Selective synthesis of N,N,N-trimethylated chitosan derivatives at different degree of substitution and investigation of structure-activity relationship for activity against P. aeruginosa and MRSA

• Published in: International journal of biological macromolecules Vol. 160; pp. 548 - 557
• Main Authors: Rathinam, Sankar, Ólafsdóttir, Sigríður, Jónsdóttir, Sigríður, Hjálmarsdóttir, Martha Á., Másson, Már
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2020
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antimicrobial; Cationic; Cations - chemistry; Chitosan - chemistry; Chitosan derivatives; Conjugation; Methicillin-resistant Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests - methods; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Structure-Activity Relationship; Antimicrobial; Pseudomonas aeruginosa; Conjugation; Chitosan derivatives; Cationic; Methicillin-resistant Staphylococcus aureus
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2020.05.109

Two new cationic chitosan derivatives were synthesized using a combination of Boc and TBDMS protection strategies. This included a series of six samples of the TMCNH2/TM derivative, where some of the amino groups were N,N,N-trimethylated and the remaining was in the primary state. A series of six samples of the TACin derivative, where some of the amino groups were N-acetylated with quaternary 2-(N,N,N-trimethylammoniumyl) acetyl group and the remaining fully N-acetylated, were also synthesized. The degree of substitution (DS) for quaternary amino groups in these series ranged from 0.06–0.89. TMCDM/TM derivatives with a mix of N,N,N-trimethylated and N,N-dimethylated groups were also synthesized according to a published procedure but in this case, it was more difficult to control the DS than with the TBDMS protection strategy. Broth microdilution assay revealed a markedly different structure-activity relationship (SAR) for the two derivatives. The activity for the TMC derivatives reached a plateau above 0.2–0.3 DS whereas the activity increased continuously with DS for TACin. The highest DS TMCNH2/TM was more active than the highest DS, TACin, against Gram-positive MRSA but less active against the Gram-negative P. aeruginosa. [Display omitted] •Two new derivatives of chitosan, TMCNH2/TM, and TACin, were synthesized employing TBDMS and Boc protection strategies•17 samples were synthesized with DS 0.06 – 0.89 and characterized by NMR, IR and GPC molecular weight analysis•The structure-activity relationship (SAR) against Gram-positive MRSA and Gram-negative P. aeruginosa was investigated•High DS derivatives were more than 30 times more active than low DS derivatives•The SAR was markedly different for TMCNH2/TM and TACin