7476-06-4Relevant articles and documents
Structure-Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens
Wesseling, Charlotte M. J.,Slingerland, Cornelis J.,Veraar, Shanice,Lok, Samantha,Martin, Nathaniel I.
, p. 3314 - 3335 (2021/11/24)
Pentamidine, an FDA-approved antiparasitic drug, was recently identified as an outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and novobiocin against Gram-negative bacteria. The same study also described a preliminary structure-activity relationship using commercially available pentamidine analogues. We here report the design, synthesis, and evaluation of a broader panel of bis-amidines inspired by pentamidine. The present study both validates the previously observed synergistic activity reported for pentamidine, while further assessing the capacity for structurally similar bis-amidines to also potentiate Gram-positive specific antibiotics against Gram-negative pathogens. Among the bis-amidines prepared, a number of them were found to exhibit synergistic activity greater than pentamidine. These synergists were shown to effectively potentiate the activity of Gram-positive specific antibiotics against multiple Gram-negative pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli, including polymyxin- and carbapenem-resistant strains.
The Delicate Balance of Preorganisation and Adaptability in Multiply Bonded Host–Guest Complexes
von Krbek, Larissa K. S.,Achazi, Andreas J.,Schoder, Stefan,Gaedke, Marius,Biberger, Tobias,Paulus, Beate,Schalley, Christoph A.
supporting information, p. 2877 - 2883 (2017/03/08)
Rigidity and preorganisation are believed to be required for high affinity in multiply bonded supramolecular complexes as they help reduce the entropic penalty of the binding event. This comes at the price that such rigid complexes are sensitive to small geometric mismatches. In marked contrast, nature uses more flexible building blocks. Thus, one might consider putting the rigidity/high-affinity notion to the test. Multivalent crown/ammonium complexes are ideal for this purpose as the monovalent interaction is well understood. A series of divalent complexes with different spacer lengths and rigidities has thus been analysed to correlate chelate cooperativities and spacer properties. Too long spacers reduce chelate cooperativity compared to exactly matching ones. However, in contrast to expectation, flexible guests bind with chelate cooperativities clearly exceeding those of rigid structures. Flexible spacers adapt to small geometric host–guest mismatches. Spacer–spacer interactions help overcome the entropic penalty of conformational fixation during binding and a delicate balance of preorganisation and adaptability is at play in multivalent complexes.
Structure-activity study of pentamidine analogues as antiprotozoal agents
Bakunova, Svetlana M.,Bakunov, Stanislav A.,Patrick, Donald A.,Kumar, E. V. K. Suresh,Ohemeng, Kwasi A.,Bridges, Arlene S.,Wenzler, Tanja,Barszcz, Todd,Jones, Susan Kilgore,Werbovetz, Karl A.,Brun, Reto,Tidwell, Richard R.
scheme or table, p. 2016 - 2035 (2009/12/31)
Diamidine 1 (pentamidine) and 65 analogues (2-66) have been tested for in vitro antiprotozoal activities against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donoVani, and for cytotoxicity against mammalian cells. Dications 32, 64, and 66 exhibited antitrypanosomal potencies equal or greater than melarsoprol (IC50) 4 nM). Nine congeners (2-4, 12, 27, 30, and 64-66) were more active against P. falciparum than artemisinin (IC50) 6 nM). Eight compounds (12, 32, 33, 44, 59, 62, 64, and 66) exhibited equal or better antileishmanial activities than 1 (IC50) 1.8 M). Several congeners were more active than 1 in vivo, curing at least 2/4 infected animals in the acute mouse model of trypanosomiasis. The diimidazoline 66 was the most promising compound in the series, showing excellent in vitro activities and high selectivities against T. b. rhodesiense, P. falciparum, and L. donoVani combined with high antitrypanosomal efficacy in vivo.
