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

• Published in: International journal of molecular sciences 2024-02, Vol.25 (5), p.2584
• Main Authors: Bua, Silvia, Bonardi, Alessandro, Mük, Georgiana Ramona, Nocentini, Alessio, Gratteri, Paola, Supuran, Claudiu T
• Format: Article
• Language: English
• Subjects: Bacteria; Carbon dioxide; Drug resistance; Multidrug resistant organisms; Tuberculosis; Virulence
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25052584

2 -Benzo[e][1,2,4]thiadiazin-3(4 )-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 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 values up to a low nanomolar range (MtCA3, K = 15.1-2250 nM; MtCA2, K = 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 strains resistant to both rifampicin and isoniazid-standard reference drugs for Tuberculosis treatment.