Synthesis, Biological Evaluation, and In Silico Modeling of N-Substituted Quinoxaline-2-Carboxamides.

Ghada Bouz,Jan Zitko,Jarmila Vinšová,Pavel Bárta,Ondřej Janďourek,Sarah Bouz,Martin Doležal,Klára Konečná

doi:10.3390/ph14080768

Abstract

Despite the established treatment regimens, tuberculosis remains an alarming threat to public health according to WHO. Novel agents are needed to overcome the increasing rate of resistance and perhaps achieve eradication. As part of our long-term research on pyrazine derived compounds, we prepared a series of their ortho fused derivatives, N-phenyl- and N-benzyl quinoxaline-2-carboxamides, and evaluated their in vitro antimycobacterial activity. In vitro activity against Mycobacterium tuberculosis H37Ra (represented by minimum inhibitory concentration, MIC) ranged between 3.91–500 µg/mL, with most compounds having moderate to good activities (MIC < 15.625 µg/mL). The majority of the active compounds belonged to the N-benzyl group. In addition to antimycobacterial activity assessment, final compounds were screened for their in vitro cytotoxicity. N-(naphthalen-1-ylmethyl)quinoxaline-2-carboxamide (compound 29) was identified as a potential antineoplastic agent with selective cytotoxicity against hepatic (HepG2), ovarian (SK-OV-3), and prostate (PC-3) cancer cells lines. Molecular docking showed that human DNA topoisomerase and vascular endothelial growth factor receptor could be potential targets for 29.

Highlights

Quinoxaline is an attractive core in medicinal chemistry
To conclude, based on our experience with pyrazinecarboxamides and their antimycobacterial activity, we intended to study the influence of the quinoxaline core on such activity
We found that N-phenyl derivatives exerted the best activity against Mtb H37Ra and that the lipophilic nature of the substituent has no direct influence on the activity

Summary

Introduction

Quinoxaline is an attractive core in medicinal chemistry. Structure wise, quinoxaline is an isostere of quinoline (N for C) and naphthalene (2N for 2C), while it is a bioisostere of quinazoline, indole, benzimidazole, benzothiophene, and benzothiazole. Pyrazinamide (Figure 2a) is a first-line antitubercular drug hydrolyzed by nicotinamidases to its active form pyrazinoic acid (pyrazine-2-carboxylic acid) in the cytoplasm [1]. As an attempt to develop novel antituberculars, Seitz et al prepared several derivatives of quinoxaline-2-carboxylic acids [3]. They identified one ester of quinoxaline2-carboxylic acid, which acts as a prodrug with potent in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra (Mtb H37Ra) (refer to Figure 2b). They suggested that the acetoxy group in the compound will be reduced to the free hydroxy group

Methods

Results

Conclusion