Single-step synthesis and in vitro anti-mycobacterial activity of novel nitrofurantoin analogues. Zuma, N. H, Smit, F. J, Seldon, R., Aucamp, J., Jordaan, A., Warner, D. F, & N'Da, D. D Bioorganic Chemistry, 96:103587, Academic Press Inc., mar, 2020.
doi  abstract   bibtex   
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 $μ$M, 30-fold more potency than the parent drug, nitrofurantoin (MIC90 = 15 $μ$M), 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.
@article{Zuma2020,
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 $\mu$M, 30-fold more potency than the parent drug, nitrofurantoin (MIC90 = 15 $\mu$M), 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.},
author = {Zuma, Nonkululeko H and Smit, Frans J and Seldon, Ronnett and Aucamp, Janine and Jordaan, Audrey and Warner, Digby F and N'Da, David D},
doi = {10.1016/j.bioorg.2020.103587},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Zuma et al. - 2020 - Single-step synthesis and iin vitroi anti-mycobacterial activity of novel nitrofurantoin analogues.pdf:pdf},
issn = {10902120},
journal = {Bioorganic Chemistry},
keywords = {Analogues,Drug resistance,Nitrofurans,Nitrofurantoin,Nitroreductase,Tuberculosis,fund{\_}not{\_}ack,original},
mendeley-tags = {fund{\_}not{\_}ack,original},
month = {mar},
pages = {103587},
publisher = {Academic Press Inc.},
title = {{Single-step synthesis and in vitro anti-mycobacterial activity of novel nitrofurantoin analogues}},
volume = {96},
year = {2020}
}

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