Design, Synthesis And Evaluation Of Novel Antimycobacterial Compounds Targeting The MmpL3 Transporter Protein.

Abstract

Tuberculosis (TB) is an airborne infectious disease caused by Mycobacterium tuberculosis (M. tb). TB is one of the leading causes of death in developing countries. Current TB therapy requires a minimum six-month treatment and is associated with increasing drug resistance and decreased patient compliance. Therefore, new anti-TB compounds with novel mechanisms of action that have activity against resistant strains and can potentially reduce treatment duration are urgently needed. Mycolic acids are the primary lipid components in the mycobacterial cell wall and are responsible for mycobacterial cell wall integrity, permeability and virulence. Mycobacterial membrane protein large 3 (MmpL3) is an essential transporter responsible for the translocation of mycolic acids to the outer membrane. Published indole-2-carboxamides with suggested MmpL3 inhibition showed good potency, against whole-cell M. tb, yet had poor aqueous solubility. This project hypothesizes that bioisosteric replacement of the indole ring, will maintain anti-tubercular activity with improved aqueous solubility leading to enhanced pharmacokinetics. The project focuses on retaining the required pharmacophore and increasing the molecular heteroatom percentage by reducing lipophilic atoms. The designed and synthesized indole bioisosteres are pyrrole, mandelic acid and imidazole, coupled to lipophilic head groups ensuring anti-tubercular activity. In addition to minimum inhibitory concentration (MIC) determination, the active compounds were subjected to in vitro ADMET assays, including aqueous solubility, permeability and metabolic stability toward mouse liver S9 fractions, to determine their suitability for further in vivo preclinical evaluation.|Lead compounds had improved pharmacokinetics over their indole-2-carboxamide analogs while their potency against mycobacteria varied. It was observed that an improvement in the aqueous solubility negatively impacted the anti-tubercular potency. Pyrrole analogs were found to be the best with respect to activity and had an improved solubility, permeability and were metabolically stable.