Synthesis of Antimicrobial Benzene-1,4-diol Analogues of a Benzoquinone Metabolite From the Endophytic Fungi Xylaria Sp. Pbr 30

Abstract

The ever increasing problem of microbial resistance to currently available antimicrobial agents has led to a pressing need for development of new therapeutic and disinfecting agents. Although bioactive natural products continue to be a new source of antimicrobial agents, their use as antimicrobial drugs has often been restricted due to their low potency and high toxicity. This has necessitated a rationalized mechanistic approach of structural modification of such bioactive natural products to improve their potency, pharmacodynamics and safety. In this study, benzene-1,4-diol analogues of a bioactive benzoquinone metabolite, 2-chloro-5-methoxy-3-methylcyclohexa-2,5-diene-1,4-dione (8), were synthesized and assessed for antimicrobial activity. Synthesis and antimicrobial evaluation of 2-chloro-5-methoxy-1,4-benzenediol (59), 2-chloro-5-methoxy-1,4-diacetate-1,4-benzenediol (60), 2-methoxy-1,4-benzenediol (79), 2,5-dichloro-1,4-benzenediol (81) and 2,5-dinitro-1,4-benzenediol (82) and their intermediates was achieved. Compounds 59 and 60 were the most active against Streptococcus infantarius with minimum inhibition at 25μg/disc each, 5-chloro-2-hydroxyaniline (62) was the most active against Candida albicans (minimum inhibition at 12.5μg/disc) while 79 was the most active against Staphyloccocus aureus and Escherichia coli with minimum inhibition at 12.5μg/disc and 25μg/disc, respectively. The in vitro antiplasmodial activity of compound 62, 5-chloro-2-methoxyacetanilide (61) and 5-chloro-2-hydroxyacetanilide (63) were found to fall within the WHO scale of active compounds with IC50 values of 2.70 ± 0.14, 2.85 ± 0.25 and 9.06 ± 1.09 μg/mL against the chloroquine sensitive 3D7 and 1.24 ± 0.47, 1.29 ± 0.48 and 7.09 ± 1.94 μg/mL against chloroquine sensitive D6 isolate, respectively. On the basis of the observed activity, it is recommended that these compounds be further optimized through structure modification to identify more potent antimicrobial and antiplasmodial compounds for drug discovery.