Potent, Selective, and Membrane Permeable 2-Amino-4-Substituted Pyridine-Based Neuronal Nitric Oxide Synthase Inhibitors.

A series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS), based on a difluorobenzene ring linked to a 2-aminopyridine scaffold with different functionalities at the 4-position, is reported. In our efforts to develop novel nNOS inhibitors for the treatment of neurodegenerative diseases, we discovered 17, which showed excellent potency toward both rat (Ki 15 nM) and human nNOS (Ki 19 nM), with 1075-fold selectivity over human eNOS and 115-fold selectivity over human iNOS. 17 also showed excellent permeability (Pe = 13.7 × 10-6 cm s-1), a low efflux ratio (ER 0.48), along with good metabolic stability in mouse and human liver microsomes, with half-lives of 29 and >60 min, respectively. X-ray cocrystal structures of inhibitors bound with three NOS enzymes, namely, rat nNOS, human nNOS, and human eNOS, revealed detailed structure-activity relationships for the observed potency, selectivity, and permeability properties of the inhibitors.

Development of the Vietnamese Healthy Eating Index.

Poor dietary quality is a major contributor to malnutrition and disease burden in Vietnam, necessitating the development of a tool for improving dietary quality. Food-based dietary guidelines (FBDGs) have been proposed to do this by providing specific, culturally appropriate and actionable recommendations. We developed the Vietnamese Healthy Eating Index (VHEI) to assess the adherence to the 2016-2020 Vietnamese FBDGs and the dietary quality of the general Vietnamese population. This VHEI consists of eight component scores, 'grains', 'protein foods', 'vegetables', 'fruits', 'dairy', 'fats and oils', 'sugar and sweets' and 'salt and sauces', representing the recommendations in the FBDGs. Each component score ranges from 0 to 10, resulting in a total VHEI score between 0 (lowest adherence) and 80 (highest adherence). The VHEI was calculated using dietary intake data from the Vietnamese General Nutrition Survey 2009-2010 (n = 8225 households). Associations of the VHEI with socio-demographic characteristics, energy and nutrient intakes and food group consumptions were examined. The results showed that the mean and standard deviation score of the VHEI was 43⋅3 ± 8⋅1. The component 'sugar and sweets' scored the highest (9⋅8 ± 1⋅1), whereas the component 'dairy' scored the lowest (0⋅6 ± 1⋅6). The intake of micronutrients was positively associated with the total VHEI, both before and after adjustment for energy intake. In conclusion, the VHEI is a valuable measure of dietary quality for the Vietnamese population regarding their adherence to the FBDGs.

Elucidating the Role of Tetraethylammonium in the Silicate Condensation Reaction from Ab Initio Molecular Dynamics Simulations.

The understanding of the formation of silicate oligomers in the initial stage of zeolite synthesis is important. The use of organic structure-directing agents (OSDAs) is known to be a key factor in the formation of different silicate species and the final zeolite structure. For example, tetraethylammonium ion (TEA+) is a commonly used organic template for zeolite synthesis. In this study, ab initio molecular dynamics (AIMD) simulation is used to provide an understanding of the role of TEA+ in the formation of various silicate oligomers, ranging from dimer to 4-ring. Calculated free-energy profiles of the reaction pathways show that the formation of a 4-ring structure has the highest energy barrier (97 kJ/mol). The formation of smaller oligomers such as dimer, trimer, and 3-ring has lower activation barriers. The TEA+ ion plays an important role in regulating the predominant species in solution via its coordination with silicate structures during the condensation process. The kinetics and thermodynamics of the oligomerization reaction indicate a more favorable formation of the 3-ring over the 4-ring structure. The results from AIMD simulations are in line with the experimental observation that TEA+ favors the 3-ring and double 3-ring in solution. The results of this study imply that the role of OSDAs is not only important for the host-guest interaction but also crucial for controlling the reactivity of different silicate oligomers during the initial stage of zeolite formation.

Site conditions for regeneration of climax species, the key for restoring moist deciduous tropical forest in Southern Vietnam.

