Design, synthesis and in vitro evaluation of a series of endoperoxide hybrids designed to tackle latent tuberculosis
Year: 2023
Type: dissertation
Abstract: Mycobacterium tuberculosis (Mtb) is the world's second leading cause of death from infectious diseases (after COVID-19). The ability of Mtb to enter the nonreplicating persistence (NRP) and then transition to latent TB contributes to Mtb's drug tolerance and treatment failure in chronically infected individuals. The DosRST two-component regulatory system regulates the Mtb physiology to promote NRP, in which peroxides such as the natural antimalarial drug artemisinin and synthetic 1,2,4-trioxolanes have been demonstrated to inhibit this system and re-sensitize Mtb. Hence, we proposed hybridizing two separate anti-TB classes by combining the 1,2,4-trioxane-containing moieties with the indole-2-carboxamide scaffold (MmpL3 inhibitors) and the benzothiazinone scaffold (DprE1 inhibitors), to establish a dual mode of action, by increasing Mtb's sensitivity to the active anti-TB pharmacophore while also targeting the DosRST signalling. These hybrid compounds prepared were evaluated for their in vitro antimycobacterial activity, and the drug metabolism and pharmacokinetics parameters were also assessed. Additionally, we evaluated ~1519 DprE1 inhibitors disclosed in the literature from 2009-2022 by performing an in-depth analysis of physicochemical descriptors and absorption, distribution, metabolism, elimination, and toxicology properties to deepen our understanding of DprE1 inhibitors and build machine learning classification models.
Author: Amado, Patrícia Sofia Menalha
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7055627000