Simple amphiphilic α-hydrazido acids: Rational design, synthesis, and in vitro bioactivity profile of a novel class of potential antimicrobial compounds

Amabili, Paolo; Biavasco, Francesca; Brenciani, Andrea; Citterio, Barbara; Corbisiero, Dario; Ferrazzano, Lucia; Fioriti, Simona; Guerra, Giulia; Orena, Mario; Rinaldi, Samuele

doi:10.1016/j.ejmech.2020.112072

Cited by 9 publications

(6 citation statements)

References 85 publications

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“…Additional rationally designed SAMP scaffolds evaluated include lysine N-alkylamides (145) reduced amide-based compounds ( 146) and a range of others based on aromatic linkers (147)(148)(149) which have produced effective antimicrobial compounds (Figure 11). Additional SMAMP-type compounds include the recently reported substituted a-hydrazido amino acids developed by Amabili and co-workers (150). The mono-charged ahydrazido amino acids can be regarded as mimics of b-amino acids and they were designed with a range of both N-and Cterminal lipophilic groups to yield potent amphiphilic compounds (150).…”

Section: Synthetic Mimics Of Antimicrobial Peptides (Smamps/smhdps)mentioning

confidence: 99%

“…Additional SMAMP-type compounds include the recently reported substituted a-hydrazido amino acids developed by Amabili and co-workers (150). The mono-charged ahydrazido amino acids can be regarded as mimics of b-amino acids and they were designed with a range of both N-and Cterminal lipophilic groups to yield potent amphiphilic compounds (150). The versatile bicyclic norbornane scaffold has also been used for the generation of SMAMPs (151).…”

Section: Synthetic Mimics Of Antimicrobial Peptides (Smamps/smhdps)mentioning

confidence: 99%

“…Such structures can be obtained by careful sequence optimization or by tuning the stereochemistry. This has been exemplified for numerous of the scaffolds previously described including the tripeptides (166), SMAMPs (133), DKPs and ahydrazido acids (150). Most studies on these types of small AMP mimics claim that the lead compounds are "amphiphilic" but only a few provide any structural or quantifiable physicochemical data in support, which is also likely dependent, to some extent, on the challenges associated with obtaining crystals.…”

Section: Structure-activity Relationshipmentioning

confidence: 99%

“…A plethora of natural and unnatural cationic and hydrophobic building blocks have been employed to generate bioactive compounds and a move from the traditional amino acid-like scaffold provides the chemist with additional freedom to toggle these substituents further. It is clear that several compounds with good efficiency can be obtained slightly outside the 2 + 2 pharmacophore with examples such as the hydantoins and a-hydrazido amino acids that are active despite only displaying a single cationic residue (143,150). In general, a higher number of charges appear to be needed e.g.…”

Section: Structure-activity Relationshipmentioning

confidence: 99%

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Antimicrobial Peptide Mimics for Clinical Use: Does Size Matter?

2022

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The search for efficient antimicrobial therapies that can alleviate suffering caused by infections from resistant bacteria is more urgent than ever before. Infections caused by multi-resistant pathogens represent a significant and increasing burden to healthcare and society and researcher are investigating new classes of bioactive compounds to slow down this development. Antimicrobial peptides from the innate immune system represent one promising class that offers a potential solution to the antibiotic resistance problem due to their mode of action on the microbial membranes. However, challenges associated with pharmacokinetics, bioavailability and off-target toxicity are slowing down the advancement and use of innate defensive peptides. Improving the therapeutic properties of these peptides is a strategy for reducing the clinical limitations and synthetic mimics of antimicrobial peptides are emerging as a promising class of molecules for a variety of antimicrobial applications. These compounds can be made significantly shorter while maintaining, or even improving antimicrobial properties, and several downsized synthetic mimics are now in clinical development for a range of infectious diseases. A variety of strategies can be employed to prepare these small compounds and this review describes the different compounds developed to date by adhering to a minimum pharmacophore based on an amphiphilic balance between cationic charge and hydrophobicity. These compounds can be made as small as dipeptides, circumventing the need for large compounds with elaborate three-dimensional structures to generate simplified and potent antimicrobial mimics for a range of medical applications. This review highlight key and recent development in the field of small antimicrobial peptide mimics as a promising class of antimicrobials, illustrating just how small you can go.

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Section: Synthetic Mimics Of Antimicrobial Peptides (Smamps/smhdps)mentioning

confidence: 99%

Section: Synthetic Mimics Of Antimicrobial Peptides (Smamps/smhdps)mentioning

confidence: 99%

Section: Structure-activity Relationshipmentioning

confidence: 99%

Section: Structure-activity Relationshipmentioning

confidence: 99%

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Antimicrobial Peptide Mimics for Clinical Use: Does Size Matter?

2022

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“…Functional organic materials [ 1 ] have become increasingly important in many different fields of application, such as electronics [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ], biomedicine [ 14 , 15 , 16 , 17 , 18 , 19 ], and analytics [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. A rational design allows for the tailoring of the molecular property and applicability of these molecular materials [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. In particular, structure-property relationships help with the understanding of the materials’ characteristics, thus improving their performance.…”

Section: Introductionmentioning

confidence: 99%

Amphipolar, Amphiphilic 2,4-diarylpyrano[2,3-b]indoles as Turn-ON Luminophores in Acidic and Basic Media

et al. 2022

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A versatile amphiphilic pyrano[2,3-b]indole for halochromic turn-ON luminescence in acidic or basic media is accessed by an insertion-coupling-cycloisomerization and adjusting solubilizing and phenolic functionalities. While almost non-emissive in neutral solutions, treatment with acids or bases like trifluoroacetic acid (TFA) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) reveals distinct luminescence at wavelengths of 540 nm or 630 nm in propan-2-ol, respectively. Turn-ON emission can be detected at pH values as mild as pH = 5.31 or 8.70. Quantum yields in propan-2-ol are substantial for protonated (Φf = 0.058) and deprotonated (Φf = 0.059) species. Photometrically, pKa1 of 3.5 and pKa2 of 10.5 were determined in propan-2-ol. With lipophilic polyether sidechains and hydrophilic protonation and deprotonation sites the molecule can be regarded as amphipolar, which results in good solubility properties for different organic solvents. In aqueous media, an organic co-solvent like propan-2-ol (35%) or tetrahydrofuran (25%) is needed, and the solution can be diluted with pure water without precipitation of the compound. At higher concentrations of water, a turbid solution is formed, which indicates the formation of micellar structures or clusters. With dynamic light scattering we could show that these clusters increase in size with increasing water content.

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Lipoic acid modified antimicrobial peptide with enhanced antimicrobial properties

Zhou

et al. 2020

Bioorganic & Medicinal Chemistry

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Simple amphiphilic α-hydrazido acids: Rational design, synthesis, and in vitro bioactivity profile of a novel class of potential antimicrobial compounds

Cited by 9 publications

References 85 publications

Antimicrobial Peptide Mimics for Clinical Use: Does Size Matter?

Antimicrobial Peptide Mimics for Clinical Use: Does Size Matter?

Amphipolar, Amphiphilic 2,4-diarylpyrano[2,3-b]indoles as Turn-ON Luminophores in Acidic and Basic Media

Lipoic acid modified antimicrobial peptide with enhanced antimicrobial properties

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