Recent clinical reports on the unexpected effectiveness of sulfa drugs in combination therapy against Mycobacterium tuberculosis stimulated our interest in understanding better the potential relationships between sulfa structure and antimycobacterial activity. Sulfa drugs are susceptible to the deactivating action of arylamine N-acetyltransferases (NATs), enzymes endogenous within both patient and pathogen in tuberculosis. The metabolic products, N4-acetyl compounds, have lower antibacterial activities than their un-acetylated counterparts, compromising their role in effective chemotherapy. A potential strategy for the improvement of antimicrobial character emphasizes blocking the deactivating effects of NATs through changes in sulfa drug structure. In particular, Krebs had observed some time ago the unique behavior of sulfamethazine towards acetylating and de-acetylating enzymes. Using methods which we had previously developed for the chemical synthesis of NAT metabolites of sulfa drugs, we focused on the preparation of functionalized sulfamethazines as potential sources for drug discovery. In an example typical of the synthesis of our compounds, addition of valeric anhydride to a rapidly stirred slurry of sulfamethazine in valeric acid at 80°C, followed by further warming for an hour, readily led to the N4-valeroylated derivative (I, 78%), the structure of which was fully supported by spectrometric and elemental analysis data. Subsequent treatment of I with acetic anhydride in pyridine produced the N1-acetyl-N4-valeroylsulfamethazine (II, 93%). The ability to strictly control the site and extent of acylation permits a considered study of the effects of blocking the action of NATs. Some of our materials have shown activity in vitro against the virulent experimental laboratory strain M. tuberculosis Erdman, with a representative minimum inhibitory concentration of 16 mg/mL for compound I. We conclude that further investigation will be warranted of the synthesis and antitubercular nature of these sulfa drug derivatives in combination therapy.

Selective sulfa drug acylations for antitubercular drug design

256th National Meeting (2018)

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