Structure and evaluation of antibacterial and antitubercular properties of new basic and heterocyclic 3-formylrifamycin SV derivatives obtained via ‘click chemistry’ approach

Abstract

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.