Synthesis of Fmoc-Triazine Amino Acids and Its Application in the Synthesis of Short Antibacterial Peptidomimetics

Gunasekaran, P.; Kim, Eun Young; Lee, Jian; Ryu, Eung K.; Shin, Song Yub; Bang, Jeong Kyu

doi:10.3390/ijms21103602

Cited by 12 publications

(10 citation statements)

References 38 publications

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“…>512 [64] x < 0.156 Synthesis of TOB-Based Chimeras. The chimeric molecules were synthesized by sequential nucleophilic aromatic substitution reactions at alternative positions of 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) with a variety of membrane-active warheads such as TOB, CIP, NMP, and CYC as shown in Scheme 1A,B.…”

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confidence: 99%

Chimeric Tobramycin-Based Adjuvant TOB-TOB-CIP Potentiates Fluoroquinolone and β-Lactam Antibiotics against Multidrug-Resistant Pseudomonas aeruginosa

Dhiman

Ramirez

et al. 2023

ACS Infect. Dis.

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According to the World Health Organization, antibiotic resistance is a global health threat. Of particular importance are infections caused by multidrug-resistant Gram-negative bacteria including Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa for which limited treatment options exist. Multiple and simultaneously occurring resistance mechanisms including outer membrane impermeability, overexpression of efflux pumps, antibiotic-modifying enzymes, and modification of genes and antibiotic targets have made antibiotic drug development more difficult against these pathogens. One strategy to cope with these challenges is the use of outer membrane permeabilizers that increase the intracellular concentration of antibiotics when used in combination. In some circumstances, this approach can rescue antibiotics from resistance or repurpose currently marketed antibiotics. Tobramycin-based hybrid antibiotic adjuvants that combine two outer membrane-active components have been previously shown to potentiate antibiotics by facilitating transit through the outer membrane, resulting in increased antibiotic accumulation within the cell. Herein, we extended the concept of tobramycin-based hybrid antibiotic adjuvants to tobramycin-based chimeras by engineering up to three different membrane-active antibiotic warheads such as tobramycin, 1-(1-naphthylmethyl)-piperazine, ciprofloxacin, and cyclam into a central 1,3,5-triazine scaffold. Chimera 4 (TOB-TOB-CIP) consistently synergized with ciprofloxacin, levofloxacin, and moxifloxacin against wild-type and fluoroquinolone-resistant P. aeruginosa. Moreover, the susceptibility breakpoints of ceftazidime, aztreonam, and imipenem were reached using the triple combination of chimera 4 with ceftazidime/avibactam, aztreonam/avibactam, and imipenem/relebactam, respectively, against β-lactamase-harboring P. aeruginosa. Our findings demonstrate that tobramycin-based chimeras form a novel class of antibiotic potentiators capable of restoring the activity of antibiotics against P. aeruginosa.

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confidence: 99%

Chimeric Tobramycin-Based Adjuvant TOB-TOB-CIP Potentiates Fluoroquinolone and β-Lactam Antibiotics against Multidrug-Resistant Pseudomonas aeruginosa

Dhiman

Ramirez

et al. 2023

ACS Infect. Dis.

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“…In early 2020, Gunasekaran et al 98 described the Fmoc-triazine based derivatives 51a−51j (Figure 21) as antimicrobial peptidomimetics with a great proteolytic stability and devoid of hemolytic activity. Triazine heterocycles nowadays find considerable attention as novel scaffolds in medicinal chemistry due to their remarkable pharmacological properties.…”

Section: Apoptosis Protein Peptidomimetic Inhibitors (Aips)mentioning

confidence: 99%

Peptidomimetics: An Overview of Recent Medicinal Chemistry Efforts toward the Discovery of Novel Small Molecule Inhibitors

2022

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The use of peptides as therapeutics has often been associated with several drawbacks such as poor absorption, low stability to proteolytic digestion, and fast clearance. Peptidomimetics are developed by modifications of native peptides with the aim of obtaining molecules that are more suitable for clinical development and, for this reason, are widely used as tools in medicinal chemistry programs. The effort to disclose innovative peptidomimetic therapies is recurrent and constantly evolving as demonstrated by the new lead compounds in clinical trials. Synthetic strategies for the development of peptidomimetics have also been implemented with time. This perspective highlights some of the most recent efforts for the design and synthesis of peptidomimetic agents together with their biological evaluation toward a panel of targets.

