Bis(N-amidinohydrazones) and N-(amidino)-N'-aryl-bishydrazones: New classes of antibacterial/antifungal agents

Bioorg Med Chem. 2017 Jan 1;25(1):58-66. doi: 10.1016/j.bmc.2016.10.009.

Sanjib K Shrestha ¹, Liliia M Kril ², Keith D Green ¹, Stefan Kwiatkowski ³, Vitaliy M Sviripa ⁴, Justin R Nickell ¹, Linda P Dwoskin ¹, David S Watt ⁵, Sylvie Garneau-Tsodikova ⁶

Affiliations

1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536-0596, USA.
2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536-0596, USA; Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA.
3 Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, USA.
4 Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA.
5 Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, USA; Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, USA. Electronic address: [email protected].
6 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536-0596, USA. Electronic address: [email protected].

PMID: 27769670 DOI: 10.1016/j.bmc.2016.10.009

Abstract

The emergence of multidrug-resistant Bacterial and Fungal strains poses a threat to human health that requires the design and synthesis of new classes of antimicrobial agents. We evaluated bis(N-amidinohydrazones) and N-(amidino)-N'-aryl-bishydrazones for their Antibacterial and Antifungal activities against panels of Gram-positive/Gram-negative bacteria as well as fungi. We investigated their potential to develop resistance against both bacteria and fungi by a multi-step resistance-selection method, explored their potential to induce the production of Reactive Oxygen Species, and assessed their toxicity. In summary, we found that these compounds exhibited broad-spectrum Antibacterial and Antifungal activities against most of the tested strains with minimum inhibitory concentration (MIC) values ranging from <0.5 to >500μM against bacteria and 1.0 to >31.3μg/mL against fungi; and in most cases, they exhibited either superior or similar antimicrobial activity compared to those of the standard drugs used in the clinic. We also observed minimal emergence of drug resistance to these newly synthesized compounds by bacteria and fungi even after 15 passages, and we found weak to moderate inhibition of the human Ether-à-go-go-related gene (hERG) channel with acceptable IC₅₀ values ranging from 1.12 to 3.29μM. Overall, these studies show that bis(N-amidinohydrazones) and N-(amidino)-N'-aryl-bishydrazones are potentially promising scaffolds for the discovery of novel Antibacterial and Antifungal agents.

Keywords

Bishydrazones; Candida albicans; Cytotoxicity; Resistance; Staphylococcus aureus; hERG channel.

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