Abstract
Tuberculosis has been described as a global health crisis since the 1990s, with an estimated 1.4 million deaths in the last year. Herein, a series of 20 1H-indoles were synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Furthermore, the top hit compounds were active against multidrug-resistant strains, without cross-resistance with first-line drugs. Exposing HepG2 and Vero cells to the molecules for 72 h showed that one of the evaluated structures was devoid of apparent toxicity. In addition, this 3-phenyl-1H-indole showed no genotoxicity signals. Finally, time-kill and pharmacodynamic model analyses demonstrated that this compound has bactericidal activity at concentrations close to the Minimum Inhibitory Concentration, coupled with a strong time-dependent behavior. To the best of our knowledge, this study describes the activity of 3-phenyl-1H-indole against Mtb for the first time.
Highlights
Tuberculosis (TB) is an ancient disease, dating back to 70,000 years ago, and remains a global public health emergency causing more than 1 million deaths each year
The present study describes the synthesis of 3-phenyl-1H-indoles and their in vitro activity against drug-susceptible and drug-resistant Mycobacterium tuberculosis (Mtb) strains
The method was highly regioselective, allowing 3-phenyl-1H-indoles to be obtained in a catalytic system based on palladium(II) acetate/bis(diphenylphosphino)methane [Pd(OAc)2/dppm] using water as solvent
Summary
Tuberculosis (TB) is an ancient disease, dating back to 70,000 years ago, and remains a global public health emergency causing more than 1 million deaths each year. The intracellular pathogen Mycobacterium tuberculosis (Mtb), the causative agent of human TB, is absorbed by the alveolar macrophages of the lung. At this point, most infections are eliminated by a functioning immune system. Our research group has synthesized and evaluated different heterocyclic compounds against drug-susceptible and drug-resistant Mtb strains, with some encouraging results [8–10]. The indole scaffold has been described in compounds endowed with antitubercular activity [11]. To the best of our knowledge, 3-phenyl-1H-indoles have not yet been evaluated as possible inhibitors of Mtb growth Within this context, the present study describes the synthesis of 3-phenyl-1H-indoles and their in vitro activity against drug-susceptible and drug-resistant Mtb strains. Antimycobacterial kinetic behavior was shown, with concomitant exploration of a pharmacodynamic model
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