Fluorine and chlorine substituted adamantyl-urea as molecular tools for inhibition of human soluble epoxide hydrolase with picomolar efficacy.

Series of 1,3-disubstituted ureas and diadamantyl disubstituted diureas with fluorinated and chlorinated adamantane residues were shown to inhibit human soluble epoxide hydrolase (sEH) with inhibition potency ranging from 40 pM to 9.2 nM. The measured IC50 values for some molecules were below the accuracy limit of the existing in vitro assays. Such an increase in activity was achieved by minimal structural modifications to the molecules of known inhibitors, including 4-[trans-4-(1-adamantylcarbamoylamino)cyclohexyl]oxybenzoic acid. For the chlorinated homologue of the latter the sharp jump in inhibitory activity can be (according to molecular dynamics data) the result of interactions - Cl-π interaction. Considering the extremely high inhibitory activity, acceptable solubility and partial blockage of metabolically sensitive centres in their structures, some compounds are of interest for further in vivo biotesting.

Distribution and evolution of H1N1 influenza A viruses with adamantanes-resistant mutations worldwide from 1918 to 2019.

H1N1 influenza is a kind of acute respiratory infectious disease that has a high socioeconomic and medical burden each year around the world. In the past decades, H1N1 influenza viruses have exhibited high resistance to adamantanes, which has become a serious issue. To understand the up-to-date distribution and evolution of H1N1 influenza viruses with adamantanes-resistant mutations, we conducted a deep analysis of 15875 M2 protein and 8351 MP nucleotides sequences. Results of the distribution analyses showed that 77.32% of H1N1 influenza viruses harbored-resistance mutations of which 73.52% were S31N, And the mutant variants mainly appeared in North America and Europe and H1N1 influenza viruses with S31N mutation became the circulating strains since 2009 all over the world. In addition, 80.65% of human H1N1 influenza viruses and 74.61% of swine H1N1 influenza viruses exhibited adamantanes resistance, while the frequency was only 1.86% in avian H1N1 influenza viruses. Studies from evolutionary analyses indicated that the avian-origin swine H1N1 influenza viruses replaced the classical human H1N1 influenza viruses and became the circulating strains after 2009; The interspecies transmission among avian, swine, and human strains over the past 20 years contributed to the 2009 swine influenza pandemic. Results of our study clearly clarify the historical drug resistance level of H1N1 influenza viruses around the world and demonstrated the evolution of adamantanes-resistant mutations in H1N1 influenza viruses. Our findings emphasize the necessity for monitoring the adamantanes susceptibility of H1N1 influenza viruses and draw attention to analyses of the evolution of drug-resistant H1N1 influenza variants.

Co-crystallization of an organic solid and a tetraaryladamantane at room temperature.

Tetraaryladamantanes have proven useful as chaperones for the co-crystallization of small molecules that do not readily crystallize by themselves. The co-crystals are often useful for structure elucidation. Usually, the small molecules are encapsulated in the crystal lattice of the aryladamantane that forms during rapid thermal crystallization. Thus far, co-crystallization has been limited to liquids as guest molecules. Here we report the co-crystal structures of phenol, which is solid at room temperature, with both 1,3,5,7-tetrakis(2,4-dimethoxyphenyl)adamantane (TDA) and 1,3,5,7-tetrakis(2,4-diethoxyphenyl)adamantane (TEO). The co-crystals were obtained from solutions in dichloromethane by slow evaporation or diffusion. The implications for generating other co-crystals of two solids are briefly discussed.

Evaluation of the diagnostic ratios of adamantanes for identifying seriously weathered spilled oils from simulated experiment and actual oil spills.

The composition and physical properties of spilled oil have great changes during the seriously weathering process. It brings great difficulties to the source identification of oil spill. So the stable and trustworthy diagnostic ratios (DRs) for accurate identification of severely weathered spilled oils are very important. The explosion of Sinopec pipeline happened on November 22, 2013 at Qingdao, China. Local beaches at Jiaozhou Bay were polluted by spilled oils. We have collected original spilled oil samples from an area free from human interference near the oil leakage point after the accident. Synchronized with actual beach weathering, laboratory experiments were conducted to simulate oil weathering for 360 days by using the collected original spilled oil samples. Based on t test and the repeatability limit method, 50 diagnostic ratios (DRs) of adamantanes were screened. Four DRs, namely 1,3-dimethyladamantane/total dimethyladamantane, 1-methyladamantane/(1-methyladamantane + 1,3-dimethyladamantane), dialkyl diamantane/total diamantane, and diamantane/(diamantane + dialkyl diamantane), have maintained remarkable stability during the simulated weathering experiments and field weathering process. These stable ratios can retain the characteristics of oil source during weathering. They are very beneficial to improve the accuracy of identifying the source of severely weathered oil and can be used as an effective supplement to existing index system for source identification.

