Evaluation of bisphenylthiazoles as a promising class for combating multidrug-resistant fungal infections

• Published in: PloS one Vol. 16; no. 11; p. e0258465
• Main Authors: Hagras, Mohamed, Abutaleb, Nader S, Sayed, Ahmed M, Salama, Ehab A, Seleem, Mohamed N, Mayhoub, Abdelrahman S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.11.2021; Public Library of Science (PLoS)
• Subjects: Amphotericin B; Amphotericin B - adverse effects; Antibacterial activity; Antibacterial agents; Antifungal activity; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antimicrobial agents; Biology and Life Sciences; Candidiasis - drug therapy; Candidiasis - microbiology; Candidiasis - pathology; Care and treatment; Clinical isolates; Complications and side effects; Cyclohexane; Diamines; Drug resistance in microorganisms; Drug Resistance, Multiple - drug effects; Ethylenediamine; Fluconazole - adverse effects; Fungal infections; Fungi; Fungicides; Gram-positive bacteria; Humans; Hydrazine; Hydrazines; Medicine and Health Sciences; Microbial Sensitivity Tests; Microbiota; Mortality; Multidrug resistance; Multidrug resistant organisms; Mycoses - drug therapy; Mycoses - microbiology; Nitrogen; Organic chemistry; Pathogens; Patient outcomes; Pharmaceuticals; Pharmacy; Research and Analysis Methods; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Toxicity; Tropical diseases; Veterinary colleges; Veterinary medicine; Yeasts; Egypt; Cairo Egypt; Indiana; United States > US; Maryland; Virginia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0258465

To minimize the intrinsic toxicity of the antibacterial agent hydrazinyloxadiazole 1, the hydrazine moiety was replaced with ethylenediamine (compound 7). This replacement generated a potent antifungal agent with no antibacterial activity. Notably, use of a 1,2-diaminocyclohexane moiety, as a conformationally-restricted isostere for ethylenediamine, potentiated the antifungal activity in both the cis and trans forms of N-(5-(2-([1,1'-biphenyl]-4-yl)-4-methylthiazol-5-yl)-1,3,4-oxadiazol-2-yl)cyclohexane-1,2-diamine (compounds 16 and 17). Both compounds 16 and 17 were void of any antibacterial activity; nonetheless, they showed equipotent antifungal activity in vitro to that of the most potent approved antifungal agent, amphotericin B. The promising antifungal effects of compounds 16 and 17 were maintained when assessed against an additional panel of 26 yeast and mold clinical isolates, including the Candida auris and C. krusei. Furthermore, compound 17 showed superior activity to amphotericin B in vitro against Candida glabrata and Cryptococcus gattii. Additionally, neither compound inhibited the normal human microbiota, and both possessed excellent safety profiles and were 16 times more tolerable than amphotericin B.