2H-Benzo[e][1,2,4]thiadiazin-3(4H)-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 beta-class CA isozymes. BTD derivatives show chemical features meeting the criteria for a potent inhibition of beta-class CA isozymes. Specifically, three beta-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.
Benzothiadiazinone-1,1-Dioxide Carbonic Anhydrase Inhibitors Suppress the Growth of Drug-Resistant Mycobacterium tuberculosis Strains / Bua, Silvia; Bonardi, Alessandro; Mük, Georgiana Ramona; Nocentini, Alessio; Gratteri, Paola; Supuran, Claudiu T.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1422-0067. - ELETTRONICO. - 25:(2024), pp. 2584.0-2584.0. [10.3390/ijms25052584]
Benzothiadiazinone-1,1-Dioxide Carbonic Anhydrase Inhibitors Suppress the Growth of Drug-Resistant Mycobacterium tuberculosis Strains
Bua, Silvia;Bonardi, Alessandro
;Nocentini, Alessio
;Gratteri, Paola;Supuran, Claudiu T.
2024
Abstract
2H-Benzo[e][1,2,4]thiadiazin-3(4H)-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 beta-class CA isozymes. BTD derivatives show chemical features meeting the criteria for a potent inhibition of beta-class CA isozymes. Specifically, three beta-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.File | Dimensione | Formato | |
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