dc.contributor.author | Zuma, Nonkululeko H. | |
dc.contributor.author | Smit, Frans J. | |
dc.contributor.author | Aucamp, Janine | |
dc.contributor.author | N'Da, David D. | |
dc.contributor.author | Seldon, Ronnett | |
dc.date.accessioned | 2020-03-18T12:46:08Z | |
dc.date.available | 2020-03-18T12:46:08Z | |
dc.date.issued | 2020 | |
dc.identifier.citation | Zuma, N.H. et al. 2020. Single-step synthesis and in vitro anti-mycobacterial activity of novel nitrofurantoin analogues. Bioorganic chemistry, 96: #103587. [https://doi.org/10.1016/j.bioorg.2020.103587] | en_US |
dc.identifier.issn | 0045-2068 | |
dc.identifier.uri | http://hdl.handle.net/10394/34411 | |
dc.identifier.uri | https://www.sciencedirect.com/science/article/pii/S0045206819316736 | |
dc.identifier.uri | https://doi.org/10.1016/j.bioorg.2020.103587 | |
dc.description.abstract | 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 MIC90 = 0.5 μM, 30-fold more potency than the parent drug, nitrofurantoin (MIC90 = 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 | en_US |
dc.language.iso | en | en_US |
dc.publisher | Elsevier | en_US |
dc.subject | Nitrofurans | en_US |
dc.subject | Nitrofurantoin | en_US |
dc.subject | Tuberculosis | en_US |
dc.subject | Analogues | en_US |
dc.subject | Nitroreductase | en_US |
dc.subject | Drug resistance | en_US |
dc.title | Single-step synthesis and in vitro anti-mycobacterial activity of novel nitrofurantoin analogues | en_US |
dc.type | Article | en_US |
dc.contributor.researchID | 20926588 - Smit, Frans Johannes | |
dc.contributor.researchID | 23978538 - Zuma, Nonkululeko Hazel | |
dc.contributor.researchID | 20505698 - Aucamp, Janine | |
dc.contributor.researchID | 20883072 - N'Da, David Dago | |