Suchita Prasad

Synthesis and evaluation of c-Src kinase inhibitory activity of pyridin-2(1H)-one derivatives

Src kinase, a prototype member of the Src family of kinases (SFKs), is over-expressed in various human tumors, and has become a target for anticancer drug design. In this perspective, a series of eighteen 2-pyridone derivatives were synthesized and evaluated for their c-Src kinase inhibitory activity. Among them, eight compounds exhibited c-Src kinase inhibitory activity with IC50 value of less than 25μM. Compound 1-[2-(dimethylamino)ethyl]-5-(2-hydroxy-4-methoxybenzoyl)pyridin-2(1H)-one (36) exhibited the highest c-Src kinase inhibition with an IC50 value of 12.5μM. Furthermore, the kinase inhibitory activity of compound 36 was studied against EGFR, MAPK and PDK, however no significant activity was observed at the highest tested concentration (300μM). These results provide insights for further optimization of this scaffold for designing the next generation of 2-pyridone derivatives as candidate Src kinase inhibitors.

Fabrication of nanostructures through self-assembly of non-ionic amphiphiles for biomedical applications

Fabrication of self-assembled nanostructures with defined size and morphology represents a formidable challenge and thus, has gained tremendous momentum in research because of their potential applications in various biological systems. Herein, we report on the synthesis of novel non-ionic amphiphiles using 2,2-di(prop-2-yn-1-yl)propane-1,3-diol as a core further functionalized with poly(ethylene glycol) monomethyl ether and alkyl chains employing a chemo-enzymatic approach. Surface tension and fluorescence measurements along with dynamic light scattering studies revealed that all of the amphiphilic systems spontaneously self-assemble in aqueous solution, which is further supplemented by cryogenic transmission electron microscopy. The solubilization behavior of these systems as evidenced from UV-Vis and fluorescence spectroscopy and high performance liquid chromatography suggested the effective encapsulation of hydrophobic entities like Nile red, nimodipine, curcumin and dexamethasone. A comparative study with a standard excipient, Cremophor® ELP demonstrated that our nanocarriers exhibited superior/equivalent solubilization behavior for curcumin. Confocal laser scanning microscopy revealed efficient uptake of encapsulated dye in the cytosol of lung cancer cells, thus suggesting, that the reported amphiphilic systems can transport drugs into cells. A study of cytotoxicity showed that the synthesized amphiphilic systems are non-cytotoxic at the concentrations studied. The release profile of encapsulated Nile red incubated with/without a hydrolase enzyme Candida antarctica lipase demonstrated that the dye is stable in the amphiphilic nanostructures in the absence of enzyme for up to 12 days, however, more than 90% release of the dye occurred in 12 days when incubated with lipase. The results advocate the potential of these nanostructures as prospective drug delivery vehicles.

Acetamide Derivatives of Chromen‐2‐ones as Potent Cholinesterase Inhibitors

Alzheimers disease (AD), a neurodegenerative disorder, is a serious medical issue worldwide with drastic social consequences. Inhibition of cholinesterase is one of the rational and effective approaches to retard the symptoms of AD and, hence, consistent efforts are being made to develop efficient anti‐cholinesterase agents. In pursuit of this, a series of 19 acetamide derivatives of chromen‐2‐ones were synthesized and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential. All the synthesized compounds exhibited significant anti‐AChE and anti‐BChE activity, with IC50 values in the range of 0.24–10.19 μM and 0.64–30.08 μM, respectively, using donepezil hydrochloride as the standard. Out of 19 compounds screened, 3 compounds, viz. 22, 40, and 43, caused 50% inhibition of AChE at 0.24, 0.25, and 0.25 μM, respectively. A kinetic study revealed them to be mixed‐type inhibitors, binding with both the CAS and PAS sites of AChE. The above‐selected compounds were found to be effective inhibitors of AChE‐induced and self‐mediated Aβ1–42 aggregation. ADMET predictions demonstrated that these compounds may possess suitable blood–brain barrier (BBB) permeability. Hemolytic assay results revealed that these compounds did not lyse human RBCs up to a thousand times of their IC50 value. MTT assays performed for the shortlisted compounds showed them to be negligibly toxic after 24 h of treatment with the SH‐SY5Y neuroblastoma cells. These results provide insights for further optimization of the scaffolds for designing the next generation of compounds as lead cholinesterase inhibitors.

Nonionic Dendritic and Carbohydrate Based Amphiphiles: Self‐Assembly and Transport Behavior

Herein, a new series of non-ionic dendritic and carbohydrate based amphiphiles is synthesized employing biocompatible starting materials and studied for supramolecular aggregate formation in aqueous solution. The dendritic amphiphiles 12 and 13 possessing poly(glycerol) [G2.0] as hydrophilic unit and C-10 and C-18 hydrophobic alkyl chains, respectively, exhibit low critical aggregation concentration (CAC) in the order of 10-5 m and hydrodynamic diameters in the 8-10 nm range and supplemented by cryogenic transmission electron microscopy. Ultraviolet-visible (UV-Vis) and fluorescence spectroscopy suggests the effective solubilization of hydrophobic guests by the self-assembled architectures, with the nanotransporters 12 and 13 possessing the highest encapsulation efficiency of 80.74 and 98.03% for curcumin. Efficient uptake of encapsulated curcumin in adenocarcinomic human alveolar basal epithelial (A549) cells is observed by confocal laser scanning microscopy. Amphiphiles 12 and 13 are non-cytotoxic at the concentrations studied, however, curcumin encapsulated samples efficiently reduce the viability of A549 cells in vitro. Experimental studies indicate the ability of amphiphile 13 to encapsulate 1-anilinonaphthalene-8-sulfonic acid (ANS) and curcumin with binding constant of 1.16 × 1055 m-1 and 1.43 × 106 m-1 , respectively. Overall, our findings demonstrate the potential of these dendritic amphiphiles for the development of prospective nanocarriers for the solubilization of hydrophobic drugs.

Synthesis and characterization of novel benzoxazine-based arylidinyl succinimide derivatives

ABSTRACT 1,4-Benzoxazine skeleton holds substantial promise for further exploration owing to its immense pharmacological potential. In this pursuit, a series of 20 novel benzoxazine-based arylidinyl succinimide derivatives (23–42) were synthesized in moderate to good yields by the reaction of ethyl 2-(7-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)acetate (22) with various aromatic aldehydes under Wittig reaction conditions in the presence of triphenylphosphine and ethanol. All these synthesized compounds were fully characterized from their spectral data (1H, 13C, and 2D NMR, IR, UV, high-resolution mass spectroscopy (HRMS)) and further confirmed by X-ray crystallographic analysis of a representative compound (32). Antibacterial activity of obtained arylidinyl succinimide derivatives was evaluated against both Gram-positive and Gram-negative bacterial strains and were found to exhibit insignificant activity as compared to the reference. GRAPHICAL ABSTRACT