Novel thieno[2,3-d]pyrimidines: their design, synthesis, crystal structure analysis and pharmacological evaluation

Novel thieno[2,3-d]pyrimidines containing a cyclohexane ring fused with a six- or five-membered heterocyclic moiety along with a benzylic nitrile were designed as potential inhibitors of PDE4. Expeditious synthesis of these compounds was carried out via a multi-step sequence consisting of a few key steps such as Gewald reaction, Dieckmann type cyclisation and Krapcho decarboxylation. This newly developed strategy involved construction of the thienopyrimidine ring followed by the cyclohexanone moiety and subsequently the fused heterocyclic ring. A number of thieno[2,3-d]pyrimidine based derivatives were synthesized using this method some of which showed promising PDE4B inhibitory properties. One of them was tested for PDE4D inhibition in vitro and dose dependent inhibition of TNF-α. A few selected molecules were docked into the PE4B protein the results of which showed good overall correlations to their observed PDE4B inhibitory properties in vitro. The crystal structure analysis of representative compounds along with hydrogen bonding patterns and molecular arrangement present within the molecule is described.     

AlCl3 induced C-arylation/cyclization in a single pot: a new route to benzofuran fused N-heterocycles of pharmacological interest

A new and one-pot synthesis of benzofuran fused N-heterocycles has been accomplished via AlCl₃-mediated C-C followed by C-O bond formation between 2,3-dichloropyrazine or its derivatives and phenols. The methodology provided novel compounds as potential inhibitors of PDE4B. The single crystal X-ray data of a synthesized benzofuran derivative are presented. Scope of the methodology, in vitro pharmacological data of some of the synthesized compounds, along with docking study of an active compound are described.     

Suppression or enhancement of interfacial instability in two-layer plane Couette flow of FENE-P fluids past a deformable solid layer

The linear stability of two-layer plane Couette flow of FENE-P fluids past a deformable solid layer is analyzed in order to examine the effect of solid deformability on the interfacial instability due to elasticity and viscosity stratification at the two-fluid interface. The solid layer is modeled using both linear viscoelastic and neo-Hookean constitutive equations. The limiting case of two-layer flow of upper-convected Maxwell (UCM) fluids is used as a starting point, and results for the FENE-P case are obtained by numerically continuing the UCM results for the interfacial mode to finite values of the chain extensibility parameter. For the case of two-layer plane Couette flow past a rigid solid surface, our results show that the finite extensibility of the polymer chain significantly alters the neutral stability boundaries of the interfacial instability. In particular, the two-layer Couette flow of FENE-P fluids is found to be unstable in a larger range of nondimensional parameters when compared to two-layer flow of UCM fluids. The presence of the deformable solid layer is shown to completely suppress the interfacial instability in most of the parameter regimes where the interfacial mode is unstable, while it could have a completely destabilizing effect in other parameter regimes even when the interfacial mode is stable in rigid channels. When compared with two-layer UCM flow, the two-layer FENE-P case is found in general to require solid layers with relatively lower shear modulii in order to suppress the interfacial instability. The results from the linear elastic solid model are compared with those obtained using the (more rigorous) neo-Hookean model for the solid, and good agreement is found between the two models for neutral stability curves pertaining to the two-fluid interfacial mode. The present study thus provides an important extension of the earlier analysis of two-layer UCM flow [V. Shankar, Stability of two-layer viscoelastic plane Couette flow past a deformable solid layer: implications of fluid viscosity stratification, J. Non-Newtonian Fluid Mech. 125 (2005) 143–158] to more accurate constitutive models for the fluid and solid layers, and reaffirms the central conclusion of instability suppression in two-layer flows of viscoelastic fluids by soft elastomeric coatings in more realistic settings.     

Controlled Drug Delivery Systems: Current Status and Future Directions

The drug delivery system enables the release of the active pharmaceutical ingredient to achieve a desired therapeutic response. Conventional drug delivery systems (tablets, capsules, syrups, ointments, etc.) suffer from poor bioavailability and fluctuations in plasma drug level and are unable to achieve sustained release. Without an efficient delivery mechanism, the whole therapeutic process can be rendered useless. Moreover, the drug has to be delivered at a specified controlled rate and at the target site as precisely as possible to achieve maximum efficacy and safety. Controlled drug delivery systems are developed to combat the problems associated with conventional drug delivery. There has been a tremendous evolution in controlled drug delivery systems from the past two decades ranging from macro scale and nano scale to intelligent targeted delivery. The initial part of this review provides a basic understanding of drug delivery systems with an emphasis on the pharmacokinetics of the drug. It also discusses the conventional drug delivery systems and their limitations. Further, controlled drug delivery systems are discussed in detail with the design considerations, classifications and drawings. In addition, nano-drug delivery, targeted and smart drug delivery using stimuli-responsive and intelligent biomaterials is discussed with recent key findings. The paper concludes with the challenges faced and future directions in controlled drug delivery.     

Production of Lipid and Fatty Acids during Growth of <Emphasis Type="Italic">Aspergillus terreus</Emphasis> on Hydrocarbon Substrates

An Aspergillus terreus, isolated from oil contaminated soil, could degrade a wide range of petroleum hydrocarbons including the immediate oxidation products of hydrocarbons, like alkanols and alkanals. Among all the linear chain carbon substrates, highest growth of 39.1 ± 3.8 g l⁻¹ (wet weight) was observed when n-hexadecane was used as the sole source of carbon. The growth of the fungus on this highly hydrophobic substrate was associated with the morphological change of the hyphae and increase production of lipid in the cells. The lipid production in the hydrocarbon (n-hexadecane) grown cells was sevenfold higher than the corresponding glucose grown cells. The fatty acid profile of the lipid content formed in the hydrocarbon grown cells was significantly different from the glucose grown cells and was composed of fatty acids with chain length C₁₄ to C₃₃ as revealed from the liquid chromatography electrospray ionization mass spectrometry analyses. Among the ranges, the fatty acids with chain lengths C₁₄ to C₁₈ were predominant in the profile. Considering the fatty acid profile and the high level of lipid production, this A. terreus mediated production of lipid is envisaged to have potential application in the oleochemical industries including the production of biodiesel.     

Synthesis of new 1,2-dideoxy C-linked carbo-β-amino acids and α/β-peptides with 11/9-helix,helix-turn and helix-turn-helix structures

The present study describes the synthesis of new C-linked carbo-β-amino acids [β-Caa_(1,2-ddx)], with a 1,2-dideoxy D-xylo furanoside side chain (a tetrahydro furan derivative). The stereochemistry at the newly created amine centers was determined by modified Mosher method. The (S)-β-Caa_(1,2-ddx) prepared from d-mannose diacetonide were utilized for the synthesis of 1:1 α/β-peptides with L-Ala. The conformational analysis (NMR, MD and CD) revealed the presence of 11/9-helix, helix induced helix-turn (HT) and helix-turn-helix (HTH) in these peptides. These side chains with tetrahydrofuran ring facilitated the formation of robust helix, unlike some other side chains from earlier studies.