Structural insight into the inhibition of acetylcholinesterase by 2,3,4, 5-tetrahydro-1, 5-benzothiazepines

Nawaz, Syed Junaid; Umbreen, Sumaira; Kahlid, Asaad; Ansari, Farzana Latif; Atta-ur-Rahman, _; Choudhary, Muhammad Iqbal

doi:10.1080/14756360701533080

Cited by 10 publications

(3 citation statements)

References 22 publications

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“…We already have reported a number of new inhibitors of ChEs. We have performed in vitro testing and studied inhibition kinetics and pharmacological profiles combined with in silico tools, such as molecular docking and 3D-QSAR (CoMFA and CoMSIA) studies [ 15 - 24 ]. Benzothiazepine derivatives, two seven-membered N and S heterocyclic ring systems, have been associated with broad spectrum biological activities [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

In silico modeling of the specific inhibitory potential of thiophene-2,3-dihydro-1,5-benzothiazepine against BChE in the formation of β-amyloid plaques associated with Alzheimer's disease

Ul-Haq

Khan

Kalsoom

et al. 2010

Theor Biol Med Model

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BackgroundAlzheimer's disease, known to be associated with the gradual loss of memory, is characterized by low concentration of acetylcholine in the hippocampus and cortex part of the brain. Inhibition of acetylcholinesterase has successfully been used as a drug target to treat Alzheimer's disease but drug resistance shown by butyrylcholinesterase remains a matter of concern in treating Alzheimer's disease. Apart from the many other reasons for Alzheimer's disease, its association with the genesis of fibrils by β-amyloid plaques is closely related to the increased activity of butyrylcholinesterase. Although few data are available on the inhibition of butyrylcholinesterase, studies have shown that that butyrylcholinesterase is a genetically validated drug target and its selective inhibition reduces the formation of β-amyloid plaques.RationaleWe previously reported the inhibition of cholinesterases by 2,3-dihydro-1, 5-benzothiazepines, and considered this class of compounds as promising inhibitors for the cure of Alzheimer's disease. One compound from the same series, when substituted with a hydroxy group at C-3 in ring A and 2-thienyl moiety as ring B, showed greater activity against butyrylcholinesterase than to acetylcholinesterase. To provide insight into the binding mode of this compound (Compound A), molecular docking in combination with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases.ConclusionMolecular docking studies revealed that the potential of Compound A to inhibit cholinesterases was attributable to the cumulative effects of strong hydrogen bonds, cationic-π, π-π interactions and hydrophobic interactions. A comparison of the docking results of Compound A against both cholinesterases showed that amino acid residues in different sub-sites were engaged to stabilize the docked complex. The relatively high affinity of Compound A for butyrylcholinesterase was due to the additional hydrophobic interaction between the 2-thiophene moiety of Compound A and Ile69. The involvement of one catalytic triad residue (His438) of butyrylcholinesterase with the 3'-hydroxy group on ring A increases the selectivity of Compound A. C-C bond rotation around ring A also stabilizes and enhances the interaction of Compound A with butyrylcholinesterase. Furthermore, the classical network of hydrogen bonding interactions as formed by the catalytic triad of butyrylcholinesterase is disturbed by Compound A. This study may open a new avenue for structure-based drug design for Alzheimer's disease by considering the 3D-pharmacophoric features of the complex responsible for discriminating these two closely-related cholinesterases.

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Section: Introductionmentioning

confidence: 99%

In silico modeling of the specific inhibitory potential of thiophene-2,3-dihydro-1,5-benzothiazepine against BChE in the formation of β-amyloid plaques associated with Alzheimer's disease

Ul-Haq

Khan

Kalsoom

et al. 2010

Theor Biol Med Model

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“…Benzothiazepine 97 a , however, is fitted differently inside the active side, which allowed it to form an extra hydrogen bond with the target leading to increased affinity. [101] Lastly, for benzothiazepanes intended to elicit anti‐epileptic action, introduction of a halogen atom can improve the biological activity. Studies have been disclosed in which C2‐substituted benzothiazepanes containing a 2‐chlorophenyl or a 2‐bromophenyl group exhibited the highest activity compared to other substitution patterns, such as hydroxy or methoxy groups.…”

Section: Study Of Biological Activitymentioning

confidence: 99%

“…The study showed that the substitution of the aromatic ring with a halogen or methyl moiety could decrease the affinity of these compounds toward AChE, which may be caused by repulsion of these groups with amino acid residues in the active site. Benzothiazepine 97 a , however, is fitted differently inside the active side, which allowed it to form an extra hydrogen bond with the target leading to increased affinity [101] . Lastly, for benzothiazepanes intended to elicit anti‐epileptic action, introduction of a halogen atom can improve the biological activity.…”

Section: Study Of Biological Activitymentioning

confidence: 99%

Synthesis of the 1,5‐Benzothiazepane Scaffold – Established Methods and New Developments

et al. 2023

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The 1,5‐benzothiazepane structure is an important heterocyclic moiety present in a variety of commercial drugs and pharmaceuticals. This privileged scaffold exhibits a diversity of biological activities, including antimicrobial, antibacterial, anti‐epileptic, anti‐HIV, antidepressant, antithrombotic and anticancer properties. Its important pharmacological potential renders research into the development of new and efficient synthetic methods of high relevance. In the first part of this review, an overview of different synthetic approaches toward 1,5‐benzothiazepane and its derivatives is provided, ranging from established protocols to recent (enantioselective) methods that promote sustainability. In the second part, several structural characteristics influencing biological activity are briefly explored, providing a few insights into the structure‐activity relationships of these compounds.

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In silico studies on 2,3-dihydro-1,5-benzothiazepines as cholinesterase inhibitors

et al. 2011

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Structural insight into the inhibition of acetylcholinesterase by 2,3,4, 5-tetrahydro-1, 5-benzothiazepines

Cited by 10 publications

References 22 publications

In silico modeling of the specific inhibitory potential of thiophene-2,3-dihydro-1,5-benzothiazepine against BChE in the formation of β-amyloid plaques associated with Alzheimer's disease

In silico modeling of the specific inhibitory potential of thiophene-2,3-dihydro-1,5-benzothiazepine against BChE in the formation of β-amyloid plaques associated with Alzheimer's disease

Synthesis of the 1,5‐Benzothiazepane Scaffold – Established Methods and New Developments

In silico studies on 2,3-dihydro-1,5-benzothiazepines as cholinesterase inhibitors

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