Novel Aminoguanidine Hydrazone Analogues: From Potential Antimicrobial Agents to Potent Cholinesterase Inhibitors

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 14; no. 12; p. 1229
• Main Authors: Krátký, Martin, Štěpánková, Šárka, Konečná, Klára, Svrčková, Katarína, Maixnerová, Jana, Švarcová, Markéta, Janďourek, Ondřej, Trejtnar, František, Vinšová, Jarmila
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26.11.2021; MDPI
• Subjects: acetylcholinesterase; Alzheimer's disease; aminoguanidine; antimicrobial activity; Antimicrobial agents; butyrylcholinesterase; Cytotoxicity; Design; Drug resistance; enzyme inhibition; Gram-positive bacteria; Sodium; Staphylococcus infections; butyrylcholinesterase; molecular docking; enzyme inhibition; acetylcholinesterase; aminoguanidine; antimicrobial activity; salicylaldehydes; cytotoxicity; hydrazones
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph14121229

A series of thirty-one hydrazones of aminoguanidine, nitroaminoguanidine, 1,3-diaminoguanidine, and (thio)semicarbazide were prepared from various aldehydes, mainly chlorobenzaldehydes, halogenated salicylaldehydes, 5-nitrofurfural, and isatin (yields of 50-99%). They were characterized by spectral methods. Primarily, they were designed and evaluated as potential broad-spectrum antimicrobial agents. The compounds were effective against Gram-positive bacteria including methicillin-resistant with minimum inhibitory concentrations (MIC) from 7.8 µM, as well as Gram-negative strains with higher MIC. Antifungal evaluation against yeasts and found MIC from 62.5 µM. We also evaluated inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The compounds inhibited both enzymes with IC values of 17.95-54.93 µM for AChE and ≥1.69 µM for BuChE. Based on the substitution, it is possible to modify selectivity for a particular cholinesterase as we obtained selective inhibitors of either AChE or BuChE, as well as balanced inhibitors. The compounds act via mixed-type inhibition. Their interactions with enzymes were studied by molecular docking. Cytotoxicity was assessed in HepG2 cells. The hydrazones differ in their toxicity (IC from 5.27 to >500 µM). Some of the derivatives represent promising hits for further development. Based on the substitution pattern, it is possible to modulate bioactivity to the desired one.