Biology

B-4157 (Fig. 32; 8b) exhibited promising in vitro activity against H37Rv and MDR strains of MTb with MIC range of <114 nM to 228 nM. Tetramethylpiperidine-substituted riminophenazines (such as B-4169, Fig. 32; 8c) showed MICs of 42.4-169 nM [308]. A generalized membrane disrupting effect, interference with potassium transport, and generation of reactive oxygen intermediates have been suggested as the mechanism of action for riminophenazines [27, 309, 310], but detailed information is still not clear. The very low mutation frequency suggests that rhiminophenazines may affect multiple aspects of metabolism [27].

The 2,2,6,6-tetramethylpiperidine-substituted riminophenazines such as B4169 have superior activity to CFM against MTb growing in macrophages and are also

Fig. 31 Antitubercular rhiminophenazines

8a Ri = 4-Cl, R2 = 4-Cl, R3 = 'Pr; Clofazimine (CFM) 8b Ri = 4-CF3, R2 = 4-CF3, R3 = Et; B4157

8c R1 = 3,4,5-Cl R2 = 3,4,5-Cl, R3 = 4-(2,2,6,6-tetramethylpiperidine); B4169

less toxic in animal models [308]. The B-4157 analog has similar activity to CFM in infected mice, and at a dose of 20 mg/kg was as effective as similar doses of RIF or INH in long-term monotherapy in infected animals [307]. The in vivo potency may be due to the long half-life of CFM in tissues (>70 days after repeated dosing of human patients) [27]. The absoption, distribution, metabolism, and excretion (ADME) of CFM analogs have not yet been reported. CFM is 45-62% orally bioavailable in humans, reaches serum concentrations of 0.7-1 mg/mL, and is metabolized by the liver through dehalogenation or deamination followed by glucuronidation or by hydroxylation along with glucuronidation [27]. Riminophe-nazines are currently in the preclinical development state, but their high potency makes them attractive drug candidates.

4.6 Pyrroles 4.6.1 History

Naturally occurring pyrrolnitrin (Fig. 32; 22a) and its analogs were tested against MTb, and the most effective exhibited an MIC of 3.9 p.M [311]. However, most of the compounds from this series were cytotoxic, presumably because of the nitro group. Structural optimization of pyrrolnitrin and other azole analogs led to the discovery of the more potent pyrrole, BM-212 (Fig. 33; 22b), exhibiting MIC values of 1.68 mM against MTb [312]. BM-212 (22b) was also found to be effective against strains resistant to EMB, INH, amikacin, STR, RIF, and rifabutin, as well as against MTb growing within a human monocyte cell line.

Pyrrolnitrin lead analog 22a

Pyrrolnitrin lead analog 22a

LL-3858 22h

Fig. 32 Pyrrole-based antitubercular compounds

Fig. 33 Pyrrole SAR

Substituted Ar ring essenti ortho or para halides more potent, less cytotoxic

Substituted Ar ring essenti ortho or para halides more potent, less cytotoxic rv

- R = S or N-CH3 essential; hydrogen bond acceptor

CH3 essential for directing aryl conformation

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