Structure-based design of novel melanin-concentrating hormone receptor-1 ligands based on saturated nitrogen-containing heterocycles.

Melanin Concentrating Hormone (MCH) receptor is a G protein-coupled receptor (GPCR) with two subtypes R1 and R2. MCH-R1 is involved in the control of energy homeostasis, feeding behavior and body weight. Many studies have proved that administration of MCH-R1 antagonists significantly reduces food intake and causes weight loss in animal models.

Selective Inhibition of Plasmodium falciparum ATPase 6 by Artemisinins and Identification of New Classes of Inhibitors after Expression in Yeast.

Treatment failures with artemisinin combination therapies (ACTs) threaten global efforts to eradicate malaria. They highlight the importance of identifying drug targets and new inhibitors and of studying how existing antimalarial classes work. Here, we report the successful development of a heterologous expression-based compound-screening tool.

Dietary Milk Phospholipids Attenuate Chronic Stress-Induced Changes in Behavior and Endocrine Responses across the Lifespan.

Scope: Increasing scientific evidence is validating the use of dietary strategies to support and improve brain health throughout the lifespan, with tailored nutritional interventions catering for specific life stages. Dietary phospholipid supplementations in early life and adulthood are shown to alleviate some of the behavioral consequences associated with chronic stress. This study aims to explore the protective effects of a tailored phospholipid-enriched buttermilk on behavioral and endocrine responses induced by chronic psychosocial stress in adulthood, and to compare these effects according to the life stage at which the supplementation is started.

Structure-Activity Relationships of the Antimalarial Agent Artemisinin 10. Synthesis and Antimalarial Activity of Enantiomers of -5β-Hydroxy-d-Secoartemisinin and Analogs: Implications Regarding the Mechanism of Action.

An efficient synthesis of -6-desmethyl-5β-hydroxy-d-secoartemisinin , a tricyclic analog of -(+)-artemisinin , was accomplished and the racemate was resolved into the (+)- and (-)- enantiomers via their Mosher Ester diastereomers. Antimalarial activity resided with only the artemisinin-like enantiomer -(-)-. Several new compounds -, , , and were synthesized from - but the C-5 secondary hydroxyl group was surprisingly unreactive.

Bifidobacterium longum counters the effects of obesity: Partial successful translation from rodent to human.

Background: The human gut microbiota has emerged as a key factor in the development of obesity. Certain probiotic strains have shown anti-obesity effects. The objective of this study was to investigate whether Bifidobacterium longum APC1472 has anti-obesity effects in high-fat diet (HFD)-induced obese mice and whether B.

Isolation and Synthesis of Veranamine, an Antidepressant Lead from the Marine Sponge .

The natural product veranamine was isolated from the marine sponge . It contains a unique heterocyclic scaffold and demonstrates in vivo antidepressant activity and selective affinity for 5HT2B and sigma-1 receptors. The first total synthesis of veranamine is reported.

Identification of a new small molecule chemotype of Melanin Concentrating Hormone Receptor-1 antagonists using pharmacophore-based virtual screening.

MCH receptor is a G protein-coupled receptor with two subtypes R1 and R2. Many studies have demonstrated the role of MCH-R1 in feeding and energy homeostasis. It has been proven that oral administration of small molecule MCH-R1 antagonists significantly reduces food intake and causes a dose-dependent weight loss.

Developing HIV Prevention Interventions for Emerging Adult MSM With a History of Being Bullied: A Qualitative Study.

The experience of being bullied in childhood or adolescence affects health into adulthood and is a public health crisis. Particularly affected are sexual minority young adults who are at the greatest risk for severe and violent bullying, HIV seroconversion, and onset of a substance use disorder. Although the scholarly work in the area of bullying victimization has made great gains over the past few years via improved sampling and methodological rigor, most of the focus of health research in this area has been on prevention efforts.

Computationally Assisted Discovery and Assignment of a Highly Strained and PANC-1 Selective Alkaloid from Alaska's Deep Ocean.

We report here the orchestration of molecular ion networking and a set of computationally assisted structural elucidation approaches in the discovery of a new class of pyrroloiminoquinone alkaloids that possess selective bioactivity against pancreatic cancer cell lines. Aleutianamine represents the first in a new class of pyrroloiminoquinone alkaloids possessing a highly strained multibridged ring system, discovered from Latrunculia ( Latrunculia) austini Samaai, Kelly & Gibbons, 2006 (class Demospongiae, order Poecilosclerida, family Latrunculiidae) recovered during a NOAA deep-water exploration of the Aleutian Islands. The molecule was identified with the guidance of mass spectrometry, nuclear magnetic resonance, and molecular ion networking (MoIN) analysis.

