Abstract:Thirteen isopropyl chalcones (CA1−CA13) were synthesized and evaluated for their inhibitory activity against monoamine oxidase (MAO). All compounds inhibited MAO-B more effectively than MAO-A. Compound CA4 most potently inhibited MAO-B with an IC 50 value of 0.032 μM, similar to that of CA3 (IC 50 = 0.035 μM) and with high selectivity index (SI) values for MAO-B over respectively). The −OH (CA4) or −F (CA3) group at the para position on the A ring provided higher MAO-B inhibition than that of the other substi… Show more
“…Residues Ile180, Asn181, Tyr197, Tyr407, and Tyr444 interacted with the isatin ring through hydrophobic and polar interactions. Its similar interaction with IS15 and harmine 62 during the binding contact demonstrated its potential to inhibit MAO-A. Figure 16 ( A ) 3-D visualization of superimposed orientations of IS3 (orange), IS6 (cyan) IS7 (violet), IS13 (blue), IS15 (green), and harmine (red) in the active site of MAO-A and the co-factor FAD (yellow).…”
Sixteen isatin-based hydrazone derivatives (IS1–IS16) were synthesized and assessed for their ability to inhibit monoamine oxidases (MAOs). All the molecules showed improved inhibitory MAO-B activity compared to MAO-A. Compound IS7 most potently inhibited MAO-B with an IC50 value of 0.082 μM, followed by IS13 and IS6 (IC50 = 0.104 and 0.124 μM, respectively). Compound IS15 most potently inhibited MAO-A with an IC50 value of 1.852 μM, followed by IS3 (IC50 = 2.385 μM). Compound IS6 had the highest selectivity index (SI) value of 263.80, followed by IS7 and IS13 (233.85 and 212.57, respectively). In the kinetic study, the Ki values of IS6, IS7, and IS13 for MAO-B were 0.068 ± 0.022, 0.044 ± 0.002, and 0.061 ± 0.001 μM, respectively, and that of IS15 for MAO-A was 1.004 ± 0.171 μM, and the compounds were reversible-type inhibitors. The lead compounds were central nervous system (CNS) permeable, as per parallel artificial membrane permeability assay (PAMPA) test results. The lead compounds were examined for their cytotoxicity and potential neuroprotective benefits in hazardous lipopolysaccharide (LPS)-exposed SH-SY5Y neuroblastoma cells. Pre-treatment with lead compounds enhanced anti-oxidant levels (SOD, CAT, GSH, and GPx) and decreased ROS and pro-inflammatory cytokine (IL-6, TNF-alpha, and NF-kB) production in LPS-intoxicated SH-SY5Y cells. To confirm the promising effects of the compound, molecular docking, dynamics, and MM-GBSA binding energy were used to examine the molecular basis of the IS7-MAO-B interaction. Our findings indicate that lead compounds are potential therapeutic agents to treat neurological illnesses, such as Parkinson's disease.
“…Residues Ile180, Asn181, Tyr197, Tyr407, and Tyr444 interacted with the isatin ring through hydrophobic and polar interactions. Its similar interaction with IS15 and harmine 62 during the binding contact demonstrated its potential to inhibit MAO-A. Figure 16 ( A ) 3-D visualization of superimposed orientations of IS3 (orange), IS6 (cyan) IS7 (violet), IS13 (blue), IS15 (green), and harmine (red) in the active site of MAO-A and the co-factor FAD (yellow).…”
Sixteen isatin-based hydrazone derivatives (IS1–IS16) were synthesized and assessed for their ability to inhibit monoamine oxidases (MAOs). All the molecules showed improved inhibitory MAO-B activity compared to MAO-A. Compound IS7 most potently inhibited MAO-B with an IC50 value of 0.082 μM, followed by IS13 and IS6 (IC50 = 0.104 and 0.124 μM, respectively). Compound IS15 most potently inhibited MAO-A with an IC50 value of 1.852 μM, followed by IS3 (IC50 = 2.385 μM). Compound IS6 had the highest selectivity index (SI) value of 263.80, followed by IS7 and IS13 (233.85 and 212.57, respectively). In the kinetic study, the Ki values of IS6, IS7, and IS13 for MAO-B were 0.068 ± 0.022, 0.044 ± 0.002, and 0.061 ± 0.001 μM, respectively, and that of IS15 for MAO-A was 1.004 ± 0.171 μM, and the compounds were reversible-type inhibitors. The lead compounds were central nervous system (CNS) permeable, as per parallel artificial membrane permeability assay (PAMPA) test results. The lead compounds were examined for their cytotoxicity and potential neuroprotective benefits in hazardous lipopolysaccharide (LPS)-exposed SH-SY5Y neuroblastoma cells. Pre-treatment with lead compounds enhanced anti-oxidant levels (SOD, CAT, GSH, and GPx) and decreased ROS and pro-inflammatory cytokine (IL-6, TNF-alpha, and NF-kB) production in LPS-intoxicated SH-SY5Y cells. To confirm the promising effects of the compound, molecular docking, dynamics, and MM-GBSA binding energy were used to examine the molecular basis of the IS7-MAO-B interaction. Our findings indicate that lead compounds are potential therapeutic agents to treat neurological illnesses, such as Parkinson's disease.
