Novel 4-aminoquinolines: Synthesis, inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase, antitubercular activity, SAR, and preclinical evaluation

Herein a series of 4-aminoquinolines were synthesized in an attempt to optimize and study the structural features related to LABIO-17 biological activity, a Mycobacterium tuberculosis NADH-dependent enoyl-acyl carrier protein reductase (MtInhA) inhibitor previously identified by a virtual-ligand-screening approach. Structure-activity relationships led to novel submicromolar inhibitors of MtInhA and potent antitubercular agents. The lead compound is 87-fold more potent as enzymatic inhibitors and 32-fold more potent against M. tuberculosis H37Rv strain in comparison with LABIO-17. These molecules were also active against multidrug-resistant strains, devoid of apparent toxicity to mammalian cells and showed favorable in vitro ADME profiles. Additionally, these compounds were active in an intracellular model of tuberculosis (TB) infection, showed no genotoxicity signals, satisfactory absorption parameters and absence of in vivo acute toxicity. Finally, treatment with selected 4-amino-quinoline for two weeks produced bacteriostatic effect in a murine model of TB. Taken together, these findings indicate that this chemical class may furnish candidates for the future development of drug-sensitive and drug -resistant tuberculosis treatments.

Automated summary

A series of 4-aminoquinolines were synthesized and evaluated for their antitubercular activity. These compounds showed potent inhibitory activity against Mycobacterium tuberculosis and were effective against multidrug-resistant strains. Additionally, they exhibited satisfactory absorption properties, low toxicity, and demonstrated activity in an intracellular model of tuberculosis infection. Treatment with a selected compound showed a bacteriostatic effect in a murine model of tuberculosis. These findings suggest that this chemical class could be potential candidates for the development of tuberculosis treatments.