Dimeric peptoids as antibacterial agents.

Building upon our previous study on peptoid-based antibacterials which showed good activity against Gram-positive bacteria only, herein we report the synthesis of 34 dimeric peptoid compounds and the investigation of their activity against Gram-positive and Gram-negative pathogens. The newly designed peptoids feature a di-hydrophobic moiety incorporating phenyl, bromo-phenyl, and naphthyl groups, combined with variable lengths of cationic units such as amino and guanidine groups. The study also underscores the pivotal interplay between hydrophobicity and cationicity in optimizing efficacy against specific bacteria. The bromophenyl dimeric guanidinium peptoid compound 10j showed excellent activity against S. aureus 38 and E. coli K12 with MIC of 0.8 µg mL-1 and 6.2 µg mL-1, respectively. Further investigation into the mechanism of action revealed that the antibacterial effect might be attributed to the disruption of bacterial cell membranes, as suggested by tethered bilayer lipid membranes (tBLMs) and cytoplasmic membrane permeability studies. Notably, these promising antibacterial agents exhibited negligible toxicity against mammalian red blood cells. Additionally, the study explored the potential of 12 active compounds to disrupt established biofilms of S. aureus 38. The most effective biofilm disruptors were ethyl and octyl-naphthyl guanidinium peptoids (10c and 10 k). These compounds 10c and 10 k disrupted the established biofilms of S. aureus 38 with 51 % at 4x MIC (MIC = 17.6 µg mL-1 and 11.2 µg mL-1) and 56 %-58 % at 8x MIC (MIC = 35.2 µg mL-1 and 22.4 µg mL-1) respectively. Overall, this research contributes insights into the design principles of cationic dimeric peptoids and their antibacterial activity, with implications for the development of new antibacterial compounds.

Short Tryptamine-Based Peptoids as Potential Therapeutics for Microbial Keratitis: Structure-Function Correlation Studies.

Peptoids are peptidomimetics that have attracted considerable interest as a promising class of antimicrobials against multi-drug-resistant bacteria due to their resistance to proteolysis, bioavailability, and thermal stability compared to their corresponding peptides. Staphylococcus aureus is a significant contributor to infections worldwide and is a major pathogen in ocular infections (keratitis). S. aureus infections can be challenging to control and treat due to the development of multiple antibiotic resistance. This work describes short cationic peptoids with activity against S. aureus strains from keratitis. The peptoids were synthesized via acid amine-coupling between naphthyl-indole amine or naphthyl-phenyl amine with different amino acids to produce primary amines (series I), mono-guanidines (series II), tertiary amine salts (series III), quaternary ammonium salts (series IV), and di-guanidine (series V) peptoids. The antimicrobial activity of the peptoids was compared with ciprofloxacin, an antibiotic that is commonly used to treat keratitis. All new compounds were active against Staphylococcus aureus S.aureus 38. The most active compounds against S.aur38 were 20a and 22 with MIC = 3.9 µg mL−1 and 5.5 µg mL−1, respectively. The potency of these two active molecules was investigated against 12 S. aureus strains that were isolated from microbial keratitis. Compounds 20a and 22 were active against 12 strains with MIC = 3.2 µg mL−1 and 2.1 µg mL−1, respectively. There were two strains that were resistant to ciprofloxacin (Sa.111 and Sa.112) with MIC = 128 µg mL−1 and 256 µg mL−1, respectively. Compounds 12c and 13c were the most active against E. coli, with MIC > 12 µg mL−1. Cytoplasmic membrane permeability studies suggested that depolarization and disruption of the bacterial cell membrane could be a possible mechanism for antibacterial activity and the hemolysis studies toward horse red blood cells showed that the potent compounds are non-toxic at up to 50 µg mL−1.

Naphthyridines part 4: unprecedented synthesis of polyfunctionally substituted benzo[c][2,7]naphthyridines and benzo[c]pyrimido[4,5,6-ij][2,7]naphthyridines with structural analogy to pyrido[4,3,2-mn]acridines present in the marine tetracyclic pyridoacridine alkaloids.

An easy, efficient and one-step synthesis of the versatile, hitherto unreported of polyfunctionally substituted benzo[c][2,7]naphthyridines 4a-c is described. The reaction of 4a-c with sodium azide gives the corresponding tetracyclic ring system 6a-c in near quantitative yield, and with phenyl isothiocyanate it gives the corresponding novel 3-alkyl-2-oxo-6-phenyl-5-thioxo-3,4,5,6-tetrahydro-2H-benzo[c]pyrimido[4,5,6-ij][2,7]naphthyridine-1-carbonitriles 8a-c. Refluxing compound 4a, with alkyl amines 9a-d for 2-3 h furnished 3-alkyl-5-alkylamino-4-amino-2-oxo-2,3-dihydrobenzo[c][2,7]naphthyridine-1-carbonitriles 10a-d, as stable crystalline solids. Compounds 10a-d reacted with acetic anhydride and triethyl orthoformate to furnish novel 3,6-dialkyl-2-oxo-3,6-dihydro-2H-benzo[c]-pyrimido[4,5,6-ij][2,7]naphthyridine-1-carbonitriles 13a-c and 14a-c, respectively. Lastly, diazotization of 10a-c afforded the novel tetracyclic ring system 3,6-dialkyl-2-oxo-3,6-dihydro-2H-benzo[c][1,2,3]triazino[4,5,6-ij][2,7]naphthyridine-1-carbonitriles 16a-c.