Adamantane amine-linked chloroquinoline derivatives as chloroquine resistance modulating agents in Plasmodium falciparum.

Previously we have shown that pentacycloundecylamine-chloroquinoline (PCU-CQ) conjugates possess significant chemosensitizing abilities and can circumvent the resistance associated with chloroquine (CQ) resistant plasmodia. In order to further explore structurally related polycyclic compounds as reversed CQ agents we synthesized a series of eight aza-adamantanol (1-4) and adamantane-imine (5-8) CQ conjugates. All conjugates showed limited cytotoxicity against CHO cells (IC50 > 37 µM). Compounds 1, 2 and 5 were highly active (K1 IC50 < 100 nM) exhibiting a 3-4-fold increase in antiplasmodial activity against CQ resistant strain K1 compared to CQ. Reduced cross-resistance (resistance index, RI: 2-4.3) relative to CQ (RI = 38) was also observed for these compounds. Compound 1 which showed an 18-fold enhancement at retaining its activity against the K1 strain compared to CQ is a promising candidate to substitute CQ in P. falciparum resistant malaria.

Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors.

The ability of a number of nitrogen-containing compounds that simultaneously carry the adamantane and monoterpene moieties to inhibit Tdp1, an important enzyme of the DNA repair system, is studied. Inhibition of this enzyme has the potential to overcome chemotherapeutic resistance of some tumor types. Compound (+)-3c synthesized from 1-aminoadamantane and (+)-myrtenal, and compound 4a produced from 2-aminoadamantane and citronellal were found to be most potent as they inhibited Tdp1 with IC50 values of 6 and 3.5 µM, respectively. These compounds proved to have low cytotoxicity in colon HCT-116 and lung A-549 human tumor cell lines (CC50 > 50 µM). It was demonstrated that compound 4a at 10 µM enhanced cytotoxicity of topotecan, a topoisomerase 1 poison in clinical use, against HCT-116 more than fivefold and to a lesser extent of 1.5 increase in potency for A-549.

High-Loading Crystals of Tetraaryladamantanes and the Uptake and Release of Aromatic Hydrocarbons from the Gas Phase.

Recently, a tetraphenyladamantane octamethylether was shown to encapsulate a wide range of small molecules in its crystals. Uptake and release from the liquid phase were demonstrated, and crystalline inclusion complexes were prepared that act as formulation for obnoxious reagents. However, fewer than two equivalents of guest molecules were found within the crystal structures. Here we report the synthesis of 1,3,5,7-tetrakis(2,4-diethoxyphenyl)adamantane (TEO) and twelve X-ray crystal structures that contain up to 3.5 equivalents of guest molecules. After crystallization and drying, TEO gives a material that absorbs 30 wt % of p-xylene reversibly through the gas phase, and releases it again at 55 °C, suggesting that it may be used for the capture and release of aromatic hydrocarbons.

Antiproliferative and antiviral activity of three libraries of adamantane derivatives.

Three libraries of adamantane derivatives were synthesized and evaluated for antiviral and antiproliferative activities against a broad variety of DNA and RNA viruses. Whereas none of the compounds exhibit antiviral activity at subtoxic concentrations, antiproliferative activity was found against murine leukemia cells (L1210), human T-lymphocyte cells (CEM), and cervix carcinoma cells (HeLa) for 4, 8, and 10.

Molecular Dynamics Simulation of SARS-CoV-2 E Ion Channel: The Study of Lone Protein and its Conformational Changes in Complex with Potential Cage Inhibitors.

