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.

Faculty of Pharmacy in Hradec Králové Charles University 50005 Hradec Králové Czech Republic

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Scorpio A., Zhang Y. Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus. Nat. Med. 1996;2:662–667. doi: 10.1038/nm0696-662. PubMed DOI

World Health Organization Global Tuberculosis Report 2020. [(accessed on 4 January 2021)]; Available online: www.who.int/tb/publications/global_report/en/

Seitz L.E., Suling W.J., Reynolds R.C. Synthesis and Antimycobacterial Activity of Pyrazine and Quinoxaline Derivatives. J. Med. Chem. 2002;45:5604–5606. doi: 10.1021/jm020310n. PubMed DOI

Carta A., Loriga M., Paglietti G., Mattana A., Fiori P.L., Mollicotti P., Sechi L., Zanetti S. Synthesis, anti-mycobacterial, anti-trichomonas and anti-candida in vitro activities of 2-substituted-6,7-difluoro-3-methylquinoxaline 1,4-dioxides. Eur. J. Med. Chem. 2004;39:195–203. doi: 10.1016/j.ejmech.2003.11.008. PubMed DOI

Carta A., Paglietti G., Nikookar M.E.R., Sanna P., Sechi L., Zanetti S. Novel substituted quinoxaline 1,4-dioxides with in vitro antimycobacterial and anticandida activity. Eur. J. Med. Chem. 2002;37:355–366. doi: 10.1016/S0223-5234(02)01346-6. PubMed DOI

Jampilek J. Recent Advances in Design of Potential Quinoxaline Anti-Infectives. Curr. Med. Chem. 2014;21:4347–4373. doi: 10.2174/0929867321666141011194825. PubMed DOI

Servusová B., Vobicková J., Paterová P., Kubíček V., Kuneš J., Doležal M., Zitko J. Synthesis and antimycobacterial evaluation of N-substituted 5-chloropyrazine-2-carboxamides. Bioorganic Med. Chem. Lett. 2013;23:3589–3591. doi: 10.1016/j.bmcl.2013.04.021. PubMed DOI

Zitko J., Servusová B., Janoutová A., Paterová P., Mandíková J.R., Garaj V., Vejsová M., Marek J., Doležal M. Synthesis and antimycobacterial evaluation of 5-alkylamino-N-phenylpyrazine-2-carboxamides. Bioorganic Med. Chem. 2015;23:174–183. doi: 10.1016/j.bmc.2014.11.014. PubMed DOI

Zitko J., Servusová B., Paterová P., Mandíková J., Kubíček V., Kučera R., Hrabcová V., Kuneš J., Soukup O., Doležal M. Synthesis, Antimycobacterial Activity and In Vitro Cytotoxicity of 5-Chloro-N-phenylpyrazine-2-carboxamides. Molecules. 2013;18:14807–14825. doi: 10.3390/molecules181214807. PubMed DOI PMC

Semelková L., Janošcová P., Fernandes C., Bouz G., Janďourek O., Konečná K., Paterová P., Navrátilová L., Kuneš J., Doležal M., et al. Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids. Molecules. 2017;22:1491. doi: 10.3390/molecules22091491. PubMed DOI PMC

Franzblau S.G., Witzig R.S., McLaughlin J.C., Torres P., Madico G., Hernandez A., Degnan M.T., Cook M.B., Quenzer V.K., Ferguson R.M., et al. Rapid, low-technology MIC determination with clinical Mycobacterium tuberculosis isolates by using the microplate Alamar Blue assay. J. Clin. Microbiol. 1998;36:362–366. doi: 10.1128/JCM.36.2.362-366.1998. PubMed DOI PMC

Heinrichs M.T., May R.J., Heider F., Reimers T., Sy S.K.B., Peloquin C.A., Derendorf H. Mycobacterium tuberculosis Strains H37ra and H37rv have equivalent minimum inhibitory concentrations to most antituberculosis drugs. Int. J. Mycobacteriol. 2018;7:156. doi: 10.4103/ijmy.ijmy_33_18. PubMed DOI

