Abstract
Due to the emergence of multidrug-resistant pathogenic microorganisms, the search for novel antimicrobials is urgent. Inspired by marine alkaloids, a series of indolomethyl pyrazino [1,2-b]quinazoline-3,6-diones was prepared using a one-pot microwave-assisted multicomponent polycondensation of amino acids. The compounds were evaluated for their antimicrobial activity against a panel of nine bacterial strains and five fungal strains. Compounds 26 and 27 were the most effective against Staphylococcus aureus ATCC 29213 reference strain with MIC values of 4 μg mL−1, and a methicillin-resistant Staphylococcus aureus (MRSA) isolate with MIC values of 8 μg mL−1. It was possible to infer that enantiomer (−)-26 was responsible for the antibacterial activity (MIC 4 μg mL−1) while (+)-26 had no activity. Furthermore, compound (−)-26 was able to impair S. aureus biofilm production and no significant cytotoxicity towards differentiated and non-differentiated SH-SY5Y cells was observed. Compounds 26, 28, and 29 showed a weak antifungal activity against Trichophyton rubrum clinical isolate with MIC 128 μg mL−1 and presented a synergistic effect with fluconazole.
Highlights
Infectious diseases caused by microorganisms stand as a major threat to public health.[1]
In uenced by a large number of halogenated marine natural products with interesting antimicrobial activities isolated over the last few years,[29,38] in the present work (22–32, Fig. 1) we present a third approach through the introduction of halogen atoms in the aromatic ring of anthranilic acid (Ant) which led to the discovery of promising antimicrobial agents within this series
Regarding the structural complexity and synthetic pathways, the excellent and inspiring results obtained in the present study show that simpler molecules than neo scalin A (2) are quite promising to nd new agents to overcome MDR strains
Summary
Infectious diseases caused by microorganisms stand as a major threat to public health.[1]. Since antibiotics were rst introduced as medicines, these drugs have been used to prevent or treat infections in several applications.[2,3] antibacterial resistance has increased dramatically, becoming an emergency in healthcare during the last 40 years.[4,5,6] Among 50 emerging infectious agents that have been identi ed, 10% have developed resistance to multiple drugs including antibiotics such as vancomycin,[7,8] methicillin,[9] carbapenems,[10] and cephalosporins.[11,12,13] Despite enormous efforts, the number of therapeutically useful compounds aiming to circumvent resistance is continuously decreasing and no truly novel class of compounds has been introduced into therapy, causing the World to face the “post-antibiotic era”.14,15 In order to restrain the clinical consequences of the development and spread of antimicrobial resistance both the preservation of current antimicrobials through their appropriate use and the discovery and development of new agents are mandatory.[16]
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