Design of (quinolin-4-ylthio)carboxylic acids as new Escherichia coli DNA gyrase B inhibitors: machine learning studies, molecular docking, synthesis and biological testing

Highlights

• We have reported a set of QSAR models to predict the antimicrobial activity of quinoline derivatives.

• Machine learning methods implemented in OCHEM were used for model building with good predictive ability.

• The docking results have shown that all compounds inhibit the B subunit of DNA gyrase.

• Designed and synthesized quinoline derivatives can be considered as promising antibacterial agents against MDR E. coli strains.

Abstract

Spread of multidrug‐resistant Escherichia coli clinical isolates is a main problem in the treatment of infectious diseases. Therefore, the modern scientific approaches in decision this problem require not only a prevention strategy, but also the development of new effective inhibitory compounds with selective molecular mechanism of action and low toxicity. The goal of this work is to identify more potent molecules active against E. coli strains by using machine learning, docking studies, synthesis and biological evaluation. A set of predictive QSAR models was built with two publicly available structurally diverse data sets, including recent data deposited in PubChem. The predictive ability of these models tested by a 5-fold cross-validation, resulted in balanced accuracies (BA) of 59–98% for the binary classifiers. Test sets validation showed that the models could be instrumental in predicting the antimicrobial activity with an accuracy (with BA = 60–99 %) within the applicability domain. The models were applied to screen a virtual chemical library, which was designed to have activity against resistant E. coli strains. The eight most promising compounds were identified, synthesized and tested. All of them showed the different levels of anti-E. coli activity and acute toxicity. The docking results have shown that all studied compounds are potential DNA gyrase inhibitors through the estimated interactions with amino acid residues and magnesium ion in the enzyme active center The synthesized compounds could be used as an interesting starting point for further development of drugs with low toxicity and selective molecular action mechanism against resistant E. coli strains. The developed QSAR models are freely available online at OCHEM http://ochem.eu/article/112525 and can be used to virtual screening of potential compounds with anti-E. coli activity.

Introduction

E. coli is the most common gram-negative human pathogen and the leading cause of different types of infections such as kidneys and urinary tract infections (McLellan and Hunstad, 2016), gallbladder infections, skin and respiratory infections, intestinal infectious diseases, bacteremia and meningitis in infants (Tchesnokova et al., 2015). The important problem also is the complications caused by multi-drug resistant (MDR) E. coli - a sharp renal failure, inflammatory processes in various organs (pneumonia, encephalitis and meningitis), toxic shock (sharp hypotonia of a toxic etiology) (Rasheed et al., 2014). In the modern conditions, the emergence of new types of MDR E. coli strains is formed quicker, than a development of new and effective antibiotics. Nitrogen-containing heterocycle quinoline derivatives seem to us the promising class of biological active compounds with high antibacterial properties directed against different clinical E. coli strains (Mashkovskiy, 2017).

The most promising derivatives of 8-hydroxyquinoline and quinolones-4 (Fig. 1) are used to develop a number of potential antibacterial agents (Kamal et al., 2015; Brazhko et al., 2013; Omelianchyk et al., 2018a). Despite the different chemical structure and composition, preparations of this group are characterized by the lack of cross-resistance with antibiotics (Mashkovskiy, 2017). Introduction of chlorine atom (s) and (or) bromine in the molecule of 8-hydroxyquinolines leads to a significant increase in their bioaction, and fluoride (s) - for quinolones-4 - in general, created the preconditions for the development of synthetic antibiotics. On the basis of quinolone derivatives, a number of antimicrobial drugs, in particular, synthetic antibiotics - fluoroquinolones (ofloxacin, norfloxacin, levofloxacin, etc.) have been developed.

Derivatives of 8-hydroxyquinoline (5-NOK, enteroseptol, quinozol, etc.) are also widely used in medicine and veterinary medicine in the treatment of various infections (Mashkovskiy, 2017), have a broad spectrum of action against gram-positive (S. aureus, Enterococcus, Diplococcus, Corinebacterium) and gram-negative (Ps. vulgaris, Salmonella, Shigella) pathogens and also fungi (C. albicans). But derivatives of 8-hydroxyquinoline are ineffective against E. coli (Brazhko et al., 2013).

Recently, intensive studies are carried out among the modifications in the 7th position of quinolones-4 and halogen-substituted quinolines with methoxy group (moxifloxacin, bedaquiline) (Mashkovskiy, 2017; Kamal et al., 2015).

Thiosubstituted 2- and 4-quinolines have attracted an increasing interest among other quinoline derivatives (Fig. 2) (Brazhko et al., 2013; Omelianchyk et al., 2018a; Zavgorodniy et al., 2015; Omelianchyk et al., 2018b; Brazhko, 2014; Brazhko and Zavgorodniy, 2018). The study of antimicrobial activity of 2-thio-derivative quinoline has shown that most of the investigated compounds are active against gram-positive bacteria. Introduction to the 4th position of the quinoline ring of the methyl group (R = CH₃) and the branching of the carbon chain to the carboxylic acid residue (Fig. 3) led to a significant fungistatic action of these compounds.

Investigation of antimicrobial action 4-thioquinolines showed different degrees of activity against gram-positive and gram-negative microorganisms. The spectrum and the level of antimicrobial activity of 4-S-substituted quinolines are significantly affected by the characteristics of the carbon skeleton. Thus, the study of S-(quinaldine-4-yl)-l-cysteines and their analogues showed that the modifiers of 2-aminopropanoic acids (S-(heteryl-4-yl)-l-cysteines) are more effective than (quinolin-4-ylthio) acetate or propanoic acids derivatives (Brazhko et al., 2013; Brazhko, 2014).

All of the foregoing became a prerequisite for the in silico and in vitro study of the antibacterial activity of quinoline derivatives that will be used as a conceptual framework towards the design of further hybrid molecules with improved activity. In this work we report machine learning and molecular docking studies, design, synthesis and in vitro antibacterial activity of series of novel (quinolin-4-ylthio)carboxylic acids as quinoline derivatives against number of MDR E. coli strains.