Evaluation of Pseudopteroxazole and Pseudopterosin Derivatives against <em>Mycobacterium</em> <em>tuberculosis</em> and Other Pathogens

• Main Authors: Malcolm W. B. McCulloch, Brad Haltli, Douglas H. Marchbank, Russell G. Kerr
• Format: Article
• Language: English
• Published: MDPI AG 2012-08-01
• Series: Marine Drugs
• Subjects: pseudopteroxazoles; semi-synthesis; <em>Mycobacterium</em> <em>tuberculosis</em> antibiotic-resistance
• Online Access: http://www.mdpi.com/1660-3397/10/8/1711

Pseudopterosins and pseudopteroxazole are intriguing marine natural products that possess notable antimicrobial activity with a commensurate lack of cytotoxicity. New semi-synthetic pseudopteroxazoles, pseudopteroquinoxalines and pseudopterosin congeners along with simple synthetic mimics of the terpene skeleton were synthesized. In order to build structure-activity relationships, a set of 29 new and previously reported compounds was assessed for <em>in</em> <em>vitro</em> antimicrobial and cytotoxic activities. A number of congeners exhibited antimicrobial activity against a range of Gram-positive bacteria including <em>Mycobacterium</em> <em>tuberculosis</em> H<sub>37</sub>Rv, with four displaying notable antitubercular activity against both replicating and non-replicating persistent forms of <em>M.</em> <em>tuberculosis</em>. One new semi-synthetic compound, 21-((1<em>H</em>-imidazol-5-yl)methyl)-pseudopteroxazole (<strong>7a</strong>), was more potent than the natural products pseudopterosin and pseudopteroxazole and exhibited equipotent activity against both replicating and non-replicating persistent forms of <em>M.</em> <em>tuberculosis</em> with a near absence of <em>in</em> <em>vitro</em> cytotoxicity. Pseudopteroxazole also exhibited activity against strains of <em>M.</em> <em>tuberculosis</em> H<sub>37</sub>Rv resistant to six clinically used antibiotics.