Imran A. Khan

Metal-free, mild, nonepimerizing, chemo- and enantio- or diastereoselective N-alkylation of amines by alcohols via oxidation/imine-iminium formation/reductive amination: a pragmatic synthesis of octahydropyrazinopyridoindoles and higher ring analogues.

A mild step and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure has been developed via oxidation/imine-iminium formation/reduction cascade using TEMPO-BAIB-HEH-Brønsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen-transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Brønsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues.

A Raman spectroscopic study of uranyl minerals from Cornwall, UK

In the fields of nuclear forensics, geology and environmental science, it is important to be able to rapidly identify an unknown sample of uranyl mineral. Raman spectroscopy provides a fast, non-destructive and portable strategy for collecting data, which can then be compared against a set of known experimental information. We present a Raman study of a selection of uranyl minerals from Cornwall, UK. This includes the first Raman spectrum published for the uranyl arsenate mineral, novaekite. These spectra were collected under a standard set of conditions, using three excitation wavelengths, 325, 532 and 785 nm, the latter typically providing spectra with little fluorescence and the best resolution. The vibrational properties of these minerals are characterised by the symmetric stretching mode of the uranyl cation, seen between 750–900 cm−1, though the exact position varies with respect to the local environment. To discriminate between samples, the rest of the spectrum must be considered; the poly-anions in the structure provide a fingerprint set of Raman bands. An added complication occurs when samples of the same mineral from different mines demonstrate variations in their Raman spectra; this emphasises the need for data to be collected from a variety of locations, but also suggests that other experimental techniques could provide complementary information.

Exploring the thermodynamics and conformational aspects of nicotinic acid binding with bovine serum albumin: a detailed calorimetric, spectroscopic and molecular docking study

The present study reports comprehensive energetic and conformational aspects of the binding of an antihyperlipidemic drug, nicotinic acid (NA), with a model transport protein, bovine serum albumin (BSA) by calorimetry, light scattering, spectroscopic (absorption, fluorescence, 1H-NMR, and circular dichroism) and molecular docking methods. The calorimetric result reveals that NA binds to BSA in a sequential way with a stronger affinity (∼104 M−1) for the first binding site. The study in the presence of various co-solutes (salt, tetrabutylammonium bromide, sucrose, and surfactants) indicates the significant contribution of electrostatic as well as hydrophobic interactions but insignificant contribution of hydrogen bonding to the binding process. In addition, NA was also observed to bind with BSA through π–π interactions as revealed by 1H-NMR and the molecular docking study. The spectroscopic analysis reveals the formation of a complex via a static quenching mechanism. The presence of two sequential binding events has been successfully explained by calorimetry which has also been supported by the fluorescence study. The changes in the size as well as in the secondary structure of BSA were observed upon binding with NA. The stronger binding of NA at Sudlow site I (subdomain IIA) of BSA has been explored by the molecular docking study in combination with specific site probe experiments. Casting light on such drug–protein interactions helps in better understanding the biomolecular recognition and opens up new approaches in rational drug-design processes.

Operative conversions of 3-carboxy-4-quinolones into 3-nitro-4-quinolones via ipso-nitration: potential antifilarial agents as inhibitors of Brugia malayi thymidylate kinase

An efficient, cost effective and green methodology for ipso nitration in the synthesis of the 3-nitro derivative of 3-carboxy 4-quinolones has been developed by the quantitative use of copper acetate and silver nitrate in water. The observed regioselectivity of nitration is explained by the DFT calculations. Three of these compounds with IC50 values (2.9–3.4 μmol) against Brugia malayi thymidylate kinase may be good antifilarial agents as also evidenced by molecular docking studies.

Identification of Novel 2-((1-(Benzyl(2-hydroxy-2-phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)benzoic Acid Analogues as BMP-2 Stimulators

The synthesis and SAR studies of 10 new chemical entities (NCEs) that have shown BMP-2 stimulation and osteoblast differentiation are reported. Among these, 2-((1-(benzyl(2-hydroxy-2-phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)benzoic acid (11) was the most effective while its analogue 13 also showed good activity in inducing osteoblast BMP-2 production. Compound 11 induced osteoblast differentiation in vitro, and this effect was abrogated by a physiological BMP-2 inhibitor, noggin. It also exhibited dose dependent increase in nascent bone formation (2.16- and 3.12-fold more than the control at 1 and 5 mg/kg dose, respectively) at the fracture site in rats. At the maximum osteogenic concentration, compound 11 significantly inhibited osteoblastic proteosomal activity. This compound was safe, as it had no effect on BMP synthesis in cardiovascular tissue.

