A series of twenty-two novel N-(disubstituted-phenyl)-3-hydroxynaphthalene- 2-carboxamide derivatives was synthesized and characterized as potential antimicrobial agents. N-[3,5-bis(trifluoromethyl)phenyl]- and N-[2-chloro-5-(trifluoromethyl)phenyl]-3-hydroxy- naphthalene-2-carboxamide showed submicromolar (MICs 0.16-0.68 µM) activity against methicillin-resistant Staphylococcus aureus isolates. N-[3,5-bis(trifluoromethyl)phenyl]- and N-[4-bromo-3-(trifluoromethyl)phenyl]-3-hydroxynaphthalene-2-carboxamide revealed activity against M. tuberculosis (both MICs 10 µM) comparable with that of rifampicin. Synergistic activity was observed for the combinations of ciprofloxacin with N-[4-bromo-3-(trifluoromethyl)phenyl]- and N-(4-bromo-3-fluorophenyl)-3-hydroxynaphthalene-2-carboxamides against MRSA SA 630 isolate. The similarity-related property space assessment for the congeneric series of structurally related carboxamide derivatives was performed using the principal component analysis. Interestingly, different distribution of mono-halogenated carboxamide derivatives with the -CF3 substituent is accompanied by the increased activity profile. A symmetric matrix of Tanimoto coefficients indicated the structural dissimilarities of dichloro- and dimetoxy-substituted isomers from the remaining ones. Moreover, the quantitative sampling of similarity-related activity landscape provided a subtle picture of favorable and disallowed structural modifications that are valid for determining activity cliffs. Finally, the advanced method of neural network quantitative SAR was engaged to illustrate the key 3D steric/electronic/lipophilic features of the ligand-site composition by the systematic probing of the functional group.

Central Mining Institute Pl Gwarków 1 40 166 Katowice Poland

Department of Chemical Drugs Faculty of Pharmacy Masaryk University Palackeho 1 60200 Brno Czech Republic

Department of Chemistry University of Silesia Szkolna 9 40007 Katowice Poland

Department of Infectious Diseases and Microbiology Faculty of Veterinary Medicine University of Veterinary and Pharmaceutical Sciences Palackeho 1946 1 61242 Brno Czech Republic

Division of Biologically Active Complexes and Molecular Magnets Regional Centre of Advanced Technologies and Materials Faculty of Science Palacky University Slechtitelu 27 78371 Olomouc Czech Republic

Zobrazit více v PubMed

Valent P., Groner B., Schumacher U., Superti-Furga G., Busslinger M., Kralovics R., Zielinski C., Penninger J.M., Kerjaschki D., Stingl G., et al. Paul Ehrlich (1854–1915) and his contributions to the foundation and birth of translational medicine. J. Innate Immun. 2016;8:111–120. doi: 10.1159/000443526. PubMed DOI PMC

Devillers J. Methods for building QSARs. Methods Mol. Biol. 2013;930:3–27. PubMed

Bak A., Pizova H., Kozik V., Vorcakova K., Kos J., Treml J., Odehnalova K., Oravec M., Imramovsky A., Bobal P., et al. SAR-mediated similarity assessment of the property profile for new, silicon-based AChE/BChE inhibitors. Int. J. Mol. Sci. 2019;20:5385. doi: 10.3390/ijms20215385. PubMed DOI PMC

Colquhoun D. The quantitative analysis of drug–receptor interactions: A short history. Trends Pharmacol. Sci. 2006;27:149–157. doi: 10.1016/j.tips.2006.01.008. PubMed DOI

Bak A., Kozik V., Malik I., Jampilek J., Smolinski A. Probability-driven 3D pharmacophore mapping of antimycobacterial potential of hybrid molecules combining phenylcarbamoyloxy and N-arylpiperazine fragments. SAR QSAR Environ. Res. 2018;29:801–821. doi: 10.1080/1062936X.2018.1517278. PubMed DOI

Hann M., Oprea T. Pursuing the leadlikeness concept in pharmaceutical research. Curr. Opin. Chem. Biol. 2004;8:255–263. doi: 10.1016/j.cbpa.2004.04.003. PubMed DOI

Grammatica P. Principles of QSAR models validation: Internal and external. Qsar Comb. Sci. 2007;26:694–701. doi: 10.1002/qsar.200610151. DOI

Golbraikh A., Tropsha A. Beware of q2! J. Mol. Graph. Mod. 2002;20:269–276. doi: 10.1016/S1093-3263(01)00123-1. PubMed DOI

Merlot C., Domine D., Cleva C., Church D.J. Chemical substructures in drug discovery. Drug Discov. Today. 2003;8:594–602. doi: 10.1016/S1359-6446(03)02740-5. PubMed DOI