Tobacco cessation outcomes: The case for milestone-based services.

Introduction: This study focuses on a Midwest State's tobacco quitline. The purpose was to understand possible relationships between services provided and cessation rates.

Methods: The data examined in this study came from aggregated intake/treatment data and follow-up interview data.

Design, Synthesis, and Biological Evaluation of Peptidomimetic N-Substituted Cbz-4-Hyp-Hpa-Amides as Novel Inhibitors of Plasmodium falciparum.

A new series of peptidomimetic N-substituted Cbz-4-Hyp-Hpa-amides were designed, synthesized, and evaluated for inhibition of the Plasmodium falciparum. Substituents on the N-atom of the amide group were selected alkyl-, allyl-, aryl-, 2-hydroxyethyl-, 2-cyanoethyl-, cyanomethyl-, 2-hydroxyethyl-, 2,2-diethoxyethyl-, or 2-ethoxy-2-oxoethylamino groups, and about of 40 new compounds were synthesized and evaluated for antiplasmodial activity in vitro. Antimalarial activity has been investigated as for the final peptide mimetics, and their immediate predecessors, carrying TBDMS or TBDPS protecting groups on 4-hydroxyproline residue and 18 derivatives exhibited toxicity against P.

A novel training approach to activate alternative behaviors for smoking in depressed smokers.

The current research developed and tested a novel training strategy to alter the implicit associations between alternative behaviors to smoking and negative affect, and explored its effects on depressive symptoms and on smoking behavior as part of a quit attempt. Using a joystick, participants identified as smokers with depressive symptoms were trained to approach alternative behaviors to smoking in the context of negative affect. Specifically, in the experimental condition, participants were trained to avoid smoking-related targets and to approach alternative activities.

Mental health in 2020 for men who have sex with men in the United States.

Despite continued advances in HIV prevention and treatment, gay and bisexual men and other men who have sex with men (MSM) remain the population most impacted by HIV/AIDS in the US and many other Western countries. Additionally, MSM are disproportionately affected by various psychological problems, including depression, distress, trauma and substance use. These challenges frequently co-occur, and are associated with higher rates of behaviours related to HIV acquisition and transmission, HIV infection, and, for those living with HIV/AIDS, lower levels of treatment engagement.

Total synthesis of macrodiolide ionophores aplasmomycin A and boromycin via double ring contraction.

The half structure of the symmetrical macrodiolide aplasmomycin A was synthesized by alkylation of a C3-C10 α-sulfonyl ketone subunit, prepared from (R)-pulegone and protected as a C3 ortholactone with (2R,3R)-butanediol, by a protected 15,16-dihydroxy (12E)-allylic chloride representing C11-C17. The latter was obtained from (2S,3R)-1,2-epoxy-3-butanol and propargyl alcohol. Regio- and stereoselective 5-exo-trig cyclization of the ene diol moiety in this segment, mediated by N-bromosuccinimide, led to the (2R,3S,5R)-tetrahydrofuran substructure of aplasmomycin A.

UPLC-MS-ELSD-PDA as a powerful dereplication tool to facilitate compound identification from small-molecule natural product libraries.

The generation of natural product libraries containing column fractions, each with only a few small molecules, using a high-throughput, automated fractionation system, has made it possible to implement an improved dereplication strategy for selection and prioritization of leads in a natural product discovery program. Analysis of databased UPLC-MS-ELSD-PDA information of three leads from a biological screen employing the ependymoma cell line EphB2-EPD generated details on the possible structures of active compounds present. The procedure allows the rapid identification of known compounds and guides the isolation of unknown compounds of interest.

Synthesis, biological evaluation, hydration site thermodynamics, and chemical reactivity analysis of α-keto substituted peptidomimetics for the inhibition of Plasmodium falciparum.

A new series of peptidomimetic pseudo-prolyl-homophenylalanylketones were designed, synthesized and evaluated for inhibition of the Plasmodium falciparum cysteine proteases falcipain-2 (FP-2) and falcipain-3 (FP-3). In addition, the parasite killing activity of these compounds in human blood-cultured P. falciparum was examined.

Click chemistry decoration of amino sterols as promising strategy to developed new leishmanicidal drugs.

