3-Aryl-1-phenyl-1H-pyrazole derivatives as new multitarget directed ligands for the treatment of Alzheimer's disease, with acetylcholinesterase and monoamine oxidase inhibitory properties.
A series of 3-aryl-1-phenyl-1H-pyrazole derivatives was synthesized in good yield and assayed in vitro as inhibitors of the mice acetylcholinesterase (AChE) and two goat liver monoamine oxidase (MAO) isoforms, MAO-A and MAO-B. Most of the compounds demonstrated a good AChE and selective MAO-B inhibitory activities in the nanomolar or low micromolar range. N-((3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-yl) methylene) benzenamine (3e, pIC50 = 4.2) and N-((4-fluorophenyl)-1-phenyl-1H-pyrazole-4-yl) methylene) methanamine (3f, pIC50 = 3.47) were the most potent AChE and highly selective MAO-B inhibitors respectively. Structure activity relationships showed that chloro derivatives were more effective AChE inhibitors as compared to fluoro derivatives while reverse trend was observed in MAO-B inhibitory activity. With the aid of modeling studies, potential binding orientations as well as interactions of the compounds in the AChE and MAO-B active sites were examined.
Drug Discovery and Research Laboratory, Department of Pharmaceutical Sciences,Guru Jambheshwar University of Science and Technology, Hisar -125 001, Haryana, India.
Ashwani
A
Kumar
Drug Discovery and Research Laboratory, Department of Pharmaceutical Sciences,Guru Jambheshwar University of Science and Technology, Hisar -125 001, Haryana, India.
Sandeep
S
Jain
Drug Discovery and Research Laboratory, Department of Pharmaceutical Sciences,Guru Jambheshwar University of Science and Technology, Hisar -125 001, Haryana, India.
Milind
M
Parle
Department of Pharmaceutical Education and Research, BPSMV, Khanpur kalan, Sonepat, Haryana, India.
Neelam
N
Jain
Department of Chemistry, Kurukshetra University, Kurukshetra-136119, Haryana, India.
Parvin
P
Kumar
1H-pyrazole; AChE; Alzheimer's disease; MAO-B; molecular modeling