DNA sequence-selective C8-linked pyrrolobenzodiazepine(PBD)-heterocyclic polyamide conjugates show anti-tubercular specific activities

摘要

New chemotherapeutic agents with novel mechanisms of action are in urgent need to combat the tuberculosis pandemic. A library of twelve C8-linked pyrrolo[2,1-c][1,4]benzodiazepine(PBD)-heterocyclic polyamide conjugates (1-12) was evaluated for anti-tubercular activity and DNA sequence selectivity. The PBD-conjugates were screened against slow-growing Mycobacterium bovis BCG and M. tuberculosis H37Rv and fast-growing Escherichia coli, Pseudomonas putida and Rhodococcus sp. RHA1 bacteria. DNase I footprinting and DNA thermal denaturation experiments were used to determine the molecules’ DNA recognition properties. The PBD-conjugates were highly selective for the mycobacterial strains and exhibited significant growth inhibitory activity against the pathogenic M. tuberculosis H37Rv, with compound 4 showing MIC values (MIC = 0.08 mg/L) similar to those of rifampin and isoniazid. DNase I footprinting results showed that the PBD-conjugates with three heterocyclic moieties had enhanced sequence selectivity and produced larger footprints with distinct cleavage patterns compared to the two-heterocyclic chain PBD-conjugates. DNA melting experiments indicated a covalent binding of the PBD-conjugates to two AT-rich DNA-duplexes containing either a central GGATCC or GTATAC sequence and showed that the polyamide chains affect the interactions of the molecules with DNA. The PBD-C8-conjugates tested in this study have a remarkable anti-mycobacterial activity and can be further developed as DNA-targeted anti-tubercular drugs.