Abstract
Approximately 1 in every 4 of people in the world are infected with TB, with majority presenting clinically asymptomatic and subsequently being diagnosed with latent-TB disease or infection (LTBI) through a positive Mantoux tuberculin skin test (TST). LTBI currently has limited, prolonged treatment modalities putting those affected at potential risk for complications or resistance during treatment which warrants the development of new anti-TB agents. Previously, efforts towards further development of bactericidal agents targeting inhibition of FadD32, a dual enzymatic action ligase that is a key step in Mycobacterium tuberculosis (M. tb) cell wall biosynthesis, were focused upon. Scaffold hopping techniques were employed on formerly published potent FadD32 inhibitor analogs with coumarin-based scaffolds which led to the discovery of novel, potent 2-quinolone-based agents that still, unfortunately exhibited suboptimal characteristics pointing towards probable poor translational capabilities. A route for improving translational capabilities is employing a prodrug strategy to enhance the delivery of an agent into a human host or microbial entity. Efforts for prodrug design to allow for enhanced delivery to FadD32 and human systemic circulation were focused upon by employing larger L-amino-acid based moieties or phosphoryl ester moieties hypothesized to demonstrate advantageous physicochemical properties and therefore pharmacodynamics/pharmacokinetics (PK/PD) that could allow for efficacy. These prodrugs in comparison to their parent drugs boast up to 8-fold increased antimycobacterial activity likely through enhanced delivery to M. tb or metabolite synergism, aqueous stability comparable to FDA approved prodrug therapeutic agents, up to 225-fold increased solubility, up to doubly increased permeability, and enticing predictive PK parameters in humans. Herein, synthesis and characterization, antimicrobial evaluation, physicochemical characterization rationalized by computational chemistry and in vitro-in vivo pharmacokinetic extrapolation analysis will be described.