Synthesis and in vitro cholinesterase inhibitory potential of dihydropyridine derivatives
PAKISTAN JOURNAL OF PHARMACEUTICAL SCIENCES
Authors: Zafar, Ansa Madeeha; Iqbal, Ambar; Ashraf, Muhammad; Aslam, Samina; Naureen, Sadia; Aslam, Noreen; Jabeen, Mussarat; Sajid, Naveed; Ghafoor, Abdul; Noreen, Shazia; Shahi, Mahrzadi Noureen; Khan, Misbahul Ain
Abstract
Twelve derivatives of dihydropyridine derivatives (6-17) were synthesized and evaluated for in-vitro cholinesterases (AChE, BChE) inhibitory activity. All compounds showed potent activity with IC50 values between 0.21 +/- 0.003 to 147.14 +/- 0.12 mu M for AChE and among them five compounds showed potent activity with IC50 values 17.16 0.02 to 231.6 +/- 0.12 mu M for BChE when compared with standard Eserine (IC50 = 0.85 0.0001 mu M (AChE) & 0.04 +/- 0.0001W (BChE). The most potent compound 11 can be considered as potential lead compound showed an inhibition of 95.35 +/- 0.11 and IC50= 0.21 0.003 while compound 7 showed an inhibition of 83.45 +/- 0.13 and IC50 = 17.16 +/- 0.02. It is concluded from structural activity relationship that the presence of nitro group at C-2 and C-4 position of dihydropyridine ring increase the acetyl cholinesterase and butyrylcholinesterase activities of these compounds while presence of -Br and -Cl also enhances the activities.
Enantioseparation, in vitro testing, and structura characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases
BIOCHEMICAL JOURNAL
Authors: Marakovic, Nikola; Knezevic, Anamarija; Roncevic, Igor; Brazzolotto, Xavier; Kovarik, Zrinka; Sinko, Goran
Abstract
The enantiomers of racemic 2-hydroxylmino-N-(azidophenylpropyl)acetamide-derived triple-binding oxime reactivators were separated, and tested for inhibition and reactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibited with tabun (GA), cyclosarin (GE), sarin (GB), and VX. Both enzymes showed the greatest affinity toward the methylimidazole derivative (III) of 2-hydroxyimino-N-(azidophenylpropyl)acetamide (I). The crystal structure was determined for the complex of oxime III within human BChE, confirming that all three binding groups interacted with active site residues. In the case of BChE inhibited by GF, oximes I (k(r) =207 M-1 min(-1)) and III (k(r) =213 M-1 min(-1)) showed better reactivation efficiency than the reference oxime 2-PAM. Finally, the key mechanistic steps in the reactivation of GF-inhibited BChE with oxime III were modeled using the PM7R6 method, stressing the importance of proton transfer from N epsilon of His438 to O gamma of Ser203 for achieving successful reactivation.
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