Synthesis and Biological Activities of Novel Pleuromutilin Derivatives with a Substituted Thiadiazole Moiety as Potent Drug-Resistant Bacteria Inhibitors

Abstract

A series of novel pleuromutilin derivatives possessing thiadiazole moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the derivatives against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae were tested by the agar dilution method and Oxford cup assay. The majority of the tested compounds displayed moderate antibacterial activities. Importantly, the three compounds with amino or tertiary amine groups in their side chains, 11, 13b, and 15c, were the most active antibacterial agents. Docking experiments carried out on the peptidyl transferase center (PTC) of 23S rRNA proved that there is a reasonable direct correlation between the binding free energy (ΔGb, kcal/mol) and the antibacterial activity. Moreover, the pharmacokinetic profiles of 11 and 15c in rat were characterized by moderate clearance and oral bioavailability.

Synthesis and Biological Evaluation of Novel Thioether Pleuromutilin Derivatives

“…15) Amino substitution in the benzene ring can improve activity in comparison with the reference drugs except against Pyogens and MG, and para substitution (13i) is better for antibacterial activity than meta substitution (13h) with being found 3-10-fold more potent than erythromye and tiamulin against MSSA and MSSE. The result is consistent with the previous research results 16,17) which amino group could increase the antibacterial effect whether linking with benzene ring or not. Nitro, methoxy, hydroxy and dichloro substituents contribute little to the increased activity compared with the analogue (13a) that possesses unsubstitution benzoyl group.…”

“…Compound with meta amino substituted in the benzene ring showed the best antibacterial derivative among substituted benzeneamide derivatives. 16) Derivatives with an amino group on the terminal C14 side chain presented improved activity. 17) In addition, some efforts were focused on structural modification of valnemulin, one kinds of derivatives via modification the amino of dimethyl cysteine moiety of C14 side chain by general heterocyclic acid or chloromate or substituted benzene carboxylic acid.…”

Synthesis and Antibacterial Activity of Novel Pleuromutilin Derivatives

“…These compounds showed moderate to good activity against some Gram-positive pathogens. 24,25) Sulfonamides have been used as a C14 side chain by the team of Fang, and these novel hybrid molecules possessed more excellent antibacterial activities than sulfonamides and valnemulin. At the same time, they provide a novel design idea for new pleuromutilin derivatives.…”

Synthesis and evaluation of novel pleuromutilin derivatives with a substituted pyrimidine moiety

“…The antibacterial studies prove that heterocyclic ring bearing polar groups at the C14 side chain of pleuromutilin derivatives may raise their antibacterial activity [17,18]. This conclusion is supported by the work of Ling et al [16].…”

“…In addition, compounds bearing primary amine substituents at pyridine ring incorporated into the C14 side chain exhibited antibacterial activity [16]. The molecular docking results revealed the substituents with hydrogen donators, for example, hydroxy and amino group, at the C14 side chain enhance the binding affinities by hydrogen bondings and thus should be introduced to produce new analogues with higher antibacterial activities [17].…”