Spectroscopic and quantum mechanical investigations of (2E)-3-(2H-1,3-benzodioxol-5-yl)-N-phenylprop-2-enamide using density functional theory method

The Fourier transform infrared (FTIR) and FT-Raman of (2E)-3-(2H-1,3-benzodioxol-5-yl)-N-phenylprop-2-enamide (2BNP2E) have been recorded in the regions 4000-100 and 4000-450cm-1, respectively. A complete assignment and analysis of the fundamental vibrational modes of the molecule have been carried out. The observed fundamental modes have been compared with the harmonic vibrational frequencies computed using DFT (B3LYP) method by employing 6-311++G(d,p) basis set. The vibrational studies have been interpreted in terms of potential energy distribution. The first order hyperpolarizability (β0) and related properties (α, μ and ∆α) of this molecular system are calculated using B3LYP/6-311++G(d,p) method based on the finite-field approach. Stability of the molecule arising from hyperconjugative interactions and charge delocalization has been analyzed using natural bond orbital (NBO) analysis. The results show that electron density (ED) in the σ* and π* anti-bonding orbitals and second-order delocalization energies (E(2)) confirm the occurrence of intramolecular charge transfer (ICT) within the molecule. Molecular electrostatic potential (MEP) and HOMO-LUMO energy levels have also been constructed. The thermodynamic properties of the title compound have been calculated at different temperature and the results reveal that the standard heat capacity C, entropy S and enthalpy changes H increase with rise in temperature

Developing a methodology towards sustainable PCD compact core drilling on planet Mars

ABSTRACT This paper describes a study of core drilling into basalt rock in anticipation of a Mars mission. Since the objective is to maintain a sustainable drilling mission on this distant planet, we perform a methodical study to examine parameters which influence sustainability including PCD tool-wear and drilling forces. INTRODUCTION Two gradual modes of insert-wear are experimentally measured: flank wear (VB) and cutting edge radius wear (CERW). Furthermore, relevant equations that relate wear to several factors including rock strength and process parameters are developed. The findings suggest a strong influence of rock hardness, process parameters, and tool geometry on tool-wear. Similar functional dependence is found for the generated thrust force and torque on rock hardness, rake angle, spindle speed, and drill feed. Consequently, equations are derived to model thrust force and torque as functions of these variables

Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis

Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis

How Does the VSG Coat of Bloodstream Form African Trypanosomes Interact with External Proteins?

Variations on the statement "the variant surface glycoprotein (VSG) coat that covers the external face of the mammalian bloodstream form of Trypanosoma brucei acts a physical barrier" appear regularly in research articles and reviews. The concept of the impenetrable VSG coat is an attractive one, as it provides a clear model for understanding how a trypanosome population persists; each successive VSG protects the plasma membrane and is immunologically distinct from previous VSGs. What is the evidence that the VSG coat is an impenetrable barrier, and how do antibodies and other extracellular proteins interact with it? In this review, the nature of the extracellular surface of the bloodstream form trypanosome is described, and past experiments that investigated binding of antibodies and lectins to trypanosomes are analysed using knowledge of VSG sequence and structure that was unavailable when the experiments were performed. Epitopes for some VSG monoclonal antibodies are mapped as far as possible from previous experimental data, onto models of VSG structures. The binding of lectins to some, but not to other, VSGs is revisited with more recent knowledge of the location and nature of N-linked oligosaccharides. The conclusions are: (i) Much of the variation observed in earlier experiments can be explained by the identity of the individual VSGs. (ii) Much of an individual VSG is accessible to antibodies, and the barrier that prevents access to the cell surface is probably at the base of the VSG N-terminal domain, approximately 5 nm from the plasma membrane. This second conclusion highlights a gap in our understanding of how the VSG coat works, as several plasma membrane proteins with large extracellular domains are very unlikely to be hidden from host antibodies by VSG.The authors’ lab is funded by the Wellcome Trust (093008/Z10/Z) and the Medical Research Council (MR/L008246/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version of the article. It was first available from PLOS via http://dx.doi.org/10.1371/journal.ppat.100525

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (<b>1</b>) for VL

Association between age at disease onset of anti-neutrophil cytoplasmic antibody-associated vasculitis and clinical presentation and short-term outcomes

Objectives: ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- A nd older-onset patients are still incompletely understood. Methods: We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: &lt;65 years or ≥65 years. We adjusted associations for the type of AAV and the type of ANCA (anti-MPO, anti-PR3 or negative). Results: A total of 1338 patients with AAV were included: 66% had disease onset at &lt;65 years of age [female 50%; mean age 48.4 years (s.d. 12.6)] and 34% had disease onset at ≥65 years [female 54%; mean age 73.6 years (s.d. 6)]. ANCA (MPO) positivity was more frequent in the older group (48% vs 27%; P = 0.001). Younger patients had higher rates of musculoskeletal, cutaneous and ENT manifestations compared with older patients. Systemic, neurologic,cardiovascular involvement and worsening renal function were more frequent in the older-onset group. Damage accrual, measured with the Vasculitis Damage Index (VDI), was significantly higher in older patients, 12% of whom had a 6 month VDI ≥5, compared with 7% of younger patients (P = 0.01). Older age was an independent risk factor for early death within 6 months from diagnosis [hazard ratio 2.06 (95% CI 1.07, 3.97); P = 0.03]. Conclusion: Within 6 months of diagnosis of AAV, patients &gt;65 years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients