PZA (Fig. 6; 7a) was developed based on reports describing the antitubercular activity of vitamin B3 (niacin) . It is unlikely that PZA would be discovered in modern drug discovery programs since it has no activity against MTb under normal in vitro growth conditions although it has good activity in infected animals [106, 107].
Initial SAR studies [106-109] were performed by in vivo assays of derivatives of nicotinamide (3c) and PZA in infected mice. The presence of a pyrazine heterocy-cle with a carboxamide at the C(2) position was essential for activity. Modification of the carboxamide to tetrazole, nitrile, hydrazide, or carboxylic acid (Fig. 6; 7b-e) leads to completely inactive compounds in vivo. Substitutions on the amide nitrogen with either a methyl (Fig. 6; 7f) or an acetyl group (Fig. 6; 7g) were detrimental
Fig. 6 Derivatives of PZA screened in the murine model of TB
7a R = CONH2; Pyrazinamide (PZA)
7b R = tetrazole
7d R = CONHNH2
7i R = CONHCHjNEtj
7j R = CONH-N-(morpholinomethyl)
Fig. 7 Cycloserine
to activity. Pyrazinoic acid (7e) is considered to be the active metabolite from PZA; hence, various ester derivatives (e.g., 7h) were synthesized and found to be active in vitro but inactive in vivo probably due to premature hydrolysis or poor solubility. However, more stable aminomethylene prodrugs (7i and 7j) did not show improvement in activity presumably because they were not substrates for the amidase. The thioamide (7k), pyrimidine nucleus (7l), and the pyridazine nucleus (7m,n) were inactive or weakly active. Thus, PZA is the minimum pharmacophore; further substitutions on the amide or changes to the pyrazine ring are detrimental to activity.
Pyrazinamide likely kills MTb by intracellular acidification following hydrolysis by MTb nicotinamidase/pyrazinamidase , although inhibition of fatty acid synthase has also been proposed as a mechanism [111-113]. PZA increases serum uric acid concentrations thereby causing nongouty arthralgia and, when used in combination with INH and/or RIF, often causes some hepatotoxicity.
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