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“…Cationic antimicrobial peptides have large quantities of lysine (Lys) and arginine (Arg), making them highly susceptible to serine proteases such as trypsin, which specifically hydrolyzes the peptide bond at the C-terminal end of the Lys and Arg. In an effort to overcome the protease degradability of the AMPs, different strategies have been adopted such as (a) insertion of nonstandard ω-amino acids − and side-chain-modified α-amino acids − in the AMP sequence, (b) peptide terminal modifications, − (c) insertion of amino acids of opposite chirality, − (d) cyclization of the AMP sequences, − (e) insertion of peptidomimetic blocks in key positions of the sequence, − (f) pegylation, − (g) lipidation, , and (h) construction of hybrids . Of all the strategies employed, modification of the side-chain length of the positively charged amino acid residues, such as Lys and Arg, is the most common one.…”

Section: Introductionmentioning

confidence: 99%

Delineating the Mechanism of Action of a Protease Resistant and Salt Tolerant Synthetic Antimicrobial Peptide against Pseudomonas aeruginosa

et al. 2022

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Rapidly growing antimicrobial resistance (AMR) against antibiotics has propelled the development of synthetic antimicrobial peptides (AMPs) as potential antimicrobial agents. An antimicrobial peptide Nle-Dab-Trp-Nle-Dab-Dab-Nle-CONH 2 ( P36 ; Nle = norleucine, Dab = diaminobutyric acid, Trp = tryptophan) potent against Pseudomonas aeruginosa ( P. aeruginosa ) has been developed in the present study. Rational design strategy adopted in this study led to the improvisation of the therapeutic qualities such as activity, salt tolerance, cytotoxicity, and protease resistance of the template peptide P4 , which was earlier reported from our group. P36 exhibited salt tolerant antimicrobial potency against P. aeruginosa , along with very low cytotoxicity against mammalian cell lines. P36 was found to be nonhemolytic and resistant toward protease degradation which qualified it as a potent antimicrobial agent. We have investigated the mechanism of action of this molecule in detail using several experimental techniques (spectroscopic, biophysical, and microscopic) and molecular dynamics simulations. P36 was a membrane active AMP with membrane destabilization and deformation abilities, leading to leakage of the intracellular materials and causing eventual cell death. The interaction between P36 and the microbial membrane/membrane mimics was primarily driven by electrostatics. P36 was unstructured in water and upon binding to the microbial membrane mimic SDS, suggesting no influence of secondary structure on its antimicrobial potency. Positive charge, optimum hydrophobic–hydrophilic balance, and chain length remained the most important concerns to be addressed while designing small cationic antimicrobial peptides.

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Synthesis of Fmoc-Triazine Amino Acids and Its Application in the Synthesis of Short Antibacterial Peptidomimetics

Cited by 12 publications

References 38 publications

Chimeric Tobramycin-Based Adjuvant TOB-TOB-CIP Potentiates Fluoroquinolone and β-Lactam Antibiotics against Multidrug-Resistant Pseudomonas aeruginosa

Chimeric Tobramycin-Based Adjuvant TOB-TOB-CIP Potentiates Fluoroquinolone and β-Lactam Antibiotics against Multidrug-Resistant Pseudomonas aeruginosa

Peptidomimetics: An Overview of Recent Medicinal Chemistry Efforts toward the Discovery of Novel Small Molecule Inhibitors

Delineating the Mechanism of Action of a Protease Resistant and Salt Tolerant Synthetic Antimicrobial Peptide against Pseudomonas aeruginosa

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