2. Academic Validation
  3. Quinolone analogues of benzothiazinone: Synthesis, antitubercular structure-activity relationship and ADME profiling

Quinolone analogues of benzothiazinone: Synthesis, antitubercular structure-activity relationship and ADME profiling

  • Eur J Med Chem. 2023 Oct 5;258:115539. doi: 10.1016/j.ejmech.2023.115539.
Phelelisiwe S Dube 1,  Lesetja J Legoabe 2,  Audrey Jordaan 3,  Lester Sigauke 1,  Digby F Warner 3,  Richard M Beteck 4
Affiliations

Affiliations

  • 1 Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa.
  • 2 Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa. Electronic address: [email protected].
  • 3 Molecular Mycobacteriology Research Unit, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925, South Africa.
  • 4 Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa. Electronic address: [email protected].
PMID: 37321107 DOI: 10.1016/j.ejmech.2023.115539
Abstract

Mycobacterium tuberculosis (Mtb) has an impermeable cell wall which gives it an inherent ability to resist many Antibiotics. DprE1, an essential Enzyme in Mtb cell wall synthesis, has been validated as a target for several TB drug candidates. The most potent and developmentally advanced DprE1 inhibitor, PBTZ169, is still undergoing clinical development. With high attrition rate, there is need to populate the development pipeline. Using a scaffold hopping strategy, we imprinted the benzenoid ring of PBTZ169 onto a Quinolone nucleus. Twenty-two compounds were synthesised and screened for activity against Mtb, with six compounds exhibiting sub micromolar activity of MIC90 <0.244 μM. Compound 25 further demonstrated sub-micromolar activity when evaluated against wild-type and fluoroquinolone-resistant Mtb strains. This compound maintained its sub-micromolar activity against a DprE1 P116S mutant strain but showed a significant reduction in activity when tested against the DprE1 C387S mutant.

Keywords

Benzothiazinone; DprE1; Mycobacterium tuberculosis; Nitro compounds; Quinolone.

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