Antibacterials; Counterion; Free base guanidine; Guanidine; Hydrochloride salt; Trifluoroacetate salt; Catalysis; Information Systems; Molecular Biology; Drug Discovery; Physical and Theoretical Chemistry; Organic Chemistry; Inorganic Chemistry; General Medicine
Abstract :
[en] Trifluoroacetic acid (TFA), due to its strong acidity and low boiling point, is extensively used in protecting groups-based synthetic strategies. Indeed, synthetic compounds bearing basic functions, such as amines or guanidines (commonly found in peptido or peptidomimetic derivatives), developed in the frame of drug discovery programmes, are often isolated as trifluoroacetate (TF-Acetate) salts and their biological activity is assessed as such in in vitro, ex vivo, or in vivo experiments. However, the presence of residual amounts of TFA was reported to potentially affect the accuracy and reproducibility of a broad range of cellular assays (e. g. antimicrobial susceptibility testing, and cytotoxicity assays) limiting the further development of these derivatives. Furthermore, the impact of the counterion on biological activity, including TF-Acetate, is still controversial. Herein, we present a focused case study aiming to evaluate the activity of an antibacterial AlkylGuanidino Urea (AGU) compound obtained as TF-Acetate (1a) and hydrochloride (1b) salt forms to highlight the role of counterions in affecting the biological activity. We also prepared and tested the corresponding free base (1c). The exchange of the counterions applied to polyguanidino compounds represents an unexplored and challenging field, which required significant efforts for the successful optimization of reliable methods of preparation, also reported in this work. In the end, the biological evaluation revealed a quite similar biological profile for the salt derivatives 1a and 1b and a lower potency was found for the free base 1c.
Disciplines :
Microbiology Life sciences: Multidisciplinary, general & others
Author, co-author :
Ardino, Claudia ; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 2, 53100, Siena, Italy
Sannio, Filomena ; Dipartimento di Biotecnologie Mediche, University of Siena, Viale Bracci 16, 53100, Siena, Italy
Pasero, Carolina; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 2, 53100, Siena, Italy
Botta, Lorenzo ; Lead Discovery Siena s.r.l., Via Vittorio Alfieri 31, 53019, Castelnuovo Berardenga, Italy ; Department of Biological and Ecological Sciences, University of Tuscia, Largo Università s.n.c., 01100, Viterbo, Italy
Dreassi, Elena ; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 2, 53100, Siena, Italy
Docquier, Jean-Denis ✱; Université de Liège - ULiège > Integrative Biological Sciences (InBioS) ; Dipartimento di Biotecnologie Mediche, University of Siena, Viale Bracci 16, 53100, Siena, Italy. jddocquier@unisi.it ; Lead Discovery Siena s.r.l., Via Vittorio Alfieri 31, 53019, Castelnuovo Berardenga, Italy.
D'Agostino, Ilaria ✱; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 2, 53100, Siena, Italy. ilaria.dagostino91@gmail.com ; Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, Via de Vestini, 31, 66013, Chieti, Italy. ilaria.dagostino91@gmail.com
✱ These authors have contributed equally to this work.
Language :
English
Title :
The impact of counterions in biological activity: case study of antibacterial alkylguanidino ureas.
We thank LDS (Lead Discovery Siena) S.r.l. for financial support. Thanks are due to Prof. Lucia Pallecchi (Dipartimento di Biotecnologie Mediche, University of Siena, Italy) for kindly providing some of the clinical isolates used in this study.
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