Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents

Molecules

卷:22

Samantha L. Sampson¹  Hanri Visser¹  Elizabeth M. Streicher¹  Okobi E. Ekpo²  Sylvester I. Omoruyi²  Adaze B. Enogieru²  Digby F. Warner³  Erika Kapp⁴  Sarel F. Malan⁴  Frank T. Zindo⁴  Jacques Joubert⁴  Germaine B. Foka⁴ 

[1] DST/NRF Centre of Excellence in Biomedical Tuberculosis Research, SA MRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, Tygerberg 7505, South Africa;

[2] Department of Medical Biosciences, University of the Western Cape, Cape Town, Bellville 7550, South Africa;

[3] Medical Research Council/National Health Laboratory Service/University of Cape Town Molecular Mycobacteriology Research Unit, Department of Science and Technology/National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research, Institute of Infectious Disease and Molecular Medicine and Department of Clinical Laboratory Sciences, University of Cape Town, Cape Town, Rondebosch 7700, South Africa;

[4] School of Pharmacy, Faculty of Natural Sciences, University of the Western Cape, Cape Town, Bellville 7550, South Africa;

关键词: coumarin;    Mycobacterium tuberculosis;    cholinesterase inhibitor;    monoamine oxidase B inhibitor;    structure-activity relationship;    albumin binding;    neuroprotection;   

DOI  :  10.3390/molecules22101644

来源: DOAJ

【 摘 要 】

A medium-throughput screen using Mycobacterium tuberculosis H37Rv was employed to screen an in-house library of structurally diverse compounds for antimycobacterial activity. In this initial screen, eleven 7-substituted coumarin derivatives with confirmed monoamine oxidase-B and cholinesterase inhibitory activities, demonstrated growth inhibition of more than 50% at 50 µM. This prompted further exploration of all the 7-substituted coumarins in our library. Four compounds showed promising MIC99 values of 8.31–29.70 µM and 44.15–57.17 µM on M. tuberculosis H37Rv in independent assays using GAST-Fe and 7H9+OADC media, respectively. These compounds were found to bind to albumin, which may explain the variations in MIC between the two assays. Preliminary data showed that they were able to maintain their activity in fluoroquinolone resistant mycobacteria. Structure-activity relationships indicated that structural modification on position 4 and/or 7 of the coumarin scaffold could direct the selectivity towards either the inhibition of neuronal enzymes or the antimycobacterial effect. Moderate cytotoxicities were observed for these compounds and slight selectivity towards mycobacteria was indicated. Further neuroprotective assays showed significant neuroprotection for selected compounds irrespective of their neuronal enzyme inhibitory properties. These coumarin molecules are thus interesting lead compounds that may provide insight into the design of new antimicrobacterial and neuroprotective agents.

【 授权许可】

Unknown