BACKGROUND: The coronavirus E ion channel has previously been studied as a potential target for antiviral therapy, with several compounds found to bind to the channel. However, these compounds have low activity, searching for effective E ion channel inhibitors of great importance. OBJECTIVE: This study aimed to develop a computational approach for designing ligands for the coronaviral E ion channel and identify potential inhibitors based on this approach. METHODS: The structure of the E-ion channel was refined using molecular dynamics, and the pore responsible for binding cage compounds was selected as the inhibitor-binding site. Potential inhibitor structures were identified using molecular docking, and their binding was confirmed using molecular dynamics simulations. RESULTS: A number of potential SARS E ion channel inhibitors have been identified, and the binding modes and possible mechanisms of action of these inhibitors have been clarified. CONCLUSION: This study presents a computational approach that can be used to design ligands for E ion channels and identify potential inhibitors, providing valuable insights into the development of new antiviral therapies. The behavior of the E protein pentamer of SARS-CoV-2 in its native environment was investigated using Molecular Dynamics (MD), resulting in an equilibrated structure that could be used to develop new inhibitors through molecular docking. Simulation of the MD of E-channel complexes with amantadine analogues allowed for the identification of the main types of ligand-protein interactions that are responsible for the good binding of ligands within the channel's inner chamber.

Bond order effects on the optoelectronic properties of oxygen/sulfur functionalized adamantanes.

The objective of this work, is to study adamantanes and to tune their bandgap, since pure adamantane is considered as an insulator due to its high bandgap energy. For this, we doped adamantane with oxygen and sulfur atoms, thus obtaining 730 different structures with double bonds and 730 different structures with single bonds, for a total of 1460 structures, and compared their properties. Among all, 31 molecules were selected that best represented the reduced bandgap behavior. The calculations with greater precision in its results were made using the Local Density Approximation (LDA), in the Density-Functional Theory (DFT) formalism, with PWC functional and TNP basis set. The electronic and optical properties were analyzed, by calculating the energy gap and absorption spectrum. Importantly, we observed that molecules doped with sulfur atoms (double bonds) had their energy gap reduced significantly compared to molecules doped with sulfur and/or oxygen atom with single bonds and pristine adamantane. It was found that in the absorption spectrum, the sulfur-doped structures had their spectrum shifted to the visible region, a fact that becomes relevant for potential dyes and optoelectronic applications. From the seven selected functionalized adamantanes (ADD-04, ADD-05, ADD-07, ADD-19, ADD-20, ADD-41, and ADD-48), any of these could be used as a dye. However, the ADD-20 molecule in particular, which presented optical absorption near (RGB) primary colors, could indicate a potential quantum dot material for application in developing screens of various electronic devices.

Clinical Characteristics of Coronavirus Disease 2019 (COVID-19) among Patients at a Movement Disorders Center.

It is not established whether SARS-CoV-2 (COVID-19) patients with movement disorders, are at greater risk for more serious outcomes than the larger COVID-19 population beyond the susceptibility associated with greater age. We reviewed electronic health records and conducted telephone interviews to collect the demographics and clinical outcomes of patients seen at our Movement Disorders Center who tested positive for COVID-19 from 8 March 2020 through 6 June 2020. Thirty-six patients were identified, 23 men and 13 women, median age of 74.5 years. They primarily carried diagnoses of idiopathic Parkinson disease (n = 22; 61%) and atypical parkinsonism (n = 7; 19%) with the balance having other diagnoses. Twenty-seven patients (75%) exhibited alteration in mental status and fifteen (42%) had abnormalities of movement as common manifestations of COVID-19; in 61% and 31%, respectively, these were the presenting symptoms of the disease. Sixty-seven percent of patients in our cohort required hospitalization, and the mortality rate was 36%. These data demonstrate that in patients with movement disorders, the likelihood of hospitalization and death after contracting COVID-19 was greater than in the general population. Patients with movement disorders frequently presented with altered mental status, generalized weakness, or worsening mobility but not anosmia.

Adamantanes might be protective from COVID-19 in patients with neurological diseases: multiple sclerosis, parkinsonism and cognitive impairment.

