Syntheses and anti-MRSA activities of the C3 analogs of mansonone F, a potent anti-bacterial sesquiterpenoid: insights into its structural requirements for anti-MRSA activity
Syntheses and excellent anti-MRSA activities of the mansonone F analogs are reported. In addition, the minimal structural requirements for its anti-MRSA activities as well as its structure–activity relationship including the C3 substituents effects on anti-MRSA activity are also described.
Introduction
During the last two decades, the increasing prevalence of antibiotic-resistant bacteria has had an enormous impact on infection control policies.1 In particular, the resistance to multiple antibiotics of Gram-positive bacterial strains, methicillin-resistant Staphylococcus aureus (MRSA), is currently considered as serious clinical problem. Even though vancomycin and teicoplanin of glycopeptide antibiotics,2 quinupristin/dalfopristin,3 and linezolid4 of new antibiotics are clinically used for the treatment of MRSA infections, the structural complexity or toxic side effects of these antibiotics as well as the recent occurrences of new resistant strains have prompted the increased efforts for novel antibiotics. Thus, the discovery of novel classes of anti-bacterial agents employing new mode of action is of great concern due to the rapid acquirement of multidrug resistance by Gram-positive pathogens.
Recently, one of the major efforts in our laboratory has been the search, design, and synthesis of novel and highly potent anti-MRSA agents. In this connection, we have recently reported isolation and excellent anti-MRSA activity of mansonone F (1), a new anti-bacterial sesquiterpenoid.5 It has been shown to have excellent anti-bacterial activities against Gram-positive bacteria, MRSA (2 μg/mL of MIC90 in vitro), which is comparable to that of vancomycin. The unique structure of Mansonone F consists of oxaphenalene skeleton and ortho-naphthoquinone moiety (Fig. 1).
We herein report syntheses and anti-MRSA activities of the C3 mansonone F analogs. In addition, we describe its structure–activity relationship, which revealed the minimal structural requirements for anti-MRSA activity and C3 substituents effects.
The mechanism of anti-bacterial activity of mansonone F has not been completely elucidated yet. However, on the basis of structural features of mansonone F, its anti-MRSA activities can be understood by two possible mode of actions.6 The first mechanism involves generation of superoxide, particularly cytotoxic superoxide radical, which was reported for anti-bacterial and anti-protozoal activities of several naphthoquinones and isoxazolyl naphthoquinones.7 However, we have observed that no strains survived when we cultured the strain of S. aureus over the MIC of mansonone F in the presence of 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron, SIGMA), a specific superoxide scavenger. This supported that the anti-bacterial activity of mansonone F is not mainly due to the production of cytotoxic superoxide radical. The possible alternative mechanism is an attack of certain nucleophile such as thiol, amine, or alcohol of the bacterial growth-related enzymes to the enedione carbonyl of mansonone F, thus rendering the corresponding enzyme inactive although base stacking or intercalation of the planar oxaphenalene system in bacterial DNA is also possible.8 This is partly supported by recent report in several literatures of 1,2 or 1,4-addition of thiol and nitrogen nucleophile to quinone moiety.9 Thus, these recent information gave us a starting point for the studies on structure–activity relationship of mansonone F that was initially focused on the identification of pharmacophoric parts of mansonone F and the role of C-ring system including C3 substituents effects on anti-bacterial effect.
Section snippets
Chemistry
Most of the structural analogs were synthesized starting from the intermediate 5 or 8 according to the divergent synthetic routes as shown in Scheme 1, Scheme 2. The known analogs 2 and 3, which are devoid of ortho-quinone moiety, were prepared from the tricyclic ketone 85a and the benzoquinone analog 4 as an A-ring equivalent of mansonone F is commercially available.
The analog 7, which consists of A,B-ring skeleton of mansonone F, was prepared by four steps sequence as shown in Scheme 1. O
Results and discussion
The in vitro anti-bacterial activities of the synthesized analogs along with the reference compounds were assayed against 140 MRSA strains according to the standard procedure, and the minimal inhibitory concentrations (MIC50, MIC90) are listed in Table 1.[10], [11]
The analogs 2 and 3 of which C7-hydrogen or C7-nitro group replaces the dicarbonyl moiety of mansonone F exhibit no anti-bacterial activities against MRSA even at more than 100 μg/mL. The analogs 4 and 7, which are devoid of C-ring or
Acknowledgements
This research was supported by Grant from Center for Bioactive Molecular Hybrids, Yonsei University.
References (11)
- et al.
Clin. Ther.
(2001) - et al.
J. Med. Chem.
(2001)et al.J. Org. Chem.
(1996)et al.J. Org. Chem.
(1999)et al.Chem. Pharm. Bull.
(1998) Methicillin-Resistant Staphylococcus aureus
(1992)Med. Res. Rev.
(2001)- et al.
Angew. Chem., Int. Ed.
(2003)
Cited by (41)
Rhodium-Catalyzed Dual C−H Activation for Regioselective Triple Annulation of Enaminones: Access to Polycyclic Naphthopyran Derivatives
2023, Advanced Synthesis and CatalysisHydroxyl-Directed Iridium-Catalyzed Synthesis of Pyrano[2,3,4-de]chromen-2-ones and Further Chalcogenation under Blue-Light Irradiation
2022, European Journal of Organic ChemistrySimple Strategy for Benzo[de]chromene-7,8-dione Synthesis via Tandem Sonogashira Coupling and Intramolecular Cyclization Reactions
2022, Asian Journal of Organic ChemistryPhytochemicals with activity against methicillin-resistant Staphylococcus aureus
2022, PhytomedicineCitation Excerpt :The MIC values of 18 terpenoids are less than 100 μg/ml, and four terpenoids (ursolic acid, oleanolic acid, salvipisone, aethiopinone) show synergistic activity in combination with antibiotic drugs. A series of mansonone F analogs revealed that both the ortho-quinone and tricyclic moieties of mansonone F were essential for their excellent anti-MRSA activities (Shin et al., 2004). Nine phenols, five cannabinoids, five coumarins, four quinones, three xanthones, 2 xanthenes, 2 diels-alder-type adducts, 1 pyridine and 1 phenylpropionic acid were also summarized due to their excellent activity and unique mechanism.