Synthesis of 2‐(2‐oxo‐2H‐chromen‐4‐yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions

Sixteen novel coumarin‐based compounds are reported as potent acetylcholinesterase (AChE) inhibitors. The most active compound in this series, 5a (IC₅₀ 0.04 ± 0.01 µM), noncompetitively inhibited AChE with a higher potency than tacrine and galantamine. Compounds 5d , 5j , and 5 m showed a moderate antilipid peroxidation activity. The compounds showed cytotoxicity in the same range as the standard drugs in HEK‐293 cells. Molecular docking demonstrated that 5a acted as a dual binding site inhibitor. The coumarin moiety occupied the peripheral anionic site and showed π‐π interaction with Trp278. The tertiary amino group displayed significant cation‐π interaction with Phe329. The aromatic group showed π‐π interaction with Trp83 at the catalytic anionic site. The long chain of methylene lay along the gorge interacting with Phe330 via hydrophobic interaction. Molecular docking was applied to postulate the selectivity toward AChE of 5a in comparison with donepezil and tacrine. Structural insights into the selectivity of the coumarin derivatives toward huAChE were explored by molecular docking and 3D QSAR and molecular dynamics simulation for 20 ns. ADMET analysis suggested that the 2‐(2‐oxo‐2H‐chromen‐4‐yl)acetamides showed a good pharmacokinetic profile and no hepatotoxicity. These coumarin derivatives showed high potential for further development as anti‐Alzheimer agents.     

Experimental and Computational Studies of Epithelial Transport of Mefenamic Acid Ester Prodrugs

Purpose. A series of ester derivatives of mefenamic acid were synthesized with the aim of suppressing local gastrointestinal toxicity of mefenamic acid. A computational method was used to assist the design of the prodrug and to gain insights into the structure relationship of these compounds as P-glycoprotein (P-gp) substrates. The prodrugs were studied for their enzymatic stability, bidirectional permeability across Caco-2 monolayer, and their potential as transporter modulatorsMethods. Bidirectional transport studies were performed using Caco-2 cells. Compounds exhibiting an efflux ratio of 2 were further examined for their potential interaction with P-gp and multidrug resistance–associated protein (MRP) using verapamil and indomethacin. Calcein efflux inhibition studies were conducted to investigate the efflux mechanism of these compounds. Geometry optimization of the esters was performed, and the spatial separation of two electron donor groups of each prodrug was measured.Results. Morpholinoethyl ester (3) and pyrrolidinoethyl ester (4) of mefenamic acid showed evidence of efflux mechanism. Inhibition by verapamil had a pronounced effect on the transport of 3 and 4. Indomethacin, however, completely inhibited the apical efflux of 3 but enhanced the efflux ratio of 4. Both compounds increased the ratio of cellular calcein accumulation by 3- to 5-fold over control. Consistent with the experimental data, the computational results suggest the involvement of P-gp or its interaction in 3 and 4 transport.Conclusions. Apical efflux of 3 is associated with P-gp and MRP, but the efflux of 4 involves P-gp and/or MRP. The computational approach used in this study provided the basis for P-gp substrates of compounds 3 and 4 from their electron donor subunits spatial separation.     

Dendrimers conjugates for colonic delivery of 5-aminosalicylic acid.

The water-soluble polyamidoamine (PAMAM) dendrimer conjugates for colonic delivery of 5-aminosalicylic acid (5-ASA) were designed. The drug was bound to the dendrimer using two different spacers containing azo-bond, p-aminobenzoic acid (PABA) and p-aminohippuric acid (PAH). Incubation of PAMAM dendrimer conjugates containing PABA and PAH spacers with rat cecal contents at 37 degrees C gradually released 5-ASA with time and the amount of drug released was 45.6 and 57.0% of the dose in 24 h, respectively. The release of the drug from the commercial prodrug, sulfasalazine was significantly faster than both conjugates (80.2% of the dose in 6 h). No 5-ASA was detected from the incubation of dendrimer conjugates with the homogenate of the stomach or phosphate buffer, pH 1.2 and 6.8. Only a small amount of 5-ASA was found after incubation of both conjugates with the homogenate of the small intestine for 12 h. It appears that this PAMAM dendrimer can be developed for use as a carrier for colon-specific drug delivery.