A series of 1,2,3-triazolylsterols was prepared from pregnenolone through reductive amination and copper(I)-catalyzed azide-alkyne cycloaddition (click chemistry). The newly generated stereocenter of the key propargylamino intermediate provided a mixture of diastereomers which were separated chromatographically, and the configuration of the R isomer was determined by X-ray crystallography. Ten triazolyl sterols were prepared, and the products and intermediates were screened in vitro against different parasites, with some compounds presenting IC50 values in the low micromolar range against Leishmania donovani.

Directed hydrogenation of acyclic homoallylic alcohols: enantioselective syntheses of (+)- and (-)-laurenditerpenol.

Laurenditerpenol is the first marine natural product shown to inhibit hypoxia-inducible factor 1 (HIF-1) activation. Preclinical studies support that the inhibition of HIF-1 is one of the molecular targets for antitumor drug discovery. The synthetically challenging molecular architecture of laurenditerpenol, its absolute stereostructure, and the biological activity of several diastereoisomers were accomplished by our group in 2007 by diastereoselective synthesis.

Expression in yeast links field polymorphisms in PfATP6 to in vitro artemisinin resistance and identifies new inhibitor classes.

Background: The mechanism of action of artemisinins against malaria is unclear, despite their widespread use in combination therapies and the emergence of resistance.

Results: Here, we report expression of PfATP6 (a SERCA pump) in yeast and demonstrate its inhibition by artemisinins. Mutations in PfATP6 identified in field isolates (such as S769N) and in laboratory clones (such as L263E) decrease susceptibility to artemisinins, whereas they increase susceptibility to unrelated inhibitors such as cyclopiazonic acid.

Stevioside methanol tetra-solvate.

Stevioside is a naturally occurring diterpenoid glycoside in Stevia rebaudiana Bertoni. The title compound, C38H60O18·4CH3OH, crystallized as its methanol tetrasolvate. Stevioside consists of an aglycone steviol (a tetra-cyclic diterpene in which the four-fused-ring system consists of three six-membered rings and one five-membered ring) and a sugar part (three glucose units).

Combined receptor-based and ligand-based approach to delineate the mode of binding of guaianolide-endoperoxides to PfATP6.

Plasmodium falciparum calcium-ATPase (PfATP6) has been reported to be a target of artemisinin and related endoperoxides. In this study, a series of previously reported guaianolide-endoperoxides (thaperoxides) were docked into a homology model of PfATP6 and also used to develop a pharmacophore model. This combined approach led to useful insights into the binding determinants of thaperoxides to the malarial enzyme.

Determination of antimalarial compound, ARB-89 (7β-hydroxy-artemisinin carbamate) in rat serum by UPLC/MS/MS and its application in pharmacokinetics.

Among all the antimalarial agents, artemisinin and its semi synthetic family of analogs are the most potent antimalarials available for the treatment of Plasmodium falciparum infections. But these analogs have a few issues such as shorter half-lives and low oral bioavailability values. In order to overcome these inherent problems, novel artemisinin analogs were synthesized from 7β-hydroxy artemisinin by the Department of Medicinal Chemistry, University of Mississippi using a new synthesis mechanism.

Computer-aided drug design of falcipain inhibitors: virtual screening, structure-activity relationships, hydration site thermodynamics, and reactivity analysis.

Falcipains (FPs) are hemoglobinases of Plasmodium falciparum that are validated targets for the development of antimalarial chemotherapy. A combined ligand- and structure-based virtual screening of commercial databases was performed to identify structural analogs of virtual screening hits previously discovered in our laboratory. A total of 28 low micromolar inhibitors of FP-2 and FP-3 were identified and the structure-activity relationship (SAR) in each series was elaborated.

Inhibitors of SARS-3CLpro: virtual screening, biological evaluation, and molecular dynamics simulation studies.

SARS-CoV from the coronaviridae family has been identified as the etiological agent of Severe Acute Respiratory Syndrome (SARS), a highly contagious upper respiratory disease that reached epidemic status in 2002. SARS-3CL(pro), a cysteine protease indispensible to the viral life cycle, has been identified as one of the key therapeutic targets against SARS. A combined ligand and structure-based virtual screening was carried out against the Asinex Platinum collection.

Identification of novel malarial cysteine protease inhibitors using structure-based virtual screening of a focused cysteine protease inhibitor library.

Malaria, in particular that caused by Plasmodium falciparum , is prevalent across the tropics, and its medicinal control is limited by widespread drug resistance. Cysteine proteases of P. falciparum , falcipain-2 (FP-2) and falcipain-3 (FP-3), are major hemoglobinases, validated as potential antimalarial drug targets.