Thioisonicotinamides and Thiosemicarbazones

The thioisonicotinamides, ethionamide (Fig. 5; 5a) and prothionamide (5b) were discovered during efforts to improve on the MTb inhibitory activity of nicotinamide. Thioisonicotinamide (Fig. 5; 5c) showed better in vivo efficacy than in vitro efficacy [97] which prompted further SAR studies on this series resulting in the observation that 2-alkyl derivatives were more active than the parent nicotinamide with 2-ethyl and 2-propyl derivatives showing the best activity. Ethionamide (5a) is a prodrug that is activated by S-oxidation by a monoxygenase (EtaA) to a 4-pyridylmethane radical intermediate that, similar to the active radical produced from INH by KatG (discussed in Sect. 2.2), reacts with NAD(P) to form a tight-binding inhibitor of InhA [98, 99]. The sulfoxide, the major metabolite produced in humans, is also active against MTb. The thioisonicotinamides have unpleasant gastrointestinal side effects.

Thiacetazone (Fig. 5; 3b) was discovered to have antitubercular activity in the 1940s and was used as an antitubercular agent despite its toxic side effects [100, 101]. Thiacetazone, similar to the thioisonicotinamides, is activated by EthA resulting in a reactive intermediate that inhibits mycolic acid oxygenation as well as cyclopropanation [102, 103]. Thiacetazone causes gastrointestinal disturbances and, particularly in HIV-infected patients, can cause severe life-threatening skin reactions known as Stevens-Johnson syndrome [104].

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