2. Academic Validation
  3. SAR study of piperidine derivatives as inhibitors of 1,4-dihydroxy-2-naphthoate isoprenyltransferase (MenA) from Mycobacterium tuberculosis

SAR study of piperidine derivatives as inhibitors of 1,4-dihydroxy-2-naphthoate isoprenyltransferase (MenA) from Mycobacterium tuberculosis

  • Eur J Med Chem. 2023 Jan 18;249:115125. doi: 10.1016/j.ejmech.2023.115125.
Kaja Berg 1,  Pooja Hegde 1,  Venugopal Pujari 2,  Marzena Brinkmann 1,  David Z Wilkins 3,  Tanya Parish 3,  Dean C Crick 4,  Courtney C Aldrich 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street Southeast, Minneapolis, MN, 55455, USA.
  • 2 Mycobacteria Research Laboratories, Microbiology, Immunology, and Pathology Department, Colorado State University, Fort Collins, CO, 80523, USA.
  • 3 Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, 98109, USA.
  • 4 Mycobacteria Research Laboratories, Microbiology, Immunology, and Pathology Department, Colorado State University, Fort Collins, CO, 80523, USA. Electronic address: [email protected].
  • 5 Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street Southeast, Minneapolis, MN, 55455, USA. Electronic address: [email protected].
PMID: 36682292 DOI: 10.1016/j.ejmech.2023.115125
Abstract

The electron transport chain (ETC) in the cell membrane consists of a series of redox complexes that transfer electrons from electron donors to acceptors and couples this electron transfer with the transfer of protons (H+) across a membrane. This process generates proton motive force which is used to produce ATP and a myriad of other functions and is essential for the long-term survival of Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis (TB), under the hypoxic conditions present within infected granulomas. Menaquinone (MK), an important carrier molecule within the mycobacterial ETC, is synthesized de novo by a cluster of enzymes known as the classic/canonical MK biosynthetic pathway. MenA (1,4-dihydroxy-2-naphthoate prenyltransferase), the antepenultimate Enzyme in this pathway, is a verified target for TB therapy. In this study, we explored structure-activity relationships of a previously discovered MenA inhibitor scaffold, seeking to improve potency and drug disposition properties. Focusing our campaign upon three molecular regions, we identified two novel inhibitors with potent activity against MenA and Mtb (IC50 = 13-22 μM, GIC50 = 8-10 μM). These analogs also displayed substantially improved pharmacokinetic parameters and potent synergy with other ETC-targeting agents, achieving nearly complete sterilization of Mtb in combination therapy within two weeks in vivo. These new inhibitors of MK biosynthesis present a promising new strategy to curb the continued spread of TB.

Keywords

1,4-dihydroxy-2-naphthoate prenyltransferase; MenA; MenA inhibitors; Menaquinone; Mtb; Mycobacterium tuberculosis; Piperidine derivatives; SAR.

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