Preprint Article Version 1 This version not peer reviewed

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

Version 1 : Received: 15 September 2017 / Approved: 15 September 2017 / Online: 15 September 2017 (17:34:38 CEST)

A peer-reviewed article of this Preprint also exists.

Kapp, E.; Visser, H.; Sampson, S.L.; Malan, S.F.; Streicher, E.M.; Foka, G.B.; Warner, D.F.; Omoruyi, S.I.; Enogieru, A.B.; Ekpo, O.E.; Zindo, F.T.; Joubert, J. Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents. Molecules 2017, 22, 1644. Kapp, E.; Visser, H.; Sampson, S.L.; Malan, S.F.; Streicher, E.M.; Foka, G.B.; Warner, D.F.; Omoruyi, S.I.; Enogieru, A.B.; Ekpo, O.E.; Zindo, F.T.; Joubert, J. Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents. Molecules 2017, 22, 1644.

Journal reference: Molecules 2017, 22, 1644
DOI: 10.3390/molecules22101644

Abstract

An in vitro medium-throughput screen using M. tuberculosis H37Rv was employed to screen an in-house library of structurally diverse compounds for antimycobacterial activity.  From 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 a 50 µM concentration.  This prompted further exploration of all the 7-substituted coumarins in our library, nineteen in total, as potential antimycobacterial agents. Four derivatives showed promising antimycobacterial activity with MIC99 values of 8.31 – 29.70 µM and 44.15 – 57.17 µM on M. tuberculosis H37Rv in independent assays using Gaste-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 antimycobacterial evaluation of moxifloxacin resistant M. tuberculosis show that these compounds are able to maintain their activity in fluoroquinolone resistant mycobacteria.   Analysis of structure activity relationships for antimycobacterial versus neuronal enzyme inhibitory activity indicate that structural modification on position 4 and/or 7 of the coumarin scaffold may be utilized to improve selectivity towards either inhibition of neuronal enzymes or antimycobacterial effect.  Cytotoxicity evaluations of the compounds indicate moderate cytotoxicity with slight selectivity towards mycobacteria.  Further neuroprotective assays on SH-SY5Y human neuroblastoma cells indicate 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/or neuroprotective agents.

Subject Areas

Coumarin; Mycobacterium tuberculosis; Cholinesterase inhibitor; Monoamine oxidase B inhibitor; Structure activity relationship; Albumin binding, Neuroprotection

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