کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1395639 | 1501132 | 2014 | 26 صفحه PDF | دانلود رایگان |
• Copper(I)-catalyzed azide–alkyne cycloaddition as synthetic method of new rifamycin derivatives.
• Intramolecular heterocyclisation of rifamycin “aromatic core”.
• Most activity: antibacterial at 0.03 nmol/mL; antitubercular at 0.006 nmol/mL.
• Determined logP, water solubility and molecular docking indicated mechanism of action.
• Rigidity and basicity of substituent at C(3) is important in high biological activity.
Thirty four novel derivatives of 3-formylrifamycin SV were synthesized via reductive alkylation and copper(I)-catalysed azide–alkyne cycloaddition. According to the obtained results, ‘click chemistry’ can be successfully applied for modification of structurally complex antibiotics such as rifamycins, with the formation of desired 1,2,3-triazole products. However, when azide–alkyne cycloaddition on 3-formylrifamycin SV derivatives demanded higher amount of catalyst, lower temperature and longer reaction time because of the high volatility of substrates, an unexpected intramolecular condensation with the formation of 3,4-dihydrobenzo[g]quinazoline heterocyclic system took place. Structures of new derivatives in solution were determined using one- and two-dimensional NMR methods and FT-IR spectroscopy. Computational DFT and PM6 methods were employed to correlate their conformation and acid–base properties to biological activity and establish SAR of the novel compounds. Microbiological, physico-chemical (logP, solubility) and structural studies of newly synthesised rifamycins indicated that for the presence of relatively high antibacterial (MIC ∼0.01 nmol/mL) and antitubercular (MIC ∼0.006 nmol/mL) activities, a rigid and basic substituent at C(3) arm, containing a protonated nitrogen atom “open” toward intermolecular interactions, is required.
Synthesis of novel functionalized at C(3) carbon derivatives of 3-formylrifamycin SV and their antibacterial and antitubercular potency in view of mechanism of action.Figure optionsDownload as PowerPoint slide
Journal: European Journal of Medicinal Chemistry - Volume 84, 12 September 2014, Pages 651–676