Understanding the requirements and tolerances of the seedlings of climax species is fundamental for tropical forest restoration. This study investigates how the presence and abundance of seedlings of a previously dominant, now threatened species (Dipterocapus dyeri Pierre), varies across a range of environmental conditions. Dipterocapus dyeri seedling abundance and site characteristics were recorded at 122 observation points (4 m2) at nine clusters from two sites. Seedling presence (p = 0.065) and abundance varied significantly (p = 0.001) between the two sites, and was strongly correlated with adult D. dyeri dominance and lower soil pH, and weakly correlated with canopy openness and total stand basal area. Dipterocarpus dyeri seedlings were also grown in shade houses with three light levels on two soils. Seedling survival was significantly lower at the lowest light level (<10% full irradiance) at 13% for the forest soil and 25% for degraded soil. At higher irradiance the seedling survival rates were greater than 99%. Moisture levels remained high at the lowest light level and many seedlings died from fungal infection. We concluded that secondary forests which contain adequate numbers of adult D. dyeri as seed sources, light availability, soil pH of < 5.0, and good drainage strongly favour survival and growth of D. dyeri seedlings. Historically, D. dyeri was dominant in moist deciduous tropical forest across south-eastern Vietnam, but today it is rare. Active management of these recovering forests is essential in order to recover this high-value, climax forest species.

Chemical profiling of HIV-1 capsid-targeting antiviral PF74.

The capsid protein (CA) of HIV-1 plays essential roles in multiple steps of the viral replication cycle by assembling into functional capsid core, controlling the kinetics of uncoating and nuclear entry, and interacting with various host factors. Targeting CA represents an attractive yet underexplored antiviral approach. Of all known CA-targeting small molecule chemotypes, the peptidomimetic PF74 is particularly interesting because it binds to the same pocket used by a few important host factors, resulting in highly desirable antiviral phenotypes. However, further development of PF74 entails understanding its pharmacophore and mitigating its poor metabolic stability. We report herein the design, synthesis, and evaluation of a large number of PF74 analogs aiming to provide a comprehensive chemical profiling of PF74 and advance the understanding on its detailed binding mechanism and pharmacophore. The analogs, containing structural variations mainly in the aniline domain and/or the indole domain, were assayed for their effect on stability of CA hexamers, antiviral activity, and cytotoxicity. Selected analogs were also tested for metabolic stability in liver microsomes, alone or in the presence of a CYP3A inhibitor. Collectively, our studies identified important pharmacophore elements and revealed additional binding features of PF74, which could aid in future design of improved ligands to better probe the molecular basis of CA-host factor interactions, design strategies to disrupt them, and ultimately identify viable CA-targeting antiviral leads.

Inducible nitric oxide synthase: Regulation, structure, and inhibition.

A considerable number of human diseases have an inflammatory component, and a key mediator of immune activation and inflammation is inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO) from l-arginine. Overexpressed or dysregulated iNOS has been implicated in numerous pathologies including sepsis, cancer, neurodegeneration, and various types of pain. Extensive knowledge has been accumulated about the roles iNOS plays in different tissues and organs. Additionally, X-ray crystal and cryogenic electron microscopy structures have shed new insights on the structure and regulation of this enzyme. Many potent iNOS inhibitors with high selectivity over related NOS isoforms, neuronal NOS, and endothelial NOS, have been discovered, and these drugs have shown promise in animal models of endotoxemia, inflammatory and neuropathic pain, arthritis, and other disorders. A major issue in iNOS inhibitor development is that promising results in animal studies have not translated to humans; there are no iNOS inhibitors approved for human use. In addition to assay limitations, both the dual modalities of iNOS and NO in disease states (ie, protective vs harmful effects) and the different roles and localizations of NOS isoforms create challenges for therapeutic intervention. This review summarizes the structure, function, and regulation of iNOS, with focus on the development of iNOS inhibitors (historical and recent). A better understanding of iNOS' complex functions is necessary before specific drug candidates can be identified for classical indications such as sepsis, heart failure, and pain; however, newer promising indications for iNOS inhibition, such as depression, neurodegenerative disorders, and epilepsy, have been discovered.

Pharmacophore-based design of novel 3-hydroxypyrimidine-2,4-dione subtypes as inhibitors of HIV reverse transcriptase-associated RNase H: Tolerance of a nonflexible linker.

The pharmacophore of active site inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H typically entails a flexible linker connecting the chelating core and the hydrophobic aromatics. We report herein that novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes with a nonflexible C-6 carbonyl linkage exhibited potent and selective biochemical inhibitory profiles with strong RNase H inhibition at low nM, weak to moderate integrase strand transfer (INST) inhibition at low µM, and no to marginal RT polymerase (pol) inhibition up to 10 µM. A few analogues also demonstrated significant antiviral activity without cytotoxicity. The overall inhibitory profile is comparable to or better than that of previous HPD subtypes with a flexible C-6 linker, suggesting that the nonflexible carbonyl linker can be tolerated in the design of novel HIV RNase H active site inhibitors.

Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold.