Sood S., Yadav A., Shrivastava R. Mycobacterium aurum is Unable to Survive Mycobacterium tuberculosis Latency Associated Stress Conditions: Implications as Non-suitable Model Organism. Indian J. Microbiol. 2016;56:198–204. doi: 10.1007/s12088-016-0564-x. PubMed DOI PMC

Mahesh R., Devadoss T., Pandey D.K., Bhatt S., Yadav S.K. Design, synthesis and structure–activity relationship of novel quinoxalin-2-carboxamides as 5-HT3 receptor antagonists for the management of depression. Bioorganic Med. Chem. Lett. 2010;20:6773–6776. doi: 10.1016/j.bmcl.2010.08.128. PubMed DOI

Owen D.R., Dodd P.G., Gayton S., Greener B.S., Harbottle G.W., Mantell S.J., Maw G.N., Osborne S.A., Rees H., Ringer T.J., et al. Structure–activity relationships of novel non-competitive mGluR1 antagonists: A potential treatment for chronic pain. Bioorganic Med. Chem. Lett. 2007;17:486–490. doi: 10.1016/j.bmcl.2006.10.015. PubMed DOI

Juhás M., Kučerová L., Horáček O., Janďourek O., Kubíček V., Konečná K., Kučera R., Barta P., Janoušek J., Paterová P., et al. N-Pyrazinoyl Substituted Amino Acids as Potential Antimycobacterial Agents—the Synthesis and Biological Evaluation of Enantiomers. Molecules. 2020;25:1518. doi: 10.3390/molecules25071518. PubMed DOI PMC

Yew W.W., Leung C.C. Antituberculosis drugs and hepatotoxicity. Respirology. 2006;11:699–707. doi: 10.1111/j.1440-1843.2006.00941.x. PubMed DOI

Kaushal T., Srivastava G., Sharma A., Negi A.S. An insight into medicinal chemistry of anticancer quinoxalines. Bioorganic Med. Chem. 2019;27:16–35. doi: 10.1016/j.bmc.2018.11.021. PubMed DOI

Chen J., Chen W., Wang F., He Z., Dai W., Li Q., Liu X., Zhang Z., Zhai D. The role of the vascular endothelial growth factor/vascular endothelial growth factor receptors axis mediated angiogenesis in curcumin-loaded nanostructured lipid carriers induced human HepG2 cells apoptosis. J. Cancer Res. Ther. 2015;11:597–605. doi: 10.4103/0973-1482.159086. PubMed DOI

Yang C., Qin S. Apatinib targets both tumor and endothelial cells in hepatocellular carcinoma. Cancer Med. 2018;7:4570–4583. doi: 10.1002/cam4.1664. PubMed DOI PMC

Novy Z., Janousek J., Barta P., Petrik M., Hajduch M., Trejtnar F. Preclinical evaluation of anti-VEGFR2 monoclonal antibody ramucirumab labelled with zirconium-89 for tumour imaging. J. Label. Compd. Radiopharm. 2021;64:262–270. doi: 10.1002/jlcr.3909. PubMed DOI

Szabo E., Schneider H., Seystahl K., Rushing E.J., Herting F., Weidner K.M., Weller M. Autocrine VEGFR1 and VEGFR2 signaling promotes survival in human glioblastoma models in vitro and in vivo. Neuro-Oncology. 2016;18:1242–1252. doi: 10.1093/neuonc/now043. PubMed DOI PMC

Kim J.Y., Hwang J., Lee S.H., Lee H.J., Jelinek J., Jeong H., Lim J.S., Kim J.M., Song K.S., Kim B.H., et al. Decreased efficacy of drugs targeting the vascular endothelial growth factor pathway by the epigenetic silencing of FLT1 in renal cancer cells. Clin. Epigenet. 2015;7:1–14. doi: 10.1186/s13148-015-0134-9. PubMed DOI PMC