Optimization of N-(1-Adamantyl)-3-Aryl Acetamides as Novel Antimycobacterial Agents
Tuberculosis (TB) is caused by the pathogen Mycobacterium tuberculosis (Mtb) and is one of the top 10 causes of death worldwide, accounting for approximately 10 million new cases per year. Current therapy for active TB pulmonary infections constitutes multiple-drug therapy for greater than six months. Treatment for MDR/XDR TB can extend for several years and includes medications with serious adverse event profiles. Nontuberculous mycobacterial (NTM) infections are opportunistic infections in immunocompromised patients and those with underlying structural lung disease. Treatment for NTM infections necessitates greater than 1 year of multiple-drug antimicrobial therapy and is associated with significant adverse effects. Due to the prevalence of resistant TB and NTM infections, the lengthy duration of therapy, and the serious adverse event profiles of current treatment options, new antimycobacterial agents with novel mechanisms of action are direly needed. Mycobacteria membrane protein large 3 (MmpL3) is a transmembrane protein responsible for shuttling mycolic acids from the cytosol to the outer membrane of mycobacteria, and its inhibition results in mycobacterial growth inhibition. Previously, urea- and indole-based MmpL3 inhibitors have demonstrated promising antimycobacterial activity with sub-μg/mL MIC values, but both series have poor aqueous solubility, limiting their advancement through the drug development pipeline. Novel acetamide-based MmpL3 inhibitors were discovered in our lab with high antimycobacterial potency and improved aqueous solubility by approximately 30-fold over urea- and indole-based inhibitors. Herein, this study reports further optimization of our acetamide-based MmpL3 inhibitors and expanding structure activity relationships by exploring di- and tri-substituted aryl substituents, varied electron-withdrawing moieties, and ionization potential resulting in improved mycobacterial growth inhibition while maintaining acceptable pharmacokinetic parameters. Generally, activity was reduced against M. abscessus for this series. However, three lead acetamides (229, 218, 223) were able to further improve Mtb activity, all achieving an Mtb MIC = 0.125 μg/mL. Additionally, two lead acetamides (220 and 231) were identified with acceptable anti-Mtb activity, moderate aqueous solubility, high plasma protein binding, good permeability, and low metabolic stability. These data support further optimization of this novel chemotype for the treatment of Mtb infections.
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