Single-step synthesis and in vitro anti-mycobacterial activity of novel nitrofurantoin analogues

• Synthesis of a series of n -alkyl and aryl nitrofurantoin analogues. • Evaluation of antimycobacterial H37Rv activity and cytotoxicity. • n -Octyl analogue 9, MIC 90 = 0.5 μM, was 30-fold more potency than nitrofurantoin. • Analogue 9 , 100-Fold more selective towards Mtb , stood as anti-TB validated hit. The emergence of drug-resistant tuberculosis (DR-TB) as well as the requirement for long, expensive and toxic drug regimens impede efforts to control and eliminate TB. Therefore, there’s a need for effective and affordable anti-mycobacterial agents which can shorten the duration of therapy and are active against Mycobacterium tuberculosis ( Mtb ) in both active and latent phases. Nitrofurantoin (NFT) is a hypoxic agent with activity against a myriad of anaerobic pathogens and, like the first-line TB drug, rifampicin (RIF), kills non-replicating bacilli. However, the poor ability of NFT to cross host cell membranes and penetrate tissue means that it does not reach therapeutic concentrations. To improve TB efficacy of NFT, a series of NFT analogues was synthesized and evaluated in vitro for anti-mycobacterial activity against the laboratory strain, Mtb H37Rv, and for potential cytotoxicity using human embryonic kidney (HEK-293) and Chinese hamster ovarian (CHO) cells. The NFT analogues showed good safety profiles, enhanced anti-mycobacterial potency, improved lipophilicity, as well as reduced protein binding affinity. Analogue 9 which contains an eight carbon aliphatic chain was the most active, equipotent to isoniazid (INH), a major front-line agent, with MIC 90 = 0.5 μM, 30-fold more potency than the parent drug, nitrofurantoin (MIC 90 = 15 μM), and 100-fold more selective towards mycobacteria. Therefore, 9 was identified as a validated hit for further investigation in the urgent search for new, safe and affordable TB drugs.