Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis, affects an estimated 10 million people worldwide, causing around 2 million human deaths yearly. The emergence of multi-drug resistant strains and lack of new drugs significantly contribute to the tuberculosis pandemic, and new chemotherapeutic agents with novel mechanisms of action are urgently required to fight this global health threat. The aim of this study was to synthesise and evaluate for biological activity a small library of C8-linked pyrrolo[2,1-c][1,4]benzodiazepine(PBD)-5′-O-[N-(salicyl)sulfamoyl]adenosine(Sal-AMS) conjugates (1-4) comprised of a PBD unit tethered to a Sal-AMS moiety through small-chain polyethylene glycol (PEG) linkers. The rationale for the design of 1-4 was provided by our recent findings that PBD-C8-polyamides, which are DNA sequence-selective binding agents, exhibited significant growth inhibitory activity against M. tuberculosis (H37Rv) and M. bovis (BCG), albeit with some degrees of mammalian cell toxicity. Therefore, we have postulated that linking the PBD unit to Sal-AMS, a potent anti-tuberculosis agent with an excellent therapeutic index, would provide highly-effective, safer anti-tubercular agents with a two-fold mechanism of action. Upon selective uptake by M. tuberculosis, Sal-AMS exerts its activity by inhibiting MbtA, a newly emerging TB enzyme-target involved in the biosynthesis of mycobacterial iron-chelators essential for virulence and growth. Multipharmacophore-containing antibiotics might have the clear advantages of slowing-down drug resistance development, broadening the antimycobacterial spectrum and potentially reducing drug cytotoxicity. Herein, the synthesis of the four novel PBD-Sal-AMS conjugates 1-4 is reported through a convergent approach. The PBD and Sal-AMS units were independently synthesised and joined through four short-chain PEG(4-6) spacers, each containing distal-end reactive groups for attaching the two therapeutic payloads. Notably, a novel oxidation method was used to access the PBD 1,4-diazepine ring. Conjugates 1-4 are currently undergoing DNA- and MbtA-binding activity evaluation and will be tested in vitro for M. tuberculosis growth inhibitory activity and human cell cytotoxicity.

Rational design, synthesis and preliminary biological evaluation of novel C8-linked pyrrolobenzodiazepine-5′-O-[N-(salicyl)sulfamoyl]adenosine conjugates (PBD-Sal-AMS) as anti-tubercular probes with dual mode of action

254th National Meeting (2017)

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