Evaluation of Pseudopteroxazole and Pseudopterosin Derivatives against Mycobacterium tuberculosis and Other Pathogens

Abstract

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 in vitro antimicrobial and cytotoxic activities. A number of congeners exhibited antimicrobial activity against a range of Gram-positive bacteria including Mycobacterium tuberculosis H37Rv, with four displaying notable antitubercular activity against both replicating and non-replicating persistent forms of M. tuberculosis. One new semi-synthetic compound, 21-((1H-imidazol-5-yl)methyl)-pseudopteroxazole (7a), was more potent than the natural products pseudopterosin and pseudopteroxazole and exhibited equipotent activity against both replicating and non-replicating persistent forms of M. tuberculosis with a near absence of in vitro cytotoxicity. Pseudopteroxazole also exhibited activity against strains of M. tuberculosis H37Rv resistant to six clinically used antibiotics.

Nordihydroguaiaretic acid (NDGA) and α-mangostin inhibit the growth of Mycobacterium tuberculosis by inducing autophagy

“…One way to develop new drugs is by studying the biological activity of natural products, semi-synthesis or the generation of new compounds [6][7][8][9]. The great diversity of natural compounds represents a powerful tool for drug discovery; such compounds could be applied, as new drugs with potential antimicrobial activity themselves or by a modulating the immune response to enhance the removal of the infective agent [10].…”

Antimycobacterial Metabolites from Marine Invertebrates

“…These results inspired synthetic studies on pseudopteroxazole derivatives and the continuing quest for antimycobacterial compounds from the gorgonian P. elisabethae . Acquired semi‐synthetic congeners possessing a lipophilic moiety at C‐21 showed decreased activity against mycobacterial model organisms ( M. smegmatis and M. diernhoferi ), thus suggesting that the substituents play an important role for the activity . In a study by McCulloch et al in 2012, a series of novel synthesized pseudopteroxazole and isopseudopteroxazole (regioisomers with changed location of N and O in the attached heterocycle) derivatives were analyzed for their activity against virulent M. tuberculosis strain H37Rv, indicating that variability in the substitution at C‐9 and/or C‐10 is not crucial for the antimycobacterial activity .…”

“…Acquired semi‐synthetic congeners possessing a lipophilic moiety at C‐21 showed decreased activity against mycobacterial model organisms ( M. smegmatis and M. diernhoferi ), thus suggesting that the substituents play an important role for the activity . In a study by McCulloch et al in 2012, a series of novel synthesized pseudopteroxazole and isopseudopteroxazole (regioisomers with changed location of N and O in the attached heterocycle) derivatives were analyzed for their activity against virulent M. tuberculosis strain H37Rv, indicating that variability in the substitution at C‐9 and/or C‐10 is not crucial for the antimycobacterial activity . Aside from diterpenes with an oxazole moiety from the West Indian sea whip P. elisabethae , two serrulatane‐like diterpenes were isolated, erogorgiaene ( 20 ) and 7‐hydroxyerogorgiaene ( 21 ), which displayed 96 and 77% growth inhibition of M. tuberculosis at 12.5 and 6.25 μg/mL, respectively, demonstrating that the hydroxy group at C‐7 does not diminish the antimycobacterial activity of these compounds .…”

Total synthesis of the pseudopterosin aglycones

“…In an attempt to compare syntheses fairly, total step count -reported as longest linear sequence -and yields are measured from commercially available starting materials by incorporating details from these referenced literature procedures. We have elected not to include synthetic studies towards the pseudopterosins that have not yet achieved the final target, [15][16][17][18][19][20][21][22][23][24][25][26][27][28] or the synthesis of simplified analogues [29][30][31][32] (including biosynthetic precursors), [33][34][35][36][37] or the synthesis of the originally proposed structure of the G-J aglycone. 38,39 We begin by presenting biosynthetic considerations, followed by an analysis of structure-goal based approaches (divided into terpene and aromatic starting materials), and we conclude with the recent transform-based strategy.…”