title: Synthesis and biological evaluation of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives.
abstract: Research activities on the oxazolidinone antibacterial class of compounds continue to focus on developing newer derivatives with improved potency, broad-spectrum activity and safety profiles superior to linezolid. Among the safety concerns with the oxazolidinone antibacterial agents is inhibition of monoamine oxidases (MAO) resulting from their structural similarity with toloxatone, a known MAO inhibitor. Diverse substitution patterns at the C-5 position of the oxazolidinone ring have been shown to significantly affect both antibacterial activity and MAO inhibition to varying degrees. Also, the antibacterial activity of compounds containing iron-chelating functionalities, such as the hydroxamic acids, 8-hydroxyquinolines and catechols have been correlated to their ability to alter iron intake and/or metabolism. Hence a series of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives were synthesized and evaluated for their antibacterial and MAO-A and -B inhibitory activities. The compounds were devoid of significant antibacterial activity but most demonstrated moderate MAO-A and -B inhibitory activities. Computer modeling studies revealed that the lack of potent antibacterial activity was due to significant steric interaction between the hydroxamic acid N-OH oxygen atom and one of the G2540 5'-phosphate oxygen atoms at the bacterial ribosomal binding site. Therefore, the replacement of the 5-acetamidomethyl group of linezolid with the 5-(N-hydroxyacetamido)methyl group present in the hydroxamic acid oxazolidinone derivatives was concluded to be detrimental to antibacterial activity. Furthermore, the 5-(hydroxamic acid)methyl oxazolidinone derivatives were also less active as MAO-A and -B inhibitors compared with linezolid and the selective inhibitors clorgyline and pargyline. In general, the 5-(hydroxamic acid)methyl oxazolidinone derivatives demonstrated moderate but selective MAO-B inhibitory activity.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait. Electronic address: dphillips@hsc.edu.kw.
authors.forename: Oludotun A
authors.initials: OA
authors.lastname: Phillips
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait. Electronic address: roselyn.dsilva@gmail.com.
authors.forename: Roselyn
authors.initials: R
authors.lastname: D'Silva
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine & Science, North Chicago 60064, USA. Electronic address: bahta26@yahoo.com.
authors.forename: Teklu O
authors.initials: TO
authors.lastname: Bahta
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait. Electronic address: ls20504@hsc.edu.kw.
authors.forename: Leyla H
authors.initials: LH
authors.lastname: Sharaf
authors.affiliation: Department of Microbiology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait. Electronic address: edet@hsc.edu.kw.
authors.forename: Edet E
authors.initials: EE
authors.lastname: Udo
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait. Electronic address: lbenov@hsc.edu.kw.
authors.forename: Ludmil
authors.initials: L
authors.lastname: Benov
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine & Science, North Chicago 60064, USA. Electronic address: Eric.Walters@RosalindFranklin.edu.
authors.forename: D
authors.initials: D
authors.lastname: Eric Walters
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023303:Oxazolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; D008996:Monoamine Oxidase Inhibitors; D023303:Oxazolidinones; D008995:Monoamine Oxidase
keywords: (N-Hydroxyalkanamido)methyl-oxazolidinones; Antibacterial activity; Gram-negative bacteria; Gram-positive bacteria; Hydroxamic acid oxazolidinones; Monoamine oxidases inhibition