“…A number of hydrophobic amino acids interacted with compound 9 d , including Phe168, Leu171, Cys172, Ile198, Ile199, Tyr326, Phe343, Tyr398, Tyr435, and Tyr435.The OH group at the para position of ring A and isopropyl tails at the para position of ring B is essential for effective inhibition against hMAO−B than other substitutions. Thus, from this study compound 9 d can be used as effective treatment for PD Figure 11 [106] …”
Section: Molecular Dynamic Study Of Chalcones Coumarins and Chromones...mentioning
Molecular dynamics (MD) simulation is an in silico method used in the biomolecular level of research to study how the protein interacts with the target with time. It provides a detailed information of the protein dynamics and ligand structure with the crucial amino acid interactions. Monoamine oxidase B (MAO−B) is a crucial isoenzyme responsible for the catalyses of oxidative deamination of various biogenic amines in the brain and peripheral tissues. The selective inhibitors of MAO−B are considered as the management of symptoms of neurodegenerative disorders like Alzheimer's disease(AD) and Parkinson disease(PD). Recently the structural scaffolds containing chalcones, coumarins and chromones derived candidates shown potent, selective, competitive and reversible type of MAO−B inhibitors. The structural similarities between the above scaffolds can produce almost similar type of interactions in the inhibitor binding cavity of MAO−B. Numerous molecular simulation reports were supported by the above mentioned fact. The current review focus on the last ten year molecular dynamics report of chalcones, coumarins and chromones towards MAO−B inhibition. The review also focuses on the software details used in the MD dynamics simulation and the structural requirement from each class of compound for the recognition of MAO−B inhibitory activity.
“…Shifting of benzyloxy pharmacophore from ortho to para position may accommodate more steric hindrance, nearer to the α, β‐unsaturated system. This would probably make less binding interactions in the active MAO‐B site (Kumar et al, 2023; Sudevan, Oh, et al, 2022).…”
Eight derivatives of benzyloxy‐derived halogenated chalcones (BB1‐BB8) were synthesized and tested for their ability to inhibit monoamine oxidases (MAOs). MAO‐A was less efficiently inhibited by all compounds than MAO‐B. Additionally, the majority of the compounds displayed significant MAO‐B inhibitory activities at 1 μM with residual activities of less than 50%. With an IC50 value of 0.062 μM, compound BB4 was the most effective in inhibiting MAO‐B, followed by compound BB2 (IC50 = 0.093 μM). The lead molecules showed good activity than the reference MAO‐B inhibitors (Lazabemide IC50 = 0.11 μM and Pargyline Pargyline IC50 = 0.14). The high selectivity index (SI) values for MAO‐B were observed in compounds BB2 and BB4 (430.108 and 645.161, respectively). Kinetics and reversibility experiments revealed that BB2 and BB4 were reversible competitive MAO‐B inhibitors with Ki values of 0.030 ± 0.014 and 0.011 ± 0.005 μM, respectively. Swiss target prediction confirmed the high probability in the targets of MAO‐B for both compounds. Hypothetical binding mode revealed that the BB2 or BB4 is similarly oriented to the binding cavity of MAO‐B. Based on the modelling results, BB4 showed a stable confirmation during the dynamic simulation. From these results, it was concluded that BB2 and BB4 were potent selective reversible MAO‐B inhibitors and they can be considered drug candidates for treating related neurodegenerative diseases such as Parkinson's disease.
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