Abstract
The emergence of multi-drug (MDR-TB) and extensively-drug resistant tuberculosis (XDR-TB) is a major threat to the global management of tuberculosis (TB) worldwide. New chemical entities are of need to treat drug-resistant TB. In this study, the mode of action of new, potent quinazoline derivatives was investigated against Mycobacterium tuberculosis (M. tb). Four derivatives 11626141, 11626142, 11626252 and 11726148 showed good activity (MIC ranging from 0.02–0.09 μg/mL) and low toxicity (TD50 ≥ 5μg/mL) in vitro against M. tb strain H37Rv and HepG2 cells, respectively. 11626252 was the most selective compound from this series. Quinazoline derivatives were found to target cytochrome bc1 by whole-genome sequencing of mutants selected with 11626142. Two resistant mutants harboured the transversion T943G (Trp312Gly) and the transition G523A (Gly175Ser) in the cytochrome bc1 complex cytochrome b subunit (QcrB). Interestingly, a third mutant QuinR-M1 contained a mutation in the Rieske iron-sulphur protein (QcrA) leading to resistance to quinazoline and other QcrB inhibitors, the first report of cross-resistance involving QcrA. Modelling of both QcrA and QcrB revealed that all three resistance mutations are located in the stigmatellin pocket, as previously observed for other QcrB inhibitors such as Q203, AX-35, and lansoprazole sulfide (LPZs). Further analysis of the mode of action in vitro revealed that 11626252 exposure leads to ATP depletion, a decrease in the oxygen consumption rate and also overexpression of the cytochrome bd oxidase in M. tb. Our findings suggest that quinazoline-derived compounds are a new and attractive chemical entity for M. tb drug development targeting two separate subunits of the cytochrome bc1 complex.
Highlights
With more than 1.7 million deaths worldwide, including 0.4 million HIV-positive patients, tuberculosis (TB) is the leading cause of death due to a single infectious agent. [1] In 2016, an estimated 10.4 million people fell ill with TB. [1] Treatment of drug-susceptible TB (DS-TB) relies on a combination therapy of isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB) for 6 months
[6] it was discovered that resistant mutants to DAQ harboured a mutation in rv3161c, a potential dioxygenase, and that DAQ act as a pro-drug in mycobacteria, the mode of action of these derivatives remains unknown in M. tb
Seventy-six original quinazoline derivatives were synthesized. (S1 Table) Different substitutions were introduced in the phenyl moiety of quinazoline scaffold as well as different amino substitutions in position 4 and different thioalkyls in position 2 of the molecule to study the structure-activity relationship (SAR) and to find the most active compounds
Summary
With more than 1.7 million deaths worldwide, including 0.4 million HIV-positive patients, tuberculosis (TB) is the leading cause of death due to a single infectious agent. [1] In 2016, an estimated 10.4 million people fell ill with TB. [1] Treatment of drug-susceptible TB (DS-TB) relies on a combination therapy of isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB) for 6 months. Despite the high efficacy of the DS-TB treatment, 490,000 new cases of TB were reported in 2016 to be resistant to both RIF and INH and classified as multidrug-resistant (MDR-TB). [1] In 2016, 6.2% of MDR-TB cases were defined as extensively-resistant TB (XDR-TB) on the basis of their resistance to the main second-line drugs. Heterocyclic compounds are the backbone of modern medicinal chemistry. This versatile chemical class provides the ability to expand the available drug-like chemical space and drive more efficient delivery of drug discovery programs. Derivatives of the quinazoline moiety, known as 1,3-benzodiazine, were previously shown to have antibacterial, antifungal, anticonvulsant, anti-inflammatory, anti-HIV, anticancer and analgesic activities, with slight modifications of the quinazoline nucleus improving activity. Derivatives of the quinazoline moiety, known as 1,3-benzodiazine, were previously shown to have antibacterial, antifungal, anticonvulsant, anti-inflammatory, anti-HIV, anticancer and analgesic activities, with slight modifications of the quinazoline nucleus improving activity. [4] For M. tb, antimycobacterial activity against strain H37Rv in vitro was previously reported for quinazoline 2-carboxylate derivatives, more precisely, thiazoloquinazoline carboxylates. [5] diaminoquinazolines (DAQ) were shown to selectively inhibit M. tb growth in a range of 1.3–6.1 μg/mL. [6] it was discovered that resistant mutants to DAQ harboured a mutation in rv3161c, a potential dioxygenase, and that DAQ act as a pro-drug in mycobacteria, the mode of action of these derivatives remains unknown in M. tb
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