Synthesis and structure-activity relationships of novel fused ring analogues of Q203 as antitubercular agents

Abstract A set of fused ring analogues of a new antitubercular agent, Q203, was designed and synthesized. To reduce the lipophilicity of Q203 caused by linearly extended side chains, shorter and heteroatoms containing fused rings were introduced into the side chain region. Antitubercular activity was tested against H37Rv-GFP replicating in liquid broth culture medium (extracellular) and within macrophages (intracellular). Many analogues showed potent extracellular activities as well as intracellular activities without cytotoxicity. Among them, compounds 18–21 displayed significant antitubercular activities with favorable metabolic stabilities. Representative compound 21 exhibited excellent in vivo pharmacokinetic values at high drug exposure levels in the plasma, which makes this compound promising candidate for a new antitubercular drug.