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 antimicr obial 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- > 500 μM against bacteria and 1.0- > 31.3 μg/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 1.12-3.29 μM. Overall, these studies sh ow that bis(N-amidinohydrazones) and N-(amidino)-N'-aryl-bishydrazones are potentially promising scaffolds for the discovery of novel antibacterial and antifungal agents.

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Published in Bioorganic & Medicinal Chemistry, v. 25, issue 1, p. 58-66.

© 2016 Elsevier Ltd. All rights reserved.

This manuscript version is made available under the CC‐BY‐NC‐ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/.

The document available for download is the author's post-peer-review final draft of the article.

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Funding Information

This work was supported by startup funds from the College of Pharmacy (to S.G.-T.) and by the Office of the Dean of the College of Medicine (to D.S.W.) at the University of Kentucky. It was also supported by NIH grant AI090048 (to S.G.-T.); and NIH grants U01 DA013519, UL1TR000117 and T32 DA016176 (to L.P.D. and J.R.N.). D.S.W. was also supported in part through collaborations involving NIH grants P20 RR020171 (to L. Hersh), CA172379 (to C. Liu), and CA187273 (to V. Rangnekar).