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Sulfanylphthalonitrile analogues as selective and potent inhibitors of monoamine oxidase B.
Bioorg Med Chem Lett. 2012 Dec 15; 22(24):7367-70.BM

Abstract

It has recently been reported that nitrile containing compounds frequently act as potent monoamine oxidase B (MAO-B) inhibitors. Modelling studies suggest that this high potency inhibition may rely, at least in part, on polar interactions between nitrile functional groups and polar moieties within the MAO-B substrate cavity. In an attempt to identify potent and selective inhibitors of MAO-B and to contribute to the known structure-activity relationships of MAO inhibition by nitrile containing compounds, the present study examined the MAO inhibitory properties of series of novel sulfanylphthalonitriles and sulfanylbenzonitriles. The results document that the evaluated compounds are potent and selective MAO-B inhibitors with most homologues possessing IC(50) values in the nanomolar range. In general, the sulfanylphthalonitriles exhibited higher binding affinities for MAO-B than the corresponding sulfanylbenzonitrile homologues. Among the compounds evaluated, 4-[(4-bromobenzyl)sulfanyl]phthalonitrile is a particularly promising inhibitor since it displayed a high degree of selectivity (8720-fold) for MAO-B over MAO-A, and potent MAO-B inhibition (IC(50)=0.025 μM). Based on these observations, this structure may serve as a lead for the development of therapies for neurodegenerative disorders such as Parkinson's disease.

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Authors+Show Affiliations

Van der Walt MM
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Terre'Blanche G
No affiliation info available
Lourens AC
No affiliation info available
Petzer A
No affiliation info available
Petzer JP
No affiliation info available

MeSH

Dose-Response Relationship, DrugHumansMolecular ConformationMonoamine OxidaseMonoamine Oxidase InhibitorsNitrilesPhthalic AcidsStructure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23122857

Citation

Van der Walt, Mietha M., et al. "Sulfanylphthalonitrile Analogues as Selective and Potent Inhibitors of Monoamine Oxidase B." Bioorganic & Medicinal Chemistry Letters, vol. 22, no. 24, 2012, pp. 7367-70.
Van der Walt MM, Terre'Blanche G, Lourens AC, et al. Sulfanylphthalonitrile analogues as selective and potent inhibitors of monoamine oxidase B. Bioorg Med Chem Lett. 2012;22(24):7367-70.
Van der Walt, M. M., Terre'Blanche, G., Lourens, A. C., Petzer, A., & Petzer, J. P. (2012). Sulfanylphthalonitrile analogues as selective and potent inhibitors of monoamine oxidase B. Bioorganic & Medicinal Chemistry Letters, 22(24), 7367-70. https://doi.org/10.1016/j.bmcl.2012.10.070
Van der Walt MM, et al. Sulfanylphthalonitrile Analogues as Selective and Potent Inhibitors of Monoamine Oxidase B. Bioorg Med Chem Lett. 2012 Dec 15;22(24):7367-70. PubMed PMID: 23122857.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sulfanylphthalonitrile analogues as selective and potent inhibitors of monoamine oxidase B. AU - Van der Walt,Mietha M, AU - Terre'Blanche,Gisella, AU - Lourens,Anna C U, AU - Petzer,Anél, AU - Petzer,Jacobus P, Y1 - 2012/10/22/ PY - 2012/08/27/received PY - 2012/10/10/revised PY - 2012/10/15/accepted PY - 2012/11/6/entrez PY - 2012/11/6/pubmed PY - 2013/5/22/medline SP - 7367 EP - 70 JF - Bioorganic & medicinal chemistry letters JO - Bioorg Med Chem Lett VL - 22 IS - 24 N2 - It has recently been reported that nitrile containing compounds frequently act as potent monoamine oxidase B (MAO-B) inhibitors. Modelling studies suggest that this high potency inhibition may rely, at least in part, on polar interactions between nitrile functional groups and polar moieties within the MAO-B substrate cavity. In an attempt to identify potent and selective inhibitors of MAO-B and to contribute to the known structure-activity relationships of MAO inhibition by nitrile containing compounds, the present study examined the MAO inhibitory properties of series of novel sulfanylphthalonitriles and sulfanylbenzonitriles. The results document that the evaluated compounds are potent and selective MAO-B inhibitors with most homologues possessing IC(50) values in the nanomolar range. In general, the sulfanylphthalonitriles exhibited higher binding affinities for MAO-B than the corresponding sulfanylbenzonitrile homologues. Among the compounds evaluated, 4-[(4-bromobenzyl)sulfanyl]phthalonitrile is a particularly promising inhibitor since it displayed a high degree of selectivity (8720-fold) for MAO-B over MAO-A, and potent MAO-B inhibition (IC(50)=0.025 μM). Based on these observations, this structure may serve as a lead for the development of therapies for neurodegenerative disorders such as Parkinson's disease. SN - 1464-3405 UR - https://www.unboundmedicine.com/medline/citation/23122857/Sulfanylphthalonitrile_analogues_as_selective_and_potent_inhibitors_of_monoamine_oxidase_B_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-894X(12)01361-3 DB - PRIME DP - Unbound Medicine ER -