Mycobacterium tuberculosis Inhibitors Based on Arylated Quinoline Carboxylic Acid Backbones with Anti-Mtb Gyrase Activity

Abstract

New antitubercular agents with either a novel mode of action or novel mode of inhibition are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new arylated quinoline carboxylic acids (QCAs) having activity against replicating and non-replicating Mycobacterium tuberculosis (Mtb), the causative agent of TB. Thus, the synthesis, characterization, and in vitro screening (MABA and LORA) of 48 QCAs modified with alkyl, aryl, alkoxy, halogens, and nitro groups in the quinoline ring led to the discovery of two QCA derivatives, 7i and 7m, adorned with C-2 2-(naphthalen-2-yl)/C-6 1-butyl and C-2 22-(phenanthren-3-yl)/C-6 isopropyl, respectively, as the best Mtb inhibitors. DNA gyrase inhibition was shown to be exhibited by both, with QCA 7m illustrating better activity up to a 1 μM test concentration. Finally, a docking model for both compounds with Mtb DNA gyrase was developed, and it showed a good correlation with in vitro results.

1-(2-(3,5-Di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl) Quinolin-1-ium Bromide

“…The unique structure of quinoline contributes to its interaction with biological systems, leading to its use in medicinal chemistry [7,8]. Quinoline and its derivatives have been employed in the synthesis of drugs with antimalarial [9,10], antitubercular [11,12], antitumor [13,14], antibacterial, and antifungal activities [15,16]. The nitrogen atom in the quinoline ring can serve as a coordination center for metal ions, a property exploited in many aspects of coordination chemistry [17,18].…”