In the last two decades, the repertoire of clinically effective antibacterials is shrinking due to the rapidly increasing of multi-drug-resistant pathogenic bacteria. New chemical classes with innovative mode of action are required to prevent a return to the pre-antibiotic era. We have recently reported the identification of a series of linear guanidine derivatives and their antibacterial properties. A batch of a promising candidate for optimization studies (compound 1) turned out to be a mixture containing two unknown species with a better biological activity than the pure compound. This serendipitous discovery led us to investigate the chemical nature of the unknown components of the mixture. Through MS analysis coupled with design and synthesis we found that the components were spontaneously generated oligomers of the original compound. Preliminary biological evaluations eventually confirmed the broad-spectrum antibacterial activity of this new family of molecules. Interestingly the symmetric dimeric derivative (2) exhibited the best profile and it was selected as lead compound for further studies.

Nowadays, the increasing of multidrug-resistant pathogenic bacteria represents a serious threat to public health, and the lack of new antibiotics is becoming a global emergency. Therefore, research in antibacterial fields is urgently needed to expand the currently available arsenal of drugs. We have recently reported an alkyl-guanidine derivative (2), characterized by a symmetrical dimeric structure, as a good candidate for further developments, with a high antibacterial activity against both Gram-positive and Gramnegative strains. In this study, starting from its chemical scaffold, we synthesized a small library of analogues. Moreover, biological and in vitro pharmacokinetic characterizations were conducted on some selected derivatives, revealing notable properties: broad-spectrum profile, activity against resistant clinical isolates, and appreciable aqueous solubility. Interestingly, 2 seems neither to select for resistant strains nor to macroscopically alter the membranes, but further studies are required to determine the mode of action.

The glucose transporter GLUT1 is very frequently overexpressed in most tumor tissues because rapidly proliferating cancer cells rely mostly on glycolysis, a low-efficiency metabolic pathway necessitating a very high glucose consumption. Blocking GLUT1 is a promising anticancer strategy, thus we developed a novel class of GLUT1-inhibitors based on the 4-aryl-substituted salicylketoxime scaffold. Some of these compounds are efficient inhibitors of glucose uptake in lung cancer cells and have a noteworthy antiproliferative effect. In contrast to their 5-aryl-substituted regioisomers, the newly synthesized compounds reported herein do not display any significant binding to the estrogen receptors. The inhibition of glucose uptake in cancer cells by these compounds was further observed by fluorescence microscopy imaging using a fluorescent analog of glucose. Therefore, blocking the ability of tumor cells to take up glucose by means of these small-molecules, or by further optimized derivatives, may represent a successful approach in the development of novel anticancer drugs.

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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 . Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11030-022-10505-6.