Facing the outbreak of coronavirus disease 2019 (COVID-19) pandemic, there is an urgent need to find protective or curable drugs to prevent or to stop the course of the coronavirus SARS-CoV-2 infection. Recent evidence accumulates that adamantanes, widely used in different neurological diseases, could be repurposed for COVID-19. We hereby report on a questionnaire-based study performed to assess severity of COVID-19 in patients suffering from multiple sclerosis (n=10), Parkinson's disease (n=5) or cognitive impairment (n=7). In all patients infection with SARS-CoV-2 was confirmed by rtPCR of nasopharyngeal swabs. They were receiving treatment with either amantadine (n=15) or memantine (n=7) in stable registered doses. All of them had two-week quarantine since documented exposure and none of them developed clinical manifestations of infectious disease. They also did not report any significant changes in neurological status in the course of primary nervous system disease. Above results warrant further studies on protective effects of adamantanes against COVID-19 manifestation, especially in subjects suffering from neurological disease.

Interaction of antivirals with a heptameric bundle model of the p7 protein of hepatitis C virus.

A series of ligands are known experimentally to affect the infectivity cycle of the hepatitis C virus. The target protein for the ligands is proposed to be p7, a 63 amino acid polytopic channel-forming protein, with possibly two transmembrane domains. Protein p7 is found to assemble into functional oligomers of various sizes, depending on the genotype (GT). Nine ligands are docked to various sites of a computationally derived heptameric bundle of p7 of GT1a. The energy of interaction, here binding energy, is calculated using three different docking programs (Autodock, MOE, LeadIT). Three protein regions are defined to which the ligands are placed, the loop region and the site with the termini as well as the mid-region which is supposed to track poses inside the putative pore. A common feature is that the loop sites and poses either within the pore or at the intermonomer space of the bundle are preferred for all ligands with proposed binding energies smaller than -10 kJ/mol. BIT225, benzamine, amantadine, and NN-DNJ show good overall scoring.

Solvent inclusion in the crystal structure of bis-[(adamantan-1-yl)methanaminium chloride] 1,4-dioxane hemisolvate monohydrate explained using the computed crystal energy landscape.

Repeated attempts to crystallize 1-adamantane-methyl-amine hydro-chloride as an anhydrate failed but the salt was successfully crystallized as a solvate (2C11H20N+·2Cl-·0.5C4H8O2·H2O), with water and 1,4-dioxane playing a structural role in the crystal and engaging in hydrogen-bonding inter-actions with the cation and anion. Computational crystal-structure prediction was used to rationalize the solvent-inclusion behaviour of this salt by computing the solvent-accessible voids in the predicted low-energy structures for the anhydrate: the global lattice-energy minimum structure, which has the same packing of the ions as the solvate, has solvent-accessible voids that account for 3.71% of the total unit-cell volume and is 6 kJ mol-1 more stable than the next most stable predicted structure.

Small molecule ligand docking to genotype specific bundle structures of hepatitis C virus (HCV) p7 protein.

The genome of hepatitis C virus encodes for an essential 63 amino acid polytopic protein p7 of most likely two transmembrane domains (TMDs). The protein is identified to self-assemble thereby rendering lipid membranes permeable to ions. A series of small molecules such as adamantanes, imino sugars and guanidinium compounds are known to interact with p7. A set of 9 of these small molecules is docked against hexameric bundles of genotypes 5a (bundle-5a) and 1b (bundle-1b) using LeadIT. Putative sites for bundle-5a are identified within the pore and at pockets on the outside of the bundle. For bundle-1b preferred sites are found at the site of the loops. Binding energies are in favour of the guanidinium compounds. Rescoring of the identified poses with HYDE reveals a dehydration penalty for the guanidinium compounds, leaving the adamantanes and imino sugar in a better position. Binding energies calculated by HYDE and those by LeadIT indicate that all compounds are moderate binders.

Influenza Antiviral Expenditures and Outpatient Prescriptions in the United States, 2003-2012.