Reymond J.L., van Deursen R., Blum L.C., Ruddigkeit L. Chemical space as a source for new drugs. MedChemComm. 2010;1:30–38. doi: 10.1039/c0md00020e. DOI

Peltason L., Bajorath J. Systematic computational analysis of structure-activity relationships: Concepts, challenges and recent advances. Future Med. Chem. 2009;1:451–466. doi: 10.4155/fmc.09.41. PubMed DOI

Polanski J., Bak A., Gieleciak R., Magdziarz T. Modeling robust QSAR. J. Chem. Inf. Model. 2003;46:2310–2318. doi: 10.1021/ci050314b. PubMed DOI

Bak A., Kozik V., Smolinski A., Jampilek J. Multidimensional (3D/4D-QSAR) probability-guided pharmacophore mapping: Investigation of activity profile for a series of drug absorption promoters. RSC Adv. 2016;6:76183–76205. doi: 10.1039/C6RA15820J. DOI

Kubinyi H. Hansch Analysis and Related Approaches. Wiley-VCH Verlag GmbH; Weinheim, Germany: 1993.

Maggiora G.M., Shanmugasundaram V. Molecular similarity measures. Methods Mol. Biol. 2011;672:39–100. PubMed

Van de Waterbeemd H., Gifford E. ADMET in silico modelling: Towards prediction paradise? Nat. Rev. Drug Discov. 2003;2:192–204. doi: 10.1038/nrd1032. PubMed DOI

Lopez-Lopez E., Prieto-Martínez F.D., Medina-Franco J.L. Activity landscape and molecular modeling to explore the SAR of dual epigenetic inhibitors: A focus on G9a and DNMT1. Molecules. 2018;23:3282. doi: 10.3390/molecules23123282. PubMed DOI PMC

Guha R., Van Drie J.H. Assessing how well a modeling protocol captures a structure—Activity landscape. J. Chem. Inf. Model. 2008;48:1716–1728. doi: 10.1021/ci8001414. PubMed DOI

Bajorath J., Peltason L., Wawer M., Guha R., Lajiness M.S., Van Drie J.H. Navigating structure—Activity landscapes. Drug Discov. Today. 2009;14:698–705. doi: 10.1016/j.drudis.2009.04.003. PubMed DOI

Hu H., Stumpfe D., Bajorath J. Systematic identification of target set-dependent activity cliffs. Future Sci. OA. 2019;5:363. doi: 10.4155/fsoa-2018-0089. PubMed DOI PMC

Gonec T., Kos J., Zadrazilova I., Pesko M., Keltosova S., Tengler J., Bobal P., Kollar P., Cizek A., Kralova K., et al. Antimycobacterial and herbicidal activity of ring-substituted 1-hydroxynaphthalene-2-carboxanilides. Bioorg. Med. Chem. 2013;21:6531–6541. doi: 10.1016/j.bmc.2013.08.030. PubMed DOI

Gonec T., Kos J., Zadrazilova I., Pesko M., Govender R., Keltosova S., Chambel B., Pereira D., Kollar P., Imramovsky A., et al. Antibacterial and herbicidal activity of ring-substituted 2-hydroxynaphthalene-1-carboxanilides. Molecules. 2013;18:9397–9419. doi: 10.3390/molecules18089397. PubMed DOI PMC

Gonec T., Zadrazilova I., Nevin E., Kauerova T., Pesko M., Kos J., Oravec M., Kollar P., Coffey A., O’Mahony J., et al. Synthesis and biological evaluation of N-alkoxyphenyl-3-hydroxynaphthalene- 2-carboxanilides. Molecules. 2015;20:9767–9787. doi: 10.3390/molecules20069767. PubMed DOI PMC

Kos J., Nevin E., Soral M., Kushkevych I., Gonec T., Bobal P., Kollar P., Coffey A., O’Mahony J., Liptaj T., et al. Synthesis and antimycobacterial properties of ring-substituted 6-hydroxynaphthalene- 2-carboxanilides. Bioorg. Med. Chem. 2015;23:2035–2043. doi: 10.1016/j.bmc.2015.03.018. PubMed DOI

Gonec T., Pospisilova S., Kauerova T., Kos J., Dohanosova J., Oravec M., Kollar P., Coffey A., Liptaj T., Cizek A., et al. N-Alkoxyphenylhydroxynaphthalenecarboxamides and their antimycobacterial activity. Molecules. 2016;21:1068. doi: 10.3390/molecules21081068. PubMed DOI PMC

Michnova H., Pospisilova S., Gonec T., Kapustikova I., Kollar P., Kozik V., Musiol R., Jendrzejewska I., Vanco J., Travnicek Z., et al. Bioactivity of methoxylated and methylated 1-hydroxynaphthalene-2-carboxanilides: Comparative molecular surface analysis. Molecules. 2019;24:2991. doi: 10.3390/molecules24162991. PubMed DOI PMC

Kauerova T., Kos J., Gonec T., Jampilek J., Kollar P. Antiproliferative and pro-apoptotic effect of novel nitro-substituted hydroxynaphthanilides on human cancer cell lines. Int. J. Mol. Sci. 2016;17:1219. doi: 10.3390/ijms17081219. PubMed DOI PMC

Kauerova T., Gonec T., Jampilek J., Hafner S., Gaiser A.K., Syrovets T., Fedr R., Soucek K., Kollar P. Ring-substituted 1-hydroxynaphthalene-2-carboxanilides inhibit proliferation and trigger mitochondria-mediated apoptosis. Int. J. Mol. Sci. 2020;21:3416. doi: 10.3390/ijms21103416. PubMed DOI PMC

Imramovsky A., Pesko M., Kralova K., Vejsova M., Stolarikova J., Vinsova J., Jampilek J. Investigating spectrum of biological activity of 4- and 5-chloro-2-hydroxy-N-[2-(arylamino)-1-alkyl-2-oxoethyl]- benzamides. Molecules. 2011;16:2414–2430. doi: 10.3390/molecules16032414. PubMed DOI PMC

Pauk K., Zadrazilova I., Imramovsky A., Vinsova J., Pokorna M., Masarikova M., Cizek A., Jampilek J. New derivatives of salicylamides: Preparation and antimicrobial activity against various bacterial species. Bioorg. Med. Chem. 2013;21:6574–6581. doi: 10.1016/j.bmc.2013.08.029. PubMed DOI

Kos J., Zadrazilova I., Pesko M., Keltosova S., Tengler J., Gonec T., Bobal P., Kauerova T., Oravec M., Kollar P., et al. Antibacterial and herbicidal activity of ring-substituted 3-hydroxynaphthalene- 2-carboxanilides. Molecules. 2013;18:7977–7997. doi: 10.3390/molecules18077977. PubMed DOI PMC

Kos J., Kapustikova I., Clements C., Gray A.I., Jampilek J. 3-Hydroxynaphthalene-2-carboxanilides and their antitrypanosomal activity. Monatsh. Chem. 2018;149:887–892. doi: 10.1007/s00706-017-2099-1. DOI

DrugBank—Niclosamide. [(accessed on 27 August 2020)]; Available online: https://www.drugbank.ca/drugs/DB06803.

Gajdar J., Tsami K., Michnova H., Gonec T., Brazdova M., Soldanova Z., Fojta M., Jampilek J., Barek J., Fischer J. Electrochemistry of ring-substituted 1-hydroxynaphthalene-2-carboxanilides: Relation to structure and biological activity. Electrochim. Acta. 2020;332:135485. doi: 10.1016/j.electacta.2019.135485. DOI

Pospisilova S., Kos J., Michnova H., Kapustikova I., Strharsky T., Oravec M., Moricz A.M., Bakonyi J., Kauerova T., Kollar P., et al. Synthesis and spectrum of biological activities of novel N-arylcinnamamides. Int. J. Mol. Sci. 2018;19:2318. doi: 10.3390/ijms19082318. PubMed DOI PMC

Spaczynska E., Mrozek-Wilczkiewicz A., Malarz K., Kos J., Gonec T., Oravec M., Gawecki R., Bak A., Dohanosova J., Kapustikova I., et al. Design and synthesis of anticancer 1-hydroxynaphthalene-2-carboxanilides with p53 independent mechanism of action. Sci. Rep. 2019;9:6387. doi: 10.1038/s41598-019-42595-y. PubMed DOI PMC

Gonec T., Kos J., Pesko M., Dohanosova J., Oravec M., Liptaj T., Kralova K., Jampilek J. Halogenated 1-hydroxynaphthalene-2-carboxanilides affecting photosynthetic electron transport in photosystem II. Molecules. 2017;22:1709. doi: 10.3390/molecules22101709. PubMed DOI PMC

Likus-Cieslik J., Smolinski A., Pietrzykowski M., Bak A. Sulphur contamination impact on seasonal and surface water chemistry on a reforested area of a former sulphur mine. Land Degrad. Dev. 2019;30:212–225. doi: 10.1002/ldr.3216. DOI

Bak A., Kozik V., Smolinski A., Jampilek J. In silico estimation of basic activity-relevant parameters for a set of drug absorption promoters. SAR QSAR Environ. Res. 2017;28:427–449. doi: 10.1080/1062936X.2017.1327459. PubMed DOI

Hann M.M., Keserü G.M. Finding the sweet spot: The role of nature and nurture in medicinal chemistry. Nat. Rev. Drug Discov. 2012;11:355–365. doi: 10.1038/nrd3701. PubMed DOI

Zadrazilova I., Pospisilova S., Masarikova M., Imramovsky A., Ferriz J.M., Vinsova J., Cizek A., Jampilek J. Salicylanilide carbamates: Promising antibacterial agents with high in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) Eur. J. Pharm. Sci. 2015;77:197–207. doi: 10.1016/j.ejps.2015.06.009. PubMed DOI

National Committee for Clinical Laboratory Standards . Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. 11th ed. NCCLS; Wayne, PA, USA: 2018.

National Committee for Clinical Laboratory Standards . Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes. 3rd ed. NCCLS; Wayne, PA, USA: 2020. PubMed

Nubel U., Dordel J., Kurt K., Strommenger B., Westh H., Shukla S.K., Zemlickova H., Leblois R., Wirth T., Jombart T., et al. A timescale for evolution, population expansion, and spatial spread of an emerging clone of methicillin-resistant Staphylococcus aureus. PLoS Pathog. 2010;6:e1000855. doi: 10.1371/journal.ppat.1000855. PubMed DOI PMC

Measuring Cell Viability/Cytotoxicity. Dojindo EU GmbH, Munich, Germany. [(accessed on 27 August 2020)]; Available online: https://www.dojindo.eu.com/Protocol/Dojindo-Cell-Proliferation-Protocol.pdf.

Bueno J. Understanding Tuberculosis—New Approaches to Fighting Against Drug Resistance. IntechOpen; Rijeka, Croatia: 2012. Antitubercular in vitro drug discovery: Tools for begin the search; pp. 147–168.

International Organization for Standardization . ISO 10993-5:2009 Biological Evaluation of Medical Devices Part 5: Tests for in Vitro Cytotoxicity. International Organization for Standardization; Geneva, Switzerland: 2009. last revision 2017.

Jampilek J. Design and discovery of new antibacterial agents: Advances, perspectives, challenges. Curr. Med. Chem. 2018;25:4972–5006. doi: 10.2174/0929867324666170918122633. PubMed DOI

Imramovsky A., Pesko M., Ferriz J.M., Kralova K., Vinsova J., Jampilek J. Photosynthesis—Inhibiting efficiency of 4-chloro-2-(chlorophenylcarbamoyl)phenyl alkylcarbamates. Bioorg. Med. Chem. Lett. 2011;21:4564–4567. doi: 10.1016/j.bmcl.2011.05.118. PubMed DOI

Kralova K., Perina M., Waisser K., Jampilek J. Structure-activity relationships of n-benzylsalicylamides for inhibition of photosynthetic electron transport. Med. Chem. 2015;11:156–164. doi: 10.2174/1573406410666140815125004. PubMed DOI

Gonec T., Kralova K., Pesko M., Jampilek J. Antimycobacterial N-alkoxyphenylhydroxy- naphthalenecarboxamides affecting photosystem II. Bioorg. Med. Chem. Lett. 2017;27:1881–1885. doi: 10.1016/j.bmcl.2017.03.050. PubMed DOI

Kos J., Zadrazilova I., Nevin E., Soral M., Gonec T., Kollar P., Oravec M., Coffey A., O’Mahony J., Liptaj T., et al. Ring-substituted 8-hydroxyquinoline-2-carboxanilides as potential antimycobacterial agents. Bioorg. Med. Chem. 2015;23:4188–4196. doi: 10.1016/j.bmc.2015.06.047. PubMed DOI

Jampilek J., Kralova K., Pesko M., Kos J. Ring-substituted 8-hydroxyquinoline-2-carboxanilides as photosystem II inhibitors. Bioorg. Med. Chem. Lett. 2016;26:3862–3865. doi: 10.1016/j.bmcl.2016.07.021. PubMed DOI

Todeschini R., Consonni V. Molecular Descriptors for Chemoinformatics. Wiley-VCH Verlag GmbH & Co. KgaA; Weinheim, Germany: 2010.

Ertl P., Schuffenhauer A. Estimation of synthetic accessibility score of drug-like molecules based on molecular complexity and fragment contributions. J. Cheminform. 2009;1:8. doi: 10.1186/1758-2946-1-8. PubMed DOI PMC

Clark D.E., Pickett S.E. Computational methods for the prediction of ‘drug-likeness’. Drug Discov. Today. 2000;5:49–58. doi: 10.1016/S1359-6446(99)01451-8. PubMed DOI

Pizova H., Havelkova M., Stepankova S., Bak A., Kauerova T., Kozik V., Oravec M., Imramovsky A., Kollar P., Bobal P., et al. Proline-based carbamates as cholinesterase inhibitors. Molecules. 2017;22:1969. doi: 10.3390/molecules22111969. PubMed DOI PMC

Holliday J.D., Salim N., Whittle M., Willett P. Analysis and display of the size dependence of chemical similarity coefficients. J. Chem. Inf. Comput. Sci. 2003;43:819–828. doi: 10.1021/ci034001x. PubMed DOI

Gieleciak R., Magdziarz T., Bak A., Polanski J. Modeling robust QSAR. 1. Coding molecules in 3D-QSAR—From a point to surface sectors and molecular volumes. J. Chem. Inf. Model. 2005;45:1447–1455. doi: 10.1021/ci0501488. PubMed DOI

Stouch T.R., Kenyon J.R., Johnson S.R., Chen X.Q., Doweyko A., Li Y. In silico ADME/Tox: Why models fail. J. Comput. Aided Mol. Des. 2003;17:83–92. doi: 10.1023/A:1025358319677. PubMed DOI

Doweyko A.M. QSAR: Dead or alive? J. Comput. Aided Mol. Des. 2008;22:81–89. doi: 10.1007/s10822-007-9162-7. PubMed DOI

Bak A., Polanski J. Modeling robust QSAR 3: SOM-4D-QSAR with iterative variable elimination IVE-PLS: Application to steroid, azo dye, and benzoic acid series. J. Chem. Inf. Model. 2007;47:1469–1480. doi: 10.1021/ci700025m. PubMed DOI

Schwalbe R., Steele-Moore L., Goodwin A.C. Antimicrobial Susceptibility Testing Protocols. 1st ed. CRC Press; Boca Raton, FL, USA: 2007.

Bonapace C.R., Bosso J.A., Friedrich L.V., White R.L. Comparison of methods of interpretation of checkerboard synergy testing. Diagn. Microbiol. Infect. Dis. 2002;44:363–366. doi: 10.1016/S0732-8893(02)00473-X. PubMed DOI

Abate G., Mshana R.N., Miorner H. Evaluation of a colorimetric assay based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) for rapid detection of rifampicin resistance in Mycobacterium tuberculosis. Int. J. Tuberc. Lung Dis. 1998;2:1011–1016. PubMed

Stanton D.T. QSAR and QSPR model interpretation using partial least squares (PLS) analysis. Curr. Comput. Aided Drug Des. 2012;8:107–127. doi: 10.2174/157340912800492357. PubMed DOI

Xie X.Q., Chen J.Z. Data mining a small molecule drug screening representative subset from NIH PubChem. J. Chem. Inf. Model. 2008;48:465–475. doi: 10.1021/ci700193u. PubMed DOI

Polanski J., Gieleciak R., Magdziarz T., Bak A. GRID formalism for the comparative molecular surface analysis: Application to the CoMFA benchmark steroids, azo dyes, and HEPT derivatives. J. Chem. Inf. Comput Sci. 2004;44:1423–1435. doi: 10.1021/ci049960l. PubMed DOI

Zupan J., Gasteiger J. Neural Networks and Drug Design for Chemists. 2nd ed. Wiley-VCH; Weinheim, Germany: 1999.

Centner V., Massart D.L., de Noord O.E., de Jong S., Vandeginste B.M.V., Sterna C. Elimination of uninformative variables for multivariate calibration. Anal. Chem. 1996;68:3851–3858. doi: 10.1021/ac960321m. PubMed DOI

Dearden J.C., Cronin M.T., Kaiser K.L. How not to develop a quantitative structure-activity or structure-property relationship (QSAR/QSPR)? Sar Qsar Environ. Res. 2009;20:241–266. doi: 10.1080/10629360902949567. PubMed DOI

Antimicrobial and ADME properties of methoxylated, methylated and nitrated 2-hydroxynaphthalene-1 carboxanilides

Towards Arginase Inhibition: Hybrid SAR Protocol for Property Mapping of Chlorinated N-arylcinnamamides

Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections

Chemistry towards Biology-Instruct: Snapshot

Insights into Antimalarial Activity of N-Phenyl-Substituted Cinnamanilides

Study of Biological Activities and ADMET-Related Properties of Novel Chlorinated N-arylcinnamamides

Photosynthesis-Inhibiting Activity of N-(Disubstituted-phenyl)-3-hydroxynaphthalene-2-carboxamides