Structure−Activity Relationships of Antitubercular Nitroimidazoles. 2. Determinants of Aerobic Activity and Quantitative Structure−Activity Relationships

• DOI: 10.1021/jm801374t
• Publication Date: 2009-02-11T18:02:13Z
• Authors: Pilho Kim; Sunhee Kang; Helena I. Boshoff; Jan Jiricek; Margaret Collins; Ramandeep Singh; Ujjini H. Manjunatha; Pornwaratt Niyomr...; Liang Zhang; Michael Goodwin; Thomas Dick; Thomas H. Keller; Cynthia S. Dowd; Clifton E. Barry
• Keywords: Thioether; Imidazole; Oxidizing agent; Structure–activity relationship

The (S)-2-nitro-6-substituted 6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines have been extensively explored for their potential use as new antituberculars based on excellent bactericidal properties aerobic whole cells of Mycobacterium tuberculosis. An oxygen atom at the 2-position imidazole ring is required activity. Here, we show that substitution this by either nitrogen or sulfur yielded equipotent analogues. Acylating amino series, oxidizing thioether, replacing ether with carbon significantly reduced potency compounds. Replacement benzylic 6-position slightly improved and facilitated exploration SAR in more soluble 6-amino series. Significant improvements were realized extending linker region between 6-(S) position terminal hydrophobic aromatic substituent. A simple four-feature QSAR model was derived to rationalize MIC results series bicyclic nitroimidazoles.