TY - JOUR
T1 - In silico and in vitro studies of two non-imidazole multiple targeting agents at histamine H3 receptors and cholinesterase enzymes
AU - Ghamari, Nakisa
AU - Dastmalchi, Siavoush
AU - Zarei, Omid
AU - Arias-Montaño, José Antonio
AU - Reiner, David
AU - Ustun‑Alkan, Fulya
AU - Stark, Holger
AU - Hamzeh-Mivehroud, Maryam
N1 - Funding Information:
This work forms part of the PhD thesis of Nakisa Ghamari at the School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. The authors would like to thank the Research Office and Biotechnology Research Center of Tabriz University of Medical Sciences for providing financial support under the Postgraduate Research Grant scheme for the PhD thesis of NG (Grant Number: 57572). Additional support was given by EU COST Actions CA15135 and CA18133 (HS).
Funding Information:
This work forms part of the PhD thesis of Nakisa Ghamari at the School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. The authors would like to thank the Research Office and Biotechnology Research Center of Tabriz University of Medical Sciences for providing financial support under the Postgraduate Research Grant scheme for the PhD thesis of NG (Grant Number: 57572). Additional support was given by EU COST Actions CA15135 and CA18133 (HS).
Publisher Copyright:
© 2019 John Wiley & Sons Ltd
PY - 2020/2/1
Y1 - 2020/2/1
N2 - Recently, multi-target directed ligands have been of research interest for multifactorial disorders such as Alzheimer's disease (AD). Since H3 receptors (H3Rs) and cholinesterases are involved in pathophysiology of AD, identification of dual-acting compounds capable of improving cholinergic neurotransmission is of importance in AD pharmacotherapy. In the present study, H3R antagonistic activity combined with anticholinesterase properties of two previously computationally identified lead compounds, that is, compound 3 (6-chloro-N-methyl-N-[3-(4-methylpiperazin-1-yl)propyl]-1H-indole-2-carboxamide) and compound 4 (7-chloro-N-[(1-methylpiperidin-3-yl)methyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxamide), was tested. Moreover, molecular docking and binding free energy calculations were conducted for binding mode and affinity prediction of studied ligands toward cholinesterases. Biological evaluations revealed inhibitory activity of ligands in nanomolar (compound 3: H3R EC50 = 0.73 nM; compound 4: H3R EC50 = 31 nM) and micromolar values (compound 3: AChE IC50 = 9.09 µM, BuChE IC50 = 21.10 µM; compound 4: AChE IC50 = 8.40 µM, BuChE IC50 = 4.93 µM) for H3R antagonism and cholinesterase inhibition, respectively. Binding free energies yielded good consistency with cholinesterase inhibitory profiles. The results of this study can be used for lead optimization where dual inhibitory activity on H3R and cholinesterases is needed. Such ligands can exert their biological activity in a synergistic manner resulting in higher potency and efficacy.
AB - Recently, multi-target directed ligands have been of research interest for multifactorial disorders such as Alzheimer's disease (AD). Since H3 receptors (H3Rs) and cholinesterases are involved in pathophysiology of AD, identification of dual-acting compounds capable of improving cholinergic neurotransmission is of importance in AD pharmacotherapy. In the present study, H3R antagonistic activity combined with anticholinesterase properties of two previously computationally identified lead compounds, that is, compound 3 (6-chloro-N-methyl-N-[3-(4-methylpiperazin-1-yl)propyl]-1H-indole-2-carboxamide) and compound 4 (7-chloro-N-[(1-methylpiperidin-3-yl)methyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxamide), was tested. Moreover, molecular docking and binding free energy calculations were conducted for binding mode and affinity prediction of studied ligands toward cholinesterases. Biological evaluations revealed inhibitory activity of ligands in nanomolar (compound 3: H3R EC50 = 0.73 nM; compound 4: H3R EC50 = 31 nM) and micromolar values (compound 3: AChE IC50 = 9.09 µM, BuChE IC50 = 21.10 µM; compound 4: AChE IC50 = 8.40 µM, BuChE IC50 = 4.93 µM) for H3R antagonism and cholinesterase inhibition, respectively. Binding free energies yielded good consistency with cholinesterase inhibitory profiles. The results of this study can be used for lead optimization where dual inhibitory activity on H3R and cholinesterases is needed. Such ligands can exert their biological activity in a synergistic manner resulting in higher potency and efficacy.
KW - anti-HR agents
KW - anticholinesterase
KW - histamine H receptor
KW - molecular docking
KW - molecular dynamics simulation
KW - multi-target directed ligands
U2 - 10.1111/cbdd.13642
DO - 10.1111/cbdd.13642
M3 - Journal article
C2 - 31661597
AN - SCOPUS:85075003416
VL - 95
SP - 279
EP - 290
JO - Chemical Biology and Drug Design (Print)
JF - Chemical Biology and Drug Design (Print)
SN - 1747-0277
IS - 2
ER -