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

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.

A Review on Multipurpose Potential of Bioactive Heterocycle Quinoxaline

“…Further in vitro cytotoxicity on human hepatocellular carcinoma (HepG2 cell line) was evaluated which showed that compound 142 was a potential antineoplastic agent with selective cytotoxicity against hepatic (HepG2), ovarian (SK‐OV‐3), and prostate (PC‐3) cancer cell lines. Moreover, compound 142 was docked to study inhibition towards mycobacterial DprE1 where outcomes were promising [7c] …”

Chemistry, Synthesis, and Structure Activity Relationship of Anticancer Quinoxalines

“…Quinoxaline molecules are named benzopyrazines or 1,4-benzodiazines [41][42][43]. There are four benzodiazines: quinoxaline, quinazolines, phthalazines, and cinnolines.…”

Late-stage diversification of indole skeletons through nitrogen atom insertion

“…In this context, the direct insertion of a nitrogen atom into the indole scaffold would represent an extremely advantageous process, as it would enable the straightforward access of N,N-heterocycles without changing the substitution pattern on the starting indole scaffold. This transformation of the indole core into such bioisosteric motifs (31,32), which are not commonly found as building blocks in medicinal chemistry libraries (33) yet are widely recognized as privileged pharmacophores in modern drug discovery (30,34), could have a transformative impact on the field of late-stage diversification, facilitating the discovery and optimization of drug candidates.…”