Effective delivery of therapeutic drugs into the human brain is one of the most challenging tasks in central nervous system drug development because of the blood-brain barrier (BBB). To overcome the BBB, both passive permeability and efflux transporter liability of a compound must be addressed. Herein, we report our optimization related to BBB penetration of neuronal nitric oxide synthase (nNOS) inhibitors toward the development of new drugs for neurodegenerative diseases. Various approaches, including enhancing lipophilicity and rigidity of new inhibitors and modulating the p Ka of amino groups, have been employed. In addition to determining inhibitor potency and selectivity, crystal structures of most newly designed compounds complexed to various nitric oxide synthase isoforms have been determined. We have discovered a new analogue (21), which exhibits not only excellent potency ( Ki < 30 nM) in nNOS inhibition but also a significantly low P-glycoprotein and breast-cancer-resistant protein substrate liability as indicated by an efflux ratio of 0.8 in the Caco-2 bidirectional assay.

Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker.

Inhibition of neuronal nitric oxide synthase (nNOS) is a promising therapeutic approach to treat neurodegenerative diseases. Recently, we have achieved considerable progress in improving the potency and isoform selectivity of human nNOS inhibitors bearing a 2-aminopyridine scaffold. However, these inhibitors still suffered from too low cell membrane permeability to enter into CNS drug development. We report herein our studies to improve permeability of nNOS inhibitors as measured by both PAMPA-BBB and Caco-2 assays. The most permeable compound (12) in this study still preserves excellent potency with human nNOS (Ki = 30 nM) and very high selectivity over other NOS isoforms, especially human eNOS (hnNOS/heNOS = 2799, the highest hnNOS/heNOS ratio we have obtained to date). X-ray crystallographic analysis reveals that 12 adopts a similar binding mode in both rat and human nNOS, in which the 2-aminopyridine and the fluorobenzene linker form crucial hydrogen bonds with glutamate and tyrosine residues, respectively.

Synthesis and activity of benzimidazole-1,3-dioxide inhibitors of separase.

Due to the oncogenic activity of cohesin protease, separase in human cancer cells, modulation of separase enzymatic activity could constitute a new therapeutic strategy for targeting resistant, separase-overexpressing aneuploid tumors. Herein, we report the synthesis, structural information, and structure-activity relationship (SAR) of separase inhibitors based on modification of the lead molecule 2,2-dimethyl-5-nitro-2H-benzimidazole-1,3-dioxide, named Sepin-1, (1) identified from a high-throughput-screen. Replacement of -NO2 at C5 with other functional groups reduce the inhibitory activity in separase enzymatic assay. Substitution of the two methyl groups with other alkyl chains at the C2 moderately improves the effects on the inhibitory activity of those compounds. Modifications on 2H-benzimidazole-1,3-dioxide or the skeleton have variable effect on inhibition of separase enzymatic activity. Density-functional theory (DFT) calculations suggest there may be a correlation between the charges on the oxide moieties on these compounds and their activity in inhibiting separase enzyme.

National prevalence and associated risk factors of hypertension and prehypertension among Vietnamese adults.

BACKGROUND: Hypertension has recently been identified as the leading risk factor for global mortality. This study aims to present the national prevalence of hypertension and prehypertension and, their determinants in Vietnamese adults. METHODS: Nationally representative data were obtained from the National Adult Overweight Survey 2005. This one visit survey included 17,199 subjects aged 25-64 years, with a mean body mass index (BMI) of 20.7 kg/m(2). RESULTS: The overall census-weighted JNC7 (the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) defined prevalence of hypertension was 20.7% (95% confidence interval (CI) = 19.4-22.1); the prevalence of prehypertension was 41.8% (95% CI = 40.4-43.1). Hypertension and prehypertension were more prevalent in men. Higher age, overweight, alcohol use (among men), and living in rural areas (among women) were independently associated with a higher prevalence of hypertension, whereas higher physical activity and education level were inversely associated. Age, BMI, and living in rural areas were independently associated with an increased prevalence of prehypertension. Among the hypertensives, 25.9% were aware of their hypertension, 12.2% were being treated, and 2.8% had their blood pressure under control; among the treated hypertensives, 32.4% had their blood pressure controlled. CONCLUSIONS: Hypertension and prehypertension are prevalent in Vietnam, but awareness, treatment, and control are low. The findings suggest that lifestyle modifications, including the prevention of overweight, the promotion of physical activity particularly in urban areas, and the reduction of high alcohol consumption, may help to prevent hypertension in Vietnam. Furthermore, increased efforts regarding education, detection, and treatment could be important in management of hypertension and cardiovascular disease risk prevention.