Abstract
The worldwide incidence of active tuberculosis (TB) infection was reported to be 9.6 million with the disease responsible for 1.5 million deaths in 2014 despite current treatment approaches that require the use of multiple antimycobacterial agents for extended periods of time. Furthermore, the emergence of the drug-resistant strains has complicated the problem with approximately 190,000 deaths attributed to multidrug-resistant TB (MDR-TB) in 2014. There is a crucial need for the discovery of new anti-TB agents and the reconsideration of older drugs with potent anti-TB activity is a common approach. Clofazimine is an old anti-leprosy agent that has good activity against MDR and extensively drug-resistant (XDR) strains. However, clofazimine’s extreme lipophilicity leads to substantial drug accumulation and drug crystallization in body organs and fatty tissues. These crystalline deposits cause gastrointestinal (GI) adverse effects, generalized tissue inflammation, and an undesired reddish-brown discoloration of the skin and conjunctiva. Therefore, structural modifications of clofazimine that would reduce its high lipophilicity while retaining good anti-TB activity would yield an improved anti-TB agent. In this project, the focus was to change the scaffold along with changing two of the substituents. The addition of hydrophilic atoms, such as nitrogen and oxygen, and the removal of lipophilic atoms, such as chlorine, decreased the lipophilicity up to 4000 folds. However, compounds 11, 13 and 16 were potent against M. tuberculosis H37Rv strains with MIC values ≤ 0.8 µg/mL. Among the three potent compounds, compound 13 had the highest solubility, with a solubility value of 3.66 µg/mL, the highest permeability, with an apparent permeability (Pe) value of 65.27 x 10-3 cm/s, and the lowest fraction retained in the membrane, with an R value of 0.299. The improved solubility, permeability and membrane retention suggests that compound 13 is a promising anti-TB agent that has a decreased tendency for lipid accumulation, suggesting improved in vivo absorption, distribution and metabolic profile. The anticipated decrease in fat tissue and body organ accumulation is expected to decrease the GI toxicity and discoloration problem which could lead to improved patient compliance.