STUDY OBJECTIVES: The clinical efficacy and cost-effectiveness of influenza antiviral use are controversial, with recent analyses suggesting potentially limited value. Thus, the objectives of this study were to describe influenza antiviral expenditures overall and by health care setting over a 10-year period (2003-2012) and to assess the correlation between outpatient influenza antiviral prescription use and influenza-like illness (ILI) outpatient visits. DESIGN: Retrospective, cross-sectional study. DATA SOURCES: IMS Health National Sales Perspectives and Xponent databases and Centers for Disease Control and Prevention ILINet national influenza surveillance system database. PATIENTS: All prescriptions for oseltamivir, rimantadine, or zanamivir from community pharmacies, mail order pharmacies, clinics, nonfederal hospitals, and other health care settings (federal hospitals, military facilities, jails and prisons, universities, staff-model health maintenance organizations, veterinary hospitals and clinics, and long-term care facilities) between January 1, 2003, and December 31, 2012. MEASUREMENTS AND MAIN RESULTS: Prescribing rates were calculated (prescriptions/1000 persons) for each year from 2003 to 2012 by using U.S. Census Bureau data. Influenza season was defined as July 1-June 30 of each calendar year. Linear regression assessed the correlation between influenza antiviral expenditures, prescription use, and ILI diagnoses. From 2003 to 2012, influenza antiviral drug expenditures accounted for $3.74 billion, with the majority from community pharmacies. After adjusting for inflation, no growth was observed for expenditures. A total of 32.8 million influenza antiviral prescriptions were dispensed from community pharmacies during the study period, and these prescriptions experienced 133.2% growth from 2003 to 2012. One third of expenditures and one quarter of dispensed prescriptions were in 2009. Influenza seasons were correlated with ILI and antiviral prescriptions. Annual community pharmacy expenditures were also associated with influenza antiviral prescriptions dispensed over the 10-year period. CONCLUSION: Influenza antivirals totaled $3.74 billion in the United States from 2003 to 2012, with the majority in 2009 and from community pharmacies. Influenza antivirals constituted a small proportion of total medication expenditures, but unforeseen pandemics resulted in unusually high use and expenditures. Influenza antiviral prescriptions dispensed from community pharmacies were associated with ILI and drug expenditures.

Determining drug efficacy parameters for mathematical models of influenza.

Antivirals are the first line of defence against influenza, so drug efficacy should be re-evaluated for each new strain. However, due to the time and expense involved in assessing the efficacy of drug treatments both in vitro and in vivo, treatment regimens are largely not re-evaluated even when strains are found to be resistant to antivirals. Mathematical models of the infection process can help in this assessment, but for accurate model predictions, we need to measure model parameters characterizing the efficacy of antivirals. We use computer simulations to explore whether in vitro experiments can be used to extract drug efficacy parameters for use in viral kinetics models. We find that the efficacy of neuraminidase inhibitors can be determined by measuring viral load during a single cycle assay, while the efficacy of adamantanes can be determined by measuring infected cells during the preparation stage for the single cycle assay.

Encapsulation of Large, Neutral Molecules in a Self-Assembled Nanocage Incorporating Six Palladium(II) Ions.

What a large interior space in a molecule! Self-assembled cage compound 1 has a nanosized cavity (8 Å in diameter) and can encapsulate as many as four molecules of o-carborane. A bulky guest, 1,3,5-tri-tert-butylbenzene, once encapsulated by means of thermally activated slippage, cannot escape from the cavity at room temperature since it is larger than the cavity entrance.

Stabilities of Hydrogen-Bonded Supramolecular Complexes with Various Numbers of Single Bonds: Attempts To Quantify a Dogma in Host-Guest Chemistry.

The disadvantage of flexible bonds in supramolecular host-guest complexes is much smaller than usually assumed. In the association of dicarboxlic acids with diamides (shown on the right), freely rotatable single bonds have only a minor disadvantageous influence on the free energy of complexation ΔGcplx . From the linear correlation between ΔGcplx and the number of single bonds n, a decrease in the free energy of complexation of only 1.3 kJ mol-1 per single bond was determined.

Application of different chemometric tools in QSAR study of azolo-adamantanes against influenza A virus.

Quantitative relationships between molecular structure and azolo-adamantanes derivatives were discovered by different chemometric tools including factor analysis based multiple linear regressions (FA-MLR), principle component regression analysis (PCRA), and genetic algorithm-partial least squares GA-PLS. The FA-MLR describes the effect of geometrical and quantum indices on enzyme inhibition activity of the studied molecules. The quality of PCRA equation was found to be better than those derived from FA-MLR. GA-PLS analysis indicated that the topological (IC4 and MPC06), constitutional (nf) and geometrical (G (N..S] parameters were the most significant ones on influenza A virus activity. Comparison of the different statistical methods employed revealed that GA-PLS represented superior results and it could explain and predict 85% and 77% of variances in the pIC(50) data, respectively.