Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(9), P. 1828 - 1881

Published: April 22, 2024

Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a–h), hydrazine monohydrate (NH2NH2•H2O) for regioselective preparation some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a–h). After synthesis characterization mentioned cinnolines (3a–h), in silico multi-targeting inhibitory properties these heterocyclic scaffolds investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2(G2019S), hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, hDHODH, which confirmed their functions roles neurodegenerative (NDs), based on molecular docking studies, obtained results were compared with wide range approved drugs well-known (with IC50, EC50, etc.) compounds. addition, ADMET prediction analysis was performed examine prospective drug synthesized compounds The from studies ADMET-related data demonstrated that series heteroaryl)-5,6-dihydrobenzo[h]cinnolines especially hit ones, can really be turned into potent core new treatment and/or due having reactionable locations, they able further organic reactions (such as cross-coupling reactions), expansion (for example, using other types monohydrates) makes avenue designing novel efficient purpose.

Language: Английский

---

In Vitro Evaluation of Novel Furo[3,2-c]coumarins as Cholinesterases and Monoamine Oxidases Inhibitors

Molecules, Journal Year: 2025, Volume and Issue: 30(8), P. 1830 - 1830

Published: April 18, 2025

Coumarin represents a privileged structural motif that is quite common in nature-derived and synthetic bioactive molecules. Some of us have recently described the straightforward preparation complex furo[3,2-c]coumarins through sequential double coupling protocol. Aiming at finding novel chemical probes for modulation key anti-Alzheimer's targets, small subset furo[3,2-c]coumarin prototypes their non-aromatic precursors were tested vitro as inhibitors ChEs (acetyl- butyrylcholinesterase, AChE BChE) MAOs (monoamine oxidases A B, MAO B). All compounds low-micromolar devoid toxic effects against SH-SY5Y cells. Lineweaver-Burk plots docking simulations suggested mixed-type kinetics inhibitor 3d (IC50 = 4.1 μM toward AChE). Its promising inhibitory profile encompasses additional, highly selective, activity monoamine oxidase with submicromolar IC50 value (561 nM).

Language: Английский

---

Synthesis, in vitro, and in silico studies of new derivatives of diphenylpiperazine scaffold: A key substructure for MAO inhibition

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 143, P. 107011 - 107011

Published: Dec. 2, 2023

Language: Английский

---

Study of the DNA damage and cell death in human peripheral blood mononuclear and HepG2/C3A cells exposed to the synthetic 3-(3-hydroxyphenyl)-7-hydroxycoumarin

Journal of Toxicology and Environmental Health, Journal Year: 2023, Volume and Issue: 87(1), P. 33 - 46

Published: Oct. 27, 2023

Hydroxycoumarins are an important source of biologically active compounds. Previous studies have shown that the number and position hydroxyl substituents in scaffold play role for observed biological activity. In present study, 3-(3-hydroxyphenyl)-7-hydroxycoumarin was synthesized, potential cytogenotoxic effects determined human HepG2/C3A cells displaying phase 1 2 enzymes (metabolizing cell ability) compared to peripheral blood mononuclear (PBMC) without xenobiotics metabolizing capacity. Cell viability with concentrations between 0.01 10 µg/ml using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) trypan blue tests. Genotoxicity utilizing comet assay, clastogenic/aneugenic employing micronucleus (MN) test. The results vitro cytotoxicity assays showed a significant decrease PBMC following exposure concentration studied compound after 48 72 hr. Comet assay observations noted DNA damage 4 hr treatment. No marked were found cells. chromosomal mutations both lines. It is note may exert beneficial pharmacological actions at low micromolar range half-life less than 24 Therefore, obtained encourage continuation on this new molecule medicinal purposes, but its toxicity higher longer times needs be investigated further studies.

Language: Английский

---

N-(coumarin-3-yl)cinnamamide Promotes Immunomodulatory, Neuroprotective, and Lung Function-Preserving Effects during Severe Malaria

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 17(1), P. 46 - 46

Published: Dec. 27, 2023

ANKA (PbA) infection in mice resembles several aspects of severe malaria humans, such as cerebral and acute respiratory distress syndrome. Herein, the effects

Language: Английский

---