Antibacterial Activity of N-Substituted-Amino Acid Triazolyl Oxazolidinones against Clinical Isolates of LinezolidResistant Gram-Positive Cocci and MDR Mycobacterium tuberculosis - Abstract
Abstract A small series of N-substituted-alaninyl and N-substituted-glycinyl-triazolyl oxazolidinone derivatives were evaluated against susceptible and drug-resistant Gram-positive cocci, including multidrug-resistant mycobacterial and linezolid-resistant clinical isolates. The 5-nitrothiophene-2-carbonyl (PH-224(D) and PH-232(L)) and the 3,5-dinitrobenzoyl (PH-214(D)) alanine containing derivatives demonstrated the
most potent ant mycobacterial activity with MIC values of 0.065, 0.26 µM and 1.1 µM, respectively, under aerobic conditions compared with rifampicin (MIC: 0.0067 µM). These three compounds also demonstrated MBC (minimum concentration values required to achieve a 2-log kill in 21 days) of 0.39 and 0.17 and 1.6 µM for PH-224(D), PH-232(L) and PH-214(D), respectively. PH-214(D), PH-224(D) and PH-232(L) also showed potent activity in low oxygen recovery assay (LORA) with MIC values, of 0.24 and 0.27, and 0.48 µM, respectively, indicating their potential usefulness in treating latent tuberculosis, which is often presumed untreatable. The 5-nitrothiophene-2-carbonyl substituted derivatives PH-224(D) and PH-232(L) were also mostly potent against fluoroquinolone-resistant (FQ-R1), isoniazid-resistant (INH-R1 and INH-R2) and rifampicin-resistant (RIF-R1 and RIF-R2) mycobacterial isolates. In addition, they showed significant intracellular antibacterial activity which is comparable to isoniazid. Against linezolid-resistant strains, the 5-nitro-2-furoyl alaninyl derivatives
PH-223(D) and PH-223(L) and 5-nitrothiophene-2-carbonyl substituted alaninyl derivatives PH-224(D) and the 5-nitro-2-furoyl glycinyl derivatives PH-145 and PH-189 showed potent activity against four LNZ-resistant CNS-strains but were less active against the two LNZ-resistant E. faecalis strains.