Novel Glycoprotein VI Antagonists as Antithrombotics: Synthesis, Biological Evaluation, and Molecular Modeling Studies on 2,3-Disubstituted Tetrahydropyrido(3,4-b)indoles

The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound 6b (ED50 = 28.36 μmol/kg po in mice) showed improved inhibition for collagen (IC50 = 6.7 μM), CRP-XL (IC50 = 53.5 μM), and convulxin (CVX) (IC50 = 5.7 μM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC50 = 10.4 μM; CRP-XL, IC50 = 158 μM; CVX, IC50 = 11 μM) than any of its enantiomers S (6c) (collagen, IC50 = 25.3 μM; CRP-XL, IC50 = 181.4 μM; CVX, IC50 = 9 μM) and R (6d) (collagen, IC50 = 126.3 μM; CRP-XL, IC50 > 500 μM; CVX, IC50 = 86.8 μM). Compound 6b also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers 6c and 6d at the GPVI receptor have been explained through docking studies.

Organocatalyzed asymmetric Michael addition by an efficient bifunctional carbohydrate–thiourea hybrid with mechanistic DFT analysis

A series of thiourea based bifunctional organocatalysts having d-glucose as a core scaffold were synthesized and examined as catalysts for the asymmetric Michael addition reaction of aryl/alkyl trans-β-nitrostyrenes over cyclohexanone and other Michael donors having active methylene. Excellent enantioselectivities (<95%), diastereoselectivities (<99%), and yields (<99%) were attained under solvent free conditions using 10 mol% of 1d0. The obtained results were explained through DFT calculations using the B3LYP/6-311G(d,p)//B3LYP/6-31G(d) basic set. The QM/MM calculations revealed the role of cyclohexanone as a solvent as well as reactant in the rate determining step imparting 31.91 kcal mol-1 of energy towards the product formation.

Deciphering the complexation process of a fluoroquinolone antibiotic, levofloxacin, with bovine serum albumin in the presence of additives

The current work aims to explore the thermodynamic and conformational aspects for the binding of fluoroquinolone antibacterial drug, levofloxacin (LFC), with bovine serum albumin (BSA) using calorimetric, spectroscopic (UV-visible, fluorescence, circular dichroism, and 1H NMR), dynamic light scattering (DLS) and computational methods (molecular docking). The binding of LFC with BSA at two sequential sites with higher affinity (~103M-1) at the first site has been explored by calorimetry whereas the binding at a single site with affinity of the order of ~104M-1 has been observed from fluorescence spectroscopy. The calorimetric study in the presence of additives along with docking analysis reveals the significant role of electrostatic, hydrogen bonding, and hydrophobic interactions in the association process. The slight conformational changes in protein as well as the changes in the water network structure around the binding cavity of protein have been observed from spectroscopic and DLS measurements. The LFC induced quenching of BSA fluorescence was observed to be initiated mainly through the static quenching process and this suggests the formation of ground state LFC-BSA association complex. The stronger interactions of LFC in the cavity of Sudlow site I (subdomain IIA) of protein have been explored from site marker calorimetric and molecular docking study.

A case series of cefixime induced Steven’s Johnson Syndrome

SJS is a rare cutaneous, severe, life-threatening drug induced hypersensitivity reaction marked by widespread inflammation of the epidermis ending in necrosis and eventual slouging of the tissue. This syndrome is associated with a rare but serious disorder of the skin, mucous membrane, genitals and eyes due to reaction to a medicament or an infection. It begins with fever and flu like symptoms followed by a painful red or purplish rash that spreads and appearance of blisters. The superficial layers of the affected skin dies, sheds and then heals. Occurrence of SJS is idiopathic or may be attributed to infections such as CMV, mycoplasma. Most common cause of SJS is drug related reactions. First time contact with antibiotics (Sulphonamides, Penicillin’s, cephalosporin’s e.g.; cefixime) or certain viral infections is more frequent in early life but more common in adults than in children and females are affected more frequently than males whereas polypharmacy may increase the susceptibility to SJS in elderly. SJS is potentially fatal with 10-40% mortality and survivors frequently suffer from permanent complications like eye sequelae. Serious eye issues such as severe conjunctivitis, iritis, corneal blisters, erosions, corneal holes, occurring with this syndrome can be disabling and lead to severe vision loss. Mucus membrane of oral cavity and gastrointestinal tract are typically inflamed. Complications include ABSTRACT