Glyceride‐Mimetic Prodrugs Incorporating Self‐Immolative Spacers Promote Lymphatic Transport,Avoid First‐Pass Metabolism,and Enhance Oral Bioavailability

First‐pass hepatic metabolism can significantly limit oral drug bioavailability. Drug transport from the intestine through the lymphatic system, rather than the portal vein, circumvents first‐pass metabolism. However, the majority of drugs do not have the requisite physicochemical properties to facilitate lymphatic access. Herein, we describe a prodrug strategy that promotes selective transport through the intestinal lymph vessels and subsequent release of drug in the systemic circulation, thereby enhancing oral bioavailability. Using testosterone (TST) as a model high first‐pass drug, glyceride‐mimetic prodrugs incorporating self‐immolative (SI) spacers, resulted in remarkable increases (up to 90‐fold) in TST plasma exposure when compared to the current commercial product testosterone undecanoate (TU). This approach opens new opportunities for the effective development of drugs where oral delivery is limited by first‐pass metabolism and provides a new avenue to enhance drug targeting to intestinal lymphoid tissue.     

A simple metal free highly diastereoselective synthesis of heteroaryl substituted (±) cyclohexanols by a branched domino reaction

A self diastereoselective, simple metal free and efficient branch domino reaction gave multiple heteroaryl substituted (±) cyclohexanols with five chiral centres in >95% yields. The reactions that occur are Claisen Schmidt condensation followed by Michael addition and Aldol reactions of heteroaryl carbaldehydes and acetyl pyridine derivatives. Mechanistic study of the reactions shows excellent self diastereoselectivity (dr > 99%) in the intermediate steps which results selectively in the formation of one set of enantiomers out of sixteen possible enantiomeric pairs. The self diastereoselectivity of reaction in all the steps dominates due to the steric hindrance induced by the bulky heteroaryl groups. The stereochemistry of the synthesized compounds is established using single crystal XRD.     

Synthesis,characterization, molecular docking and biological activity of 5,6-bis-(4-fluoro-phenyl)-3,4,7,8-tetraaza-bicyclo[8.3.1]tetradeca-1(13),4,6,10(14),11-pentaene-2,9-dione and its transition metal complexes

Macrocyclic Schiff base ligand through the condensation of 1,3-dicarbonyl-phenyl-dihydrazide with 4,4′-difluorobenzil and its Co(II), Ni(II), Cu(II) and Zn(II) metal complexes have been synthesized. The ligand and metal complexes were characterized by analytical and physicochemical methods. An octahedral geometry arising from coordination of N2O2 donor atoms from the macrocyclic framework has been proposed for all metal complexes. Synthesized ligand and metal complexes were investigated for in vitro antibacterial and antioxidant activity. Complex [Ni(C₂₂H₁₄N₄F₂O₂)(OCOCH₃)₂] has shown remarkable antibacterial activity (Minimum inhibitory concentration 8–16?μg/ml) comparable to commercial antibiotic Ciprofloxacin. Anticancer activity of synthesized compounds against Squamous Cell Carcinoma (SCC4), head and neck cancer cell line has also been studied at different concentrations and at different time points. Complexes [Co(C₂₂H₁₄N₄F₂O₂)(NO₃)₂] and [Cu(C₂₂H₁₄N₄F₂O₂)(OCOCH₃)₂] have shown remarkable anticancer results (IC₅₀ 31.1 and 43.1?μM) against the tested cell line in concentration dependent manner. Molecular docking studies were carried out to find the binding mode of the synthesized macrocyclic Schiff base ligand to Epidermal Growth Factor Receptor (EGFR) Kinase (PDB ID: 1M17).     

Microwave-assisted synthesis of near-infrared fluorescent sphingosine derivatives

Microwave-assisted synthesis of near-infrared fluorescent sphingosine derivatives is described, and the utility of the probes demonstrated by co-localization studies with visible wavelength fluorescent sphingosine derivatives.     

HClO4 x SiO2 catalysed synthesis of alkyl 3-deoxy-hex-2-enopyranosides from 2-hydroxy glucal ester: application in the synthesis of a cis-fused bicyclic ether and a 4-amino-C-glucoside

A variety of alcohols react with 2,3,4,6-tetra-O-acetyl-1,5-anhydro-D-arabino-hex-1-enopyranose 1 in the presence of a catalytic amount of HClO(4) supported on silica gel to give the corresponding alkyl 3-deoxy-hex-2-enopyranosides 2 in high yield, with short reaction times (10-45 mins) and good alpha-selectivity. Work-up merely involves filtration of the reagent, followed by chromatographic purification of the crude product. This methodology has also been employed in the synthesis of a bicyclic ether, a useful precursor for cyclic polyethers, and a 4-amino-C-glucoside.     

Faedo–Galerkin Approximation of Solution for a Nonlocal Neutral Fractional Differential Equation with Deviating Argument

In this work, we study a class of nonlocal neutral fractional differential equations with deviated argument in the separable Hilbert space. We obtain an associated integral equation and then, consider a sequence of approximate integral equations. We investigate the existence and uniqueness of the mild solution for every approximate integral equation by virtue of the theory of analytic semigroup theory via the technique of Banach fixed point theorem. Next we demonstrate the convergence of the solutions of the approximate integral equations to the solution of the associated integral equation. The Faedo–Galerkin approximation of the solution is studied and demonstrated some convergence results. Finally, we give an example.

     

Surfactant-Assisted Acid Pretreatment of Sugarcane Tops for Bioethanol Production

Sugarcane tops is one of the largest biomass resources in India and in tropical countries such as Brazil in terms of surplus availability. Conversion of this feedstock to ethanol requires pretreatment to make it more accessible for the enzymes used in saccharification. Though several pretreatment regimens have been developed for addressing biomass recalcitrance, very few seem to be promising as an industrial process. A novel hybrid method involving use of mild acid and surfactant was developed which could effectively remove lignin and improve the sugar yield from sugar cane tops. Operational parameters that affect the pretreatment efficiency (measured as yield of sugars) were studied and optimized. Changes in structural properties of the biomass were studied in relation to the pretreatment process using scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier Transform Infrared (FTIR) analysis, and the changes in chemical composition was also monitored. The biomass pretreated with the optimized novel method could yield 0.798?g of reducing sugars per gram of pretreated biomass upon enzymatic hydrolysis.     

Effect of hydrophilic polymer on complexing efficiency of cyclodextrins towards efavirenz-characterization and thermodynamic parameters

The present work describes the effect of PVP on the complexation efficiency of cyclodextrins towards efavirenz, a poorly soluble antiretroviral agent imparting irritating sensation to buccal cavity. The phase solubility study indicates 1:1 stoichiometry for binary and ternary systems. DSC and XRPD revealed complete inclusion only in the lyophilized systems. The ternary systems were autoclaved before being lyophilized for the best results. Proton NMR suggests that the chlorobenzene part of benzoxazinone ring of the drug is involved in inclusion and was confirmed by 2D-COESY. The thermodynamic parameters, indicative of complexation efficiency were calculated calorimetrically by determining the interaction enthalpy of efavirenz with cyclodextrins in the presence and absence of PVP. The value of stability constants increased in the order β-CD?<?HP-β-CD?<?M-β-CD and is still higher in the presence of PVP illustrating the facilitation of the inclusion. Molar enthalpy of interaction of autoclaved solid formulation determined calorimetrically indicated stronger interaction for efavirenz:M-βCD-PVP system (?12.20?kJ/mol) which showed highest solubility and dissolution rate. The in vitro measurement of permeability showed a ten fold increase in the flux for the autoclaved formulation containing efavirenz-M-β-CD-PVP. In conclusion, encapsulation by cyclodextrins increases the solubility and suppresses the oral irritation of efavirenz. PVP further increases the complexation efficiency and decreases the bulk of cyclodextrins.