzanne Ackloo, Dalia Barsyte-Lovejoy, Peter Brown, Masoud Vedadi, Cheryl Arrowsmith, Matthieu Schapira and Levon Halabelian
DCAF1 has been identified as a putative antiviral host target as well as a potential target to enable the proteasome-mediated degradation of therapeutic targets. It has a complex domain architecture, which contains a WD40 repeat (WDR) domain. The WDR domain is one of the most abundant protein-protein interactions (PPIs) domains in the human proteome. Given the significant role that PPIs play in many cellular processes and diseases there has been renewed interest in exploring WDR domain proteins, including DCAF1. Acting through the WDR domain, DCAF1 recruits substrate proteins to the CUL4A-RBX1-DDB1-DCAF1 E3 ubiquitin ligase complex for subsequent proteasomal degradation, which is the key process we aimed to modulate or exploit using small molecule probes. To discover novel DCAF1 probes, the interaction profiles of approximately 3 million commercially available compounds with ~8,500 proteins, including DCAF1, were rapidly predicted using Cyclica’s MatchMaker technology. Briefly, MatchMaker is a deep learning approach capable of assessing small molecule-protein interactions across the proteome. MatchMaker predictions informed the nomination of compounds based not only on predicted binding for DCAF1, but also on the lack of interaction with undesirable off-targets. Using MatchMaker predictions, alongside traditional CADD tools, we predicted and tested experimentally multiple hits for DCAF1, one of which, CYCA-117-70 was subsequently co-crystallized and deposited as the first co-crystal structure of DCAF1 in the PDB [PDB ID: 7SSE 3].
Kalsoom Saleem*, Masood Ur Rehman
Aim: Chronic use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) is commonly associated with gastric irritation and gastric ulceration. Therefore, the aim of study was to develop a novel oral drug delivery system with minimum gastric effects and improved dissolution rate for aceclofenac (ACF), a model BCS class-II drug. Methods: Self-emulsifying drug delivery systems (SEDDS) were formulated to increase the solubility and ultimately the oral bioavailability of ACF. Oleic acid was used as an oil phase, Tween 80 (T80) and Kolliphor EL (KEL) were used as surfactants, whereas, polyethylene glycol 400 (PEG 400) and propylene glycol (PG) were employed as co-surfactants. Optimized formulations (F1, F2, F3 and F4) were analyzed for droplet size, poly dispersity index (PDI), cell viability studies, in vitro dissolution in both simulated gastric fluid and simulated intestinal fluid, ex vivo permeation studies and thermodynamic stability. Results: The optimized formulations showed mean droplet sizes in the range of 111.3 ± 3.2 nm and 470.9 ± 12.52 nm, PDI from 244.6 nm to 389.4 ± 6.51 and zeta-potential from − 33 ± 4.86 mV to − 38.5 ± 5.15 mV. Cell viability studies support the safety profile of all formulations for oral administration. The in vitro dissolution studies and ex vivo permeation analysis revealed significantly improved drug release ranging from 95.68 ± 0.02% to 98.15 ± 0.71% when compared with control. The thermodynamic stability studies confirmed that all formulations remain active and stable for a longer period. Conclusion: In conclusion, development of oral SEDDS might be a promising tool to improve the dissolution of BCS class-II drugs along with significantly reduced exposure to gastric mucosa.
Hawaz Weldu*, Abel Mehari and Lia Alem
Eritrea is one of the developing countries where most of their communities are dependent on herbal medicines for the treatment of Infectious disease. However, this malpractice follows incorrect dosage, administration, formulation, frequency and other non-scientific methods with the inevitable negative effect of the practice which makes it inconvenient for the clients who seek treatment. This study was carried out to get a scientific evidence of antimicrobial activity of two selected important herbal plants. Active part from leaves of Sinapis alba and Brassica nigra were extracted by continuous hot extraction (Soxhlet technique), and different concentrations were obtained by ethanol, N-hexane, aqueous and DMSO solvents. Against Microorganisms of (Escherichia Coli and Staphylococcus aureus from bacterial strains and Candida Albicans from fungal strain) were selected for antimicrobial activity of the plants. Then the extracted solutions were diffused to selected standard organisms inoculated in Muller Hinton Agar using well diffusion technique. Ethanol extracts of S. Alba of 2500mg/ml dissolved in DMSO concentration against E. coli have shown a significant activity with inhibition zones of 30mm. This plant in the same concentration also had a considerable effect against S. aureus and C. Albcaians with a prompting result of 28mm and 25mm zones of inhibition respectively which is greater than the positive control. Moreover, this plant showed almost an equal activity at 1000mg and 250mg which are 20mm and 13mm respectively for C. Albicans, 26mm and 23mm for S. aureus and for E. coli 25mm and17mm. N-hexane extracts of the same plant also showed a remarkable activity at concentrations of 1000mg, 250mg and 50mg, where the zones of inhibition against S. aureus were 18mm, 20mm and 25mm respectively. Ethanol-extract of this plant diluted in ethanol also showed activity at the lowest concentration. Generally, both plants extracted using N-hexane and Ethanol extracts show a remarkable activity against all the selected micro-organisms.
Mahira Amirova
Tumor is one of the most wide-spread diseases across the planet, and along with this - the first in a row of the working-age population death causes. The pathogenesis of uncontrolled tissue growth and malignancy is still unexplored, making the tumor one of the most difficult, if not curable, diseases to treat. Tumor treatment today is carried out by extremely undesirable methods, the leading role among which belongs to chemo- and radiation therapy, the result of which is always inevitable - death. In this regard, there is an urgent need to find medicines that can save the lives hundreds of thousands of people without causing tangible harm to the body. Such drugs can be liposomes, which have long attracted the attention of scientists in the framework of the neoplasia treatment, but still remain at the research stage due to the high cost and complexity of industrial production. Using the data accumulated to date on liposomes and their invasiveness in tumor tissue, we propose our own version of liposome production, which, due to its relatively low toxicity and ease of manufacture, has more chances of being introduced into widespread medical practice: these are liposomes based on the liquid phase from Chaga fungus and the lipid phase with natural peptides relatively easily extracted from plants and microorganisms.
Mustafa Pehlivan
Discovery of new and specific enzyme inhibitor drugs is the growing problem in Pharmaceutical industry and the Research and there is a huge increase in billions of dollars for the development costs for new Chemotherapeutic and Highly potent new drug compounds that specifically target a certain enzyme, receptor or a protein. Recently, Computational Chemistry and Receptor based in silico drug design and discovery is becoming popular among Researchers because the developed methods help with saving time and money by reducing the costs of compounds to be synthesized for the discovery of new drug molecules. In this study, a new drug molecule discovered and computationally predicted to be highly enzyme inhibitor and possibly a potent anti-oxidant and/or anti-cancer drug compound, namely Prondicic Acid ( 2-Oxetanon-3,4-Diacetic Acid or Beta Propiolactone Diacetic Acid ) will be introduced. In addition , the computational methods for the possible activities for the derivatives of these compounds, predicted H-NMR and C-NMR datas and a possible Synthetic route to obtain the compound Prondicic Acid , and reaction mechanisms to possible modify the functional groups that could be synthetically attached to the compound’s Carboxyl groups for derivatization of other Prondicic Acid will be defined.
Tshifhiwa Ramabulana
The aim of this study was to identify and isolate potential biologically active compounds from the stems of Hypoestes aristata (Vahl) Sol. ex Roem. & Schult (Acanthaceae) and test them for their biological activities. The identification and isolation of potential bioactive compounds was achieved through chromatographic techniques such as column chromatography, preparative thin layer chromatography (PTLC), preparative high pressure liquid chromatography (Prep-HPLC), liquid chromatography-solid phase extraction-mass spectrometry (LC-SPE-MS), and ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-qTOF-MS). The characterisation and structural elucidation of the isolated compounds was mainly facilitated by spectroscopic/spectrometric techniques including 1D NMR (1HNMR, 13C-NMR, dept-135) and 2D NMR (COSY, HSQC, HMBC, NOESY) and high-resolution mass spectrometry (HRMS). From the stems of Hypoestes arisata, ten compounds that belong to the class of lignans were isolated and characterised. Among these compounds, four known butyrolactone lignans hinokinin, savinin, and cubebins; three new butyrolactone lignans (7S,8S,7’S,8’R)-7’-acetoxy-7-hydroxyhinokinin, (7S,8S,7’S,8’R)-7- acetoxy-7’-hydroxyhinokinin, and (7S,8S,7’S,8’R)-7,7’-diacetoxyhinokinin; and three new butyrolactol lignans. (7R,8S,9R,7′R,8′R)-7,7′-diacetoxycubebin, 7,7’-diacetoxy-β-cubebin, and (7S,8R,9S,7’R,8’R)-7,7’-diacetoxycubebin) were isolated. The absolute configurations of novel compounds were determined from their electronic circular dichroism (ECD) spectra and by derivatisation into (S) and (R)-MTPA esters. The newly isolated compounds are novel compounds. To the best of our knowledge, this is the first research which has isolated these compounds and confirms their absolute configurations from H. aristata. The compounds were screened for inhibition of a HIV-1 protease enzyme, hinokinin, (7S,8S,7’S,8’R)-7’-acetoxy-7-hydroxyhinokinin, (7S,8S,7’S,8’R)-7,7’- diacetoxyhinokinin, and (7R,8S,9R,7′R,8′R)-7,7′-diacetoxycubebin showed moderate protease inhibition at concentrations below 60 µM and other compounds showed insignificant inhibitory activities at concentrations above 100 µM. Additionally, the compounds (7S,8S,7’S,8’R)-7’-acetoxy-7-hydroxyhinokinin, (7S,8S,7’S,8’R)-7,7’-diacetoxyhinokinin, and (7R,8S,9R,7′R,8′R)-7,7′-diacetoxycubebin were also tested for cytotoxicity against the MCF-7 and MDA-MB-231 cancer cell lines and found to be inactive at concentrations below 90 µM
Naglaa S. Ashmawy*, Heba Al nashar, Eman M El- Labbad
Mangifera indica (MI), has been an important medicinal herb for over 4000 years. This genus Mangifera comprises about 30 species of fruiting trees of family Anacardiaceae. Mangifera was widely used in traditional medicine for therapeutic purposes by several cultures. Various parts of Mangifera tree were utilised for the treatment of a variety of ailments. Mangifera indica leaves extract grown in Egypt was subjected to successive chromatography techniques resulted in isolation of a novel non-reported xanthone derivative (TM-1). The in-vitro ability of TM-1 to inhibit elastase and tyrosinase enzymes activities was assessed. The novel compound exhibited remarkable anti-elastase and anti-tyrosinase inhibitory effects with IC50 values of 1.064 µg/mL and 1.336 µg /mL respectively compared to the positive controls. In order to assess the drugability and formulation consideration of TM-1, in silico, ADMET prediction was conducted using the SwissADME server. This included Lipinski’s rule of five, such as lipophilicity, solubility, and Pharmacokinetic properties as GIT absorption, distribution, metabolism, and skin permeation. All the physicochemical properties of TM-1 are within desirable ranges except for high polarity which may be attributed to the presence of the sugar moiety.TM-1 showed promising predicted topological aqueous solubility and reasonably predicted skin penetration suggesting the suitability of TM-1 for topical formulation. This is coherent with the in-vitro Antiaging evaluation.
Hasane Ratni
γ-Secretase (GS) is a key target for the potential treatment of Alzheimer’s disease. While inhibiting GS led to serious side effects, its modulation holds a lot of potential to deliver a safe treatment. Herein, we report the discovery of a potent and selective gamma secretase modulator (GSM) (S)-3 (RO7185876), belonging to a novel chemical class, the triazolo-azepines. This compound demonstrates an excellent in-vitro and in-vivo DMPK profile. Furthermore, based on its in-vivo efficacy in a pharmacodynamic mouse model and the outcome of the dose range finding (DRF) toxicological studies in two species, this compound was selected to undergo entry in human enabling studies (e.g. GLP toxicology and scale up activities). Furthermore, we will present a novel saturated phenyl bioisostere used in this compound design and compare its properties versus the now more standard BCP and related derivatives.
Robert K. Lesniak*, R. Jeremy Nichols, Marcus Schonemann, Jing Zhao, Chandresh R. Gajera, Grace Lam, Khanh C. Nguyen, Mark Smith and Thomas J. Montine
The most common genetic causes of Parkinson’s Disease (PD). The G2019S mutation is the most common inherited LRRK2 mutation, occurs in the kinase domain, and results in increased kinase activity. Increased Leucine Rich Repeat protein Kinase 2 (LRRK2) activity is hypothesized to cause PD in those who inherit GS-LRRK2, as well as other less common LRRK2 mutations, and possibly even contribute to the pathogenesis of sporadic PD in people without LRRK2 mutations. The clear advantage of these non-selective LRRK2 kinase inhibitors is their possible indication for all forms of PD. Unfortunately, multiple advanced compounds of this type of LRRK2 kinase inhibitor are accompanied by concerning untoward effects in lung and kidney (e.g., compounds developed by Genentech and Merck, GNE-7915 and MLi-2, respectively), calling into question the suitability of relatively non-selective LRRK2 kinase inhibitors for long-term treatment of older individuals. Furthermore, although these side-effects in lung and kidney have been reported to be reversible, the safety of long-term administration of such compounds is untested. We report the discovery and development of compound 38, an indazole-based, G2019S-selective (>2000-fold vs. WT) LRRK2 inhibitor capable of entering rodent brain (Kp=0.5) and selectively inhibiting G2019S-LRRK2. The compounds disclosed herein present a starting point for further development of brain penetrant G2019S selective inhibitors that hopefully reduce lung phenotype side-effects and pave the way to providing a precision medicine for people with PD who carry the G2019S mutation.
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