Original articleSynthesis, structure–activity relationship and in vitro anti-mycobacterial evaluation of 13-n-octylberberine derivatives
Graphical abstract
A novel series of 13-substituted berberine derivatives have been identified as potent antimytobacterial agents against both drug-susceptible and MDR strains of Mycobacterium tuberculosis.
Highlights
► 13-n-Octylberberine analogs are a promising novel class of antituberculars. ► n-Octyl group at position 13 might be essential for the activity. ► Compound 16e exhibited a potential activity against MDR strains of M. tuberculosis.
Introduction
Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. It is anticipated that there will be about 9.8 million new TB cases this year, more than in any other year in history [1], [2]. Five percent of all TB cases are now estimated to be multi-drug-resistant TB (MDR-TB), which is resistant to at least rifampin (RIF) and isoniazid (INH), the two most important first-line drugs used currently in clinic [3], [3](a), [3](b). The overall incidence of TB in HIV positive patients is 50 times that of the rate for HIV negative individuals [4], [5], [6]. In recent years, the emergence of MDR-TB and extensively-drug-resistant TB (XDR-TB) becomes one of the biggest challenges in the treatment of this disease. Although some TB drug candidates are being currently evaluated in clinical trials, there have been no approved new chemical entities for treatment of TB in the past 40 years [7], [7](a), [7](b). Therefore, there is an urgent need to discover the novel scaffold of anti-TB candiates with new mechanism of action, or without cross-resistance with current anti-mycobacterial drugs [7b].
In search for new chemical classes of anti-mycobacterial agents, the compound libraries constructed in our laboratories were screened against drug-susceptible Mycobacterium tuberculosis (M. tuberculosis) strain H37Rv with RIF and INH as reference drugs [8]. 13-n-Octylberberine (1, Fig. 1), identified from the library of berberines, appeared to show a moderate anti-tubercular activity with a MIC of 2.0 μg/mL (Table 1). In particular, compound 1 demonstrated a mild antimycobaterial activity (Table 2) against RIF- and INH-resistant strains isolated from patients in China (MIC = 4.0 μg/mL), suggesting a new mechanism of action [9]. Therefore, the new chemical entity and ideal actitity with no cross resistance of hit 1 provoked our strong interest to explore the structure–activity relationship (SAR) so as to discover candidates with novel mode of action for treatment of TB, especially MDR-TB.
Among the 13-substituted berberine analogs, compounds 2−9 (Fig. 1) showed no anti-mycobacterial activities against M. tuberculosis H37Rv in comparison with 1. The primary SAR analysis revealed that n-octyl side-chain at the 13-position of 1 might be essential for the bactericidal activity. Therefore, in the present study we retained the n-octyl group at position 13, and focused our SAR study on the variation of substituents at positions 2-, 3- and/or 9-position(s) with 1 as the lead. On the basis of this strategy, 28 new 13-n-octylberberine analogs were designed, synthesized and evaluated for their in vitro anti-tubercular activities against drug-susceptible and drug-resistant stains of M. tuberculosis.
Section snippets
Chemistry
Twenty-eight 13-n-octylberberine analogs were synthesized with commercially available berberine (2) as the starting material as described in Scheme 1, which includes three synthetic methods (Route A, B and C). The intermediate 10 was obtained via a selective reduction reaction, in which NaBH4 was used as a reducing agent and methanol as the solvent [10]. Then, the intermediate 10 reacted with n-octyl aldehyde in the solvent mixture of EtOH (80%) and HOAc, and then acidified with 2 N HCl to yield
SAR analysis for anti-mycobacterial activity
Twenty-eight 13-substituted berberine derivatives were first evaluated for their anti-tubercular activities against the multiplication of drug-susceptible M. tuberculosis strain H37Rv with the microplate alamar blue assay (MABA). RIF and INH were used as reference drugs. Structures of 28 analogs and their anti-mycobacterial activities are shown in Table 1.
SAR study was first focused on the substituents at the 9-position on the aromatic ring D of 1. Replacement methoxyl at the 9-position with
Conclusion
In conclusion, 28 new 13-n-octylberberines with different substituents on the ring A and D were synthesized and evaluated for their anti-mycobacterial activities against M. tuberculosis H37Rv with 1 as the lead. SAR analysis revealed that (i) n-octyl group at position 13 might be essential for the activity; (ii) introduction of substituents at the 2-, 3- and/or 9-positions, especially an ethoxyl, might significantly enhance the activity. Among the test compounds, compound 16e exhibited a
Chemistry
Melting point (mp) was obtained with CXM-300 melting point apparatus and uncorrected. The 1H NMR spectra was performed on a Varian Inova 400 MHz spectrometer (Varian, San Francisco, CA) and 13C NMR on a Bruker Avance III 400 spectrometer in CD3OD or DMSO-d6, with Me4Si as the internal standard. ESI high-resolution mass spectra (HRMS) were recorded on an Autospec UItima-TOF mass spectrometer (Micromass UK Ltd, Manchester, UK). Flash chromatography was performed on CombiflashRf 200 (Teledyne,
Biological activity
RIF and INH were purchased from Sigma Company. All of 13-n-octylberberine analogs were examined for their activities against the multiplication of drug-susceptible M. tuberculosis strain H37Rv with MABA at different concentration. Subsequent two-fold dilutions were performed in 100 μL of 7H9 media in the 48-well microplates, then added 100 μL of bacterial suspension to wells. The amount of bacteria to each well is 4 × 10−4 mg/mL. Plates were incubated at 37 °C. At optimal time, alamar blue
Acknowledgments
This work was supported by the National Natural Science Fundation for Young Scientists (81102312) and the National S&T Major Special Project on Major New Drug Innovation (2012ZX09301002−001−017).
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These authors made equal contributions to the work.