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1.
J Cell Biochem ; 124(11): 1734-1748, 2023 11.
Article in English | MEDLINE | ID: mdl-37796142

ABSTRACT

The pathogenic complexity of Alzheimer's disease (AD) demands the development of multitarget-directed agents aiming at improving actual pharmacotherapy. Based on the cholinergic hypothesis and considering the well-established role of butyrylcholinesterase (BuChE) in advanced stages of AD, the chemical structure of the acetylcholinesterase (AChE) inhibitor drug donepezil (1) was rationally modified for the design of new N-benzyl-piperidine derivatives (4a-d) as potential multitarget-direct AChE and BuChE inhibitors. The designed analogues were further studied through the integration of in silico and in vitro methods. ADMET predictions showed that 4a-d are anticipated to be orally bioavailable, able to cross the blood-brain barrier and be retained in the brain, and to have low toxicity. Computational docking and molecular dynamics indicated the formation of favorable complexes between 4a-d and both cholinesterases. Derivative 4a presented the lowest binding free energy estimation due to interaction with key residues from both target enzymes (-36.69 ± 4.47 and -32.23 ± 3.99 kcal/mol with AChE and BuChE, respectively). The in vitro enzymatic assay demonstrated that 4a was the most potent inhibitor of AChE (IC50 2.08 ± 0.16 µM) and BuChE (IC50 7.41 ± 0.44 µM), corroborating the in silico results and highlighting 4a as a novel multitarget-directed AChE/BuChE inhibitor.


Subject(s)
Alzheimer Disease , Butyrylcholinesterase , Humans , Butyrylcholinesterase/metabolism , Butyrylcholinesterase/therapeutic use , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/therapeutic use , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Piperidines/pharmacology , Piperidines/therapeutic use , Structure-Activity Relationship , Molecular Docking Simulation
2.
RSC Adv ; 9(35): 20356-20369, 2019 Jun 25.
Article in English | MEDLINE | ID: mdl-35514684

ABSTRACT

Herein we describe the development of an efficient one-pot regioselective synthesis protocol to obtain N-protected or N-deprotected 1,5-diaryl-3-amino-1,2,4-triazoles from N-acyl-N-Boc-carbamidothioates. This improved protocol using microwave irradiation and low reaction times (up to 1 h) furnished desired compounds in yields ranging from 50 to 84%. This chemistry is useful for a variety of aromatic groups with electronically diverse substituents. The design and correct derivation of the amino group led to compounds able to inhibit cholinesterases with good IC50 of up to 1 µM. Also, the mode of action (mixed-type) and SAR analysis for this series of compounds was described by means of kinetic and molecular modelling evaluations, showing potential for this class of compounds as new scaffolds for this biological activity.

3.
Curr Top Med Chem ; 18(2): 124-148, 2018.
Article in English | MEDLINE | ID: mdl-29595110

ABSTRACT

Coumarins are natural products characterized as 1,2 benzopyrones widely distributed in plants, as well as, in many species of fungi and bacteria. Nowadays, many synthetic procedures allow the discovery of coumarins with expanded chemical space. The ability to exert noncovalent interactions with many enzymes and receptors in live organisms lead the coumarins to exhibit a wide range of biological activities and applications. Then, this manuscript provides an overview of the use of coumarins compounds in medicinal chemistry in treating many diseases. Important examples of the last years have been selected concerning the activities of coumarins as anticoagulant, anticancer, antioxidant, antiviral, anti-diabetics, anti-inflammatory, antibacterial, antifungal and anti-neurodegerative agents. Additionally, it also includes applications of coumarins as fluorescent sensors for biological systems. Thus, this work aims to contribute to the development of new rational research projects for the treatment and diagnosis of pathologies using coumarin derivatives.


Subject(s)
Coumarins/pharmacology , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anticoagulants/chemical synthesis , Anticoagulants/chemistry , Anticoagulants/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antioxidants/chemical synthesis , Antioxidants/chemistry , Antioxidants/pharmacology , Chemistry, Pharmaceutical , Coumarins/chemical synthesis , Coumarins/chemistry , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology
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