Benzothiadiazinone-1,1-Dioxide Carbonic Anhydrase Inhibitors Suppress the Growth of Drug-Resistant <i>Mycobacterium tuberculosis</i> Strains

2 H -Benzo[e][1,2,4]thiadiazin-3(4 H )-one 1,1-dioxide (BTD) based carbonic anhydrase (CA) inhibitors are here explored as new anti-mycobacterial agents. The chemical features of BTD derivatives meet the criteria for a potent inhibition of β-class CA isozymes. BTD derivatives show chemical features meeting the criteria for a potent inhibition of β-class CA isozymes. Specifically, three β-CAs (MtCA1, MtCA2, and MtCA3) were identified in Mycobacterium tuberculosis and their inhibition was shown to exert an antitubercular action. BTDs derivatives 2a-q effectively inhibited the mycobacterial CAs, especially MtCA2 and MtCA3, with K i values up to a low nanomolar range (MtCA3, K i = 15.1-2250 nM; MtCA2, K i = 38.1-4480 nM) and with a significant selectivity ratio over the off-target human CAs I and II. A computational study was conducted to elucidate the compound structure-activity relationship. Importantly, the most potent MtCA inhibitors demonstrated efficacy in inhibiting the growth of M. tuberculosis strains resistant to both rifampicin and isoniazid-standard reference drugs for Tuberculosis treatment.