Synthesis and anti-tubercular activity of conformationally-constrained and bisquinoline analogs of TMC207

Abstract

One of the most significant breakthroughs in the battle against tuberculosis is the recent approval of the quinoline compound, TMC207, for the treatment of drug-resistant tuberculosis. To gain insight into the molecular determinants of the activity of TMC207 and to evaluate the scope of quinoline compounds as antitubercular agents, we synthesized a series of TMC207 derivatives and evaluated their anti-tubercular activity. Making the lateral chain of the drug rigid by linking it to an adjacent phenyl substituent resulted in a decrease in activity. In contrast, replacing a phenyl substituent of TMC207 with a quinoline moiety gave bisquinolines that demonstrated potent antitubercular activity in in vitro experiments, in ex vivo mouse bone marrow macrophage assays, and also in in vivo mouse model of the disease. These results provide new guiding principles for modifying the TMC207 scaffold for developing efficacious anti-tubercular drugs and set the stage for the development of bisquinolines as a promising new class of antitubercular agents.

Synthetic approaches to potent heterocyclic inhibitors of tuberculosis: A decade review

“…In the same year, Kalia et al reported the synthesis of conformationally constrained and bisquinoline analogs of TMC207 and investigated their antitubercular activity ( Kalia et al, 2015 ). Constricted analogs of TMC207 were prepared using benzyl quinoline anion with proper cyclic ketone analogs of the Mannich base as reported earlier ( Guillemont et al, 2011 ).…”

Novel candidates in the clinical development pipeline for TB drug development and their synthetic approaches

“…Conformationally constrained and bisquinoline (replacing a phenyl substituent of TMC207 with a quinoline moiety) analogues of TMC207/bedaquiline have been reported to gain insight into the molecular determinants of the activity of TMC207. However, drug rigidity of lateral chain resulted in a decrease in activity, but bisquinolines demonstrated potent antitubercular activity in in vitro experiments and also in in vivo mouse model of the disease (Kaliaa et al, 2015). Additionally, a novel series of aryl sulphonamide derivatives of amodiaquine (Khana et al, 2013;Singh et al, 2013) have been investigated for selective mycobacterial ATP synthase inhibitory activity against both replicating and non-replicating M. tuberculosis resulting in ATPase inhibitory activities (IC50) of these compounds that range between 0.36 and 5.45 µm (Singh, Roy, et al, 2015).…”

Synthesis, Docking, and Pharmacological Evaluation of Derivatives of α‐Aminoketones Appended to Sydnones as Potent Antitubercular and Antifungal Scaffolds

“…Pentacyclo‐undecane derivatized tetra‐amines having tertiary amine units in the cyclic form were prepared and found to be potent antitubercular agents . Bisquinoline analogs of TMC207 and conformational‐constrained molecules possessing tertiary amine unit were reported, and they possessed remarkable antitubercular potency . A set of 9‐benzylpurines possessing tertiary amine unit was synthesized among which 2‐chloro‐4(2‐furanyl)‐9‐benzylpurine was reported to inhibit Mycobacterium tuberculosis H 37 R V with lowest minimum inhibitory concentration (MIC) value .…”