Experimental and Computational Evaluation of Piperonylic Acid Derived Hydrazones Bearing Isatin Moieties as Dual Inhibitors of Cholinesterases and Monoamine Oxidases.

A set of piperonylic acid derived hydrazones with variable isatin moieties was synthesized and evaluated for their inhibitory activity against the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO-A/B). The results of in vitro studies revealed IC50 values in the micromolar range, with the majority of the compounds showing selectivity for the MAO-B isoform. N-[2-Oxo-1-(prop-2-ynyl)indolin-3-ylidene]benzo[d][1,3]dioxole-5-carbohydrazide (3) was identified as a lead AChE inhibitor with IC50 =0.052±0.006 µm. N-[(3E)-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]-2H-1,3-benzodioxole-5-carbohydrazide (2) was the lead MAO-B inhibitor with IC50 =0.034±0.007 µm, and showed 50 times greater selectivity for MAO-B over MAO-A. The kinetic studies revealed that compounds 2 and 3 displayed competitive and reversible inhibition of AChE and MAO-B, respectively. The molecular docking studies revealed the significance of hydrophobic interactions in the active site pocket of the enzymes under investigation. Further optimization studies might lead to the development of potential neurotherapeutic agents.

Facile Synthesis of Dabigatran Etexilate Mesylate, an Anticoagulant Drug, Using a Novel Synthon, N-Hexyl-4-nitrophenyl Carbonate.

Facile synthesis for Dabigatran etexilate mesylate (1), an anticoagulant drug, is reported using a novel synthon, n-hexyl-4-nitrophenyl carbonate (32), which substantially eliminates the formation of potential impurities 20-27, which were generated due to the use of n-hexyl chloroformate in previously reported methods. Pinner reaction to prepare a key and critical intermediate, amidine 8, was optimized using design of experiment software to establish critical process parameters to achieve 8 in 97% yield. Nucleophilic substitution of 8 with novel synthon n-hexyl-4-nitrophenyl carbonate (32) furnished the dabigatran base 9, which was then converted to its mesylate salt using methane sulfonic acid to provide 1 with an overall yield of 66% over three steps.