Fig 1.
Three core segments illustrated with box and numbering.
Fig 2.
Chemical synthesis of 2-aminothiazole analogs.
Reagents: (i) EtOH, 70°C, 2 h; (ii) R4COX, Et3N, THF, r.t., 1 h; (iii) R3NCO, Et3N, THF, r.t., 1 h.
Fig 3.
Chemical synthesis of C-4 ketone and carboxamide analogs.
Reagents: (i) EDC.HCl, HOBt, NCH3(OCH3), DIPEA, CH2Cl2, 16 h; (ii) CH3MgBr, THF, -78°C–r.t., 2 h; (iii) 1-adamantanoyl chloride, Et3N, THF, r.t., 1 h.
Fig 4.
Chemical synthesis of analogs comprised of thiazole core replacement.
Reagents:: (i) 4-(t-butyl)PhCOCl, EtOH, 1 h; (ii) EtOH, reflux, 16 h; (iii) H2SO4, r.t., 16 h; (iv) EDC, CH2Cl2, r.t., 16 h.
Fig 5.
Chemical synthesis of pyrimidine-based analogs.
Reagents: (i) 2,6-dimethylaniline, THF, reflux, 16 h; (ii) 2-(tributylstannyl)pyridine, Pd(PPh3), DMF, 100°C, 16 h.
Fig 6.
Chemical synthesis of pyrazole-based analogs.
Reagents: (i) KOtBu, BuOH, reflux, 3 h; (ii) RCOCl, THF, r.t., 1 h; (iii) RNCO, THF, 1 h.
Fig 7.
SAR at C-2 position of thiazole.
aCompounds were tested for activity against M. tuberculosis. Minimum inhibitory concentration (MIC, in μM) is the minimum concentration required to inhibit the growth of M. tuberculosis in liquid culture. MICs of active compounds are the average of two independent experiments. bToxic concentration (TC50, in μM) is the concentration required to inhibit growth of Vero cells by 50%. Selectivity index (SI) is the ratio of TC50 to MIC. Cpd = compound; Rif = rifampicin; ND = not determined.
Fig 8.
SAR at C-4 position of thiazole core.
aMIC (μM) is the minimum concentration required to inhibit the growth of M. tuberculosis in liquid culture. MICs of active compounds are the average of two independent experiments. bToxic concentration (TC50, in μM) is the concentration required to inhibit growth of Vero cells by 50%. Selectivity index (SI) is the ratio of TC50 to MIC. Cpd = compound; Rif = rifampicin; ND = not determined.
Fig 9.
SAR of thiazole core replacements.
aCompounds were tested for inhibition of M. tuberculosis. Minimum inhibitory concentration (MIC, in μM) is the minimum concentration required to completely inhibit the growth of M. tuberculosis in liquid culture. MICs of active compounds are the average of two independent experiments. bToxic concentration (TC50, in μM) is the concentration required to inhibit growth of Vero cells by 50%. Selectivity index (SI) is the ratio of TC50 to MIC. Cpd = compound; Rif = rifampicin; ND = not determined.
Table 1.
Spectrum of activity against bacterial species.
The MIC against four bacterial species was determined on solid medium using the agar serial proportion method. MIC99 is the minimum concentration required to prevent growth 99% of bacteria.
Fig 10.
The representative aminothiazole 20 possesses bactericidal activity.
M. tuberculosis was inoculated to a starting of OD590 of 0.1 in medium containing compound 20. CFU/mL was enumerated at indicated time points by serial dilution onto solid medium. The limit of detection was 20. Note that the lines for 0.625, 1.25 and 2.5 overlap.
Fig 11.
Inhibition of M. tuberculosis growth by AT compound 20.
Growth curve in standard medium. (B) Growth curve in medium plus additional 0.04 g/L ferric ammonium citrate. Cells were inoculated to a starting OD590 of 0.04 into growth medium. Data are the mean +/- standard deviation of three independent cultures.