Side Chain-modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity

Fan Dongguang; Bin Wang; Giovanni Stelitano; Karin Savková; Olga Riabova; Rui Shi; Xiaomei Wu; Laurent R. Chiarelli; Katarína Mikušová; Vadim Makarov; Yu Lu; Yuzhi Hong; Chunhua Qiao

doi:10.20944/preprints202305.1839.v2

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preprints.org > medicine and pharmacology > medicine and pharmacology > doi: 10.20944/preprints202305.1839.v2

Preprint Article Version 2 Preserved in Portico This version is not peer-reviewed

Side Chain-modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity

Version 1 : Received: 24 May 2023 / Approved: 26 May 2023 / Online: 26 May 2023 (04:12:31 CEST)
Version 2 : Received: 30 May 2023 / Approved: 1 June 2023 / Online: 1 June 2023 (07:42:34 CEST)

A peer-reviewed article of this Preprint also exists.

Fan, D.; Wang, B.; Stelitano, G.; Savková, K.; Riabova, O.; Shi, R.; Wu, X.; Chiarelli, L.R.; Mikušová, K.; Makarov, V.; Lu, Y.; Hong, Y.; Qiao, C. Side Chain-Modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity. Biomedicines 2023, 11, 1975. Fan, D.; Wang, B.; Stelitano, G.; Savková, K.; Riabova, O.; Shi, R.; Wu, X.; Chiarelli, L.R.; Mikušová, K.; Makarov, V.; Lu, Y.; Hong, Y.; Qiao, C. Side Chain-Modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity. Biomedicines 2023, 11, 1975.

Abstract

Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169, an inhibitor of the decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1) in Mycobacterium tuberculosis (Mtb), showed anti-TB potential in animal model and piloted clinical tests. Although highly potent, the BTZ type DprE1 inhibitors in general shows extremely low aqueous solubility, which adversely affect the drug like property. To improve the compounds physiochemical properties, we generated a series of BTZ analogues. Several optimized compounds had MIC values against Mtb in single digit nanomolar. The representative compound 37 displayed improved solubility and bioavailability compared to the lead compound. Additionally, compound 37 shows Mtb-killing ability in an acute infection mouse model.

Keywords

Anti-tubercular agents; DprE1 inhibitor; Structure activity relationship; in vivo activity

Subject

Medicine and Pharmacology, Medicine and Pharmacology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Comment 1

Received: 1 June 2023
Commenter: Vadim Makarov
Commenter's Conflict of Interests: Author

Comment: We made some